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  • 1.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pickering, Chris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Motivation for sucrose in sated rats is predicted by low anxiety-like behavior2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, no 3, p. 193-197Article in journal (Refereed)
    Abstract [en]

    Anxiety has been implicated in obesity and in the overconsumption of highly palatable foods such as those high in fat, sugar, or both. Also, the novelty-seeking trait has been associated with failure in weight-loss programs. The aim of this study was to investigate the associations of experimental anxiety and the self-administration of sucrose and high fat pellets in non-food deprived rats across different operant schedules. Male Wistar rats were subjected to the elevated plus-maze test (EPM) of anxiety-like behavior. The rats were tested for fixed ratio 5 (FR5) and progressive ratio (PR) operant responding for 50% sucrose, 95% sucrose, and high-fat pellets. PR active lever press response for 95% sucrose, but not the other pellet types, was correlated to % time spent on open arms (P=0.019) in the EPM. On the FR5 schedule, activity (closed arm entries) was correlated to the self-administration of 50% sucrose (P=0.027) and high-fat (P=0.002). This indicates an association of novelty-induced activity and self-administration of palatable food in sated rats, as well as a specific association of PR lever press response for 95% sucrose and low anxiety-like behavior. It has been argued that such active lever press response on PR may be interpreted as craving for the reinforcer; thus, our findings indicate an inverse relationship of experimental anxiety and craving for sucrose. This connection may have implications for human situations, since anxiety and novelty-seeking have been associated with obesity and failure in weight-loss programs.

  • 2.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pickering, Chris
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, University of Gothenburg, Addiction Biology Unit, Gothenburg.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposureManuscript (preprint) (Other academic)
    Abstract [en]

    Obesity may be induced in rodents by long-term access to dietary fat. Such treatment has been reported to have behavioural effects including reduced anxiety-like behaviour and diminished operant responding for psychostimulants. It is unclear whether such effects are secondary to metabolic changes due to excess body weight, or to the extended access to palatable food reward. The aim of this study was to investigate the effects of a short palatable diet exposure (10 days) on performance in the open field test of novelty-induced locomotion and anxiety-like behaviour in rats. We subjected rats to a free-choice high-fat or high-sugar diet, or both, for a period of 10 days. Increased caloric intake was observed in all groups but body weight at Day 10 did not differ from chow-fed controls. We report that consumption of the free-choice high-fat diets was associated with higher novelty-induced activity and reduced anxiety-like behaviour in the open field test. In addition, we used RT-PCR to show that the high-fat group had 39% higher expression of mu opioid receptor in the lateral hypothalamus, and that tyrosine hydroxylase expression was elevated more than two-fold in the ventral tegmental area of rats with access to both high-fat and high-sugar. In conclusion, these results show that subchronic exposure to a free-choice high-fat diet induces behavioural adaptations such as elevated locomotor activity and attenuated experimental anxiety. The changes observed in gene expression related to reward after high-fat diet exposure indicate that these behavioural adaptations are related to reward function.

  • 3.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Pickering, Christopher
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anxiolytic response after palatable diet consumption but not food restriction in rats2009In: Appetite, ISSN 0195-6663, E-ISSN 1095-8304, Vol. 52, no 3, p. 816-816Article in journal (Other academic)
  • 4.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hulting, Anna-Lena
    Meyerson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Anxiety-like behaviour predicts the preference for a high-carbohydrate diet in outbred rats2007In: Behavioural Pharmacology, ISSN 0955-8810, E-ISSN 1473-5849, Vol. 18, p. S41-S41Article in journal (Other academic)
  • 5.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jonsson, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

  • 6.
    Berglund, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Balldin, Jan
    Berggren, Ulf
    Eriksson, Matts
    Gustavsson, Petter
    Fahlke, Claudia
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Do men with excessive alcohol consumption and social stability have an addictive personality?2011In: Scandinavian Journal of Psychology, ISSN 0036-5564, E-ISSN 1467-9450, Vol. 52, no 3, p. 257-260Article in journal (Refereed)
    Abstract [en]

    The existence of an "addictive" personality has been extensively debated. The current study investigated personality in male individuals with excessive alcohol consumption (n = 100) in comparison to a population-based control group (n = 131). The individuals with excessive alcohol consumption were recruited by advertisements in a regional daily newspaper and controls from a population based Swedish Twin Registry. Personality was assessed by the Karolinska Scales of Personality (KSP). Comparisons were made with normative data. Furthermore, by using a multivariate projection-based approach (Principal Component Analysis; PCA), hidden structures of traits and possible relationships among the individuals with excessive consumption and the controls was investigated. The individuals with excessive alcohol consumption as well as the controls had mean values within the normative range in all scales of the KSP. Moreover, the PCA analysis revealed no systematic between-group separation. Taken together, this result demonstrates that male individuals with excessive alcohol consumption do not have a personality different from that of a general population, which supports the notion of no "addictive personality".

  • 7. Berglund, Kristina
    et al.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Balldin, Jan
    Berggren, Ulf
    Gustavsson, Petter
    Fahlke, Claudia
    Personality profile in male type 1 alcoholics2007In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 42Article in journal (Other academic)
  • 8.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanrieder, Jörg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-induced fibril formation and protein changes in rodents2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Suppl., p. S193-193Article in journal (Other academic)
  • 9.
    Daoura, Loudin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hjalmarsson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oreland, Sadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Postpartum Behavioral Profiles in Wistar Rats Following Maternal Separation: Altered Exploration and Risk-Assessment Behavior in MS15 Dams2010In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 4, article id 37Article in journal (Refereed)
    Abstract [en]

    The rodent maternal separation (MS) model is frequently used to investigate the impact of early environmental factors on adult neurobiology and behavior. The majority of MS studies assess effects in the offspring and few address the consequences of repeated pup removal in the dam. Such studies are of interest since alterations detected in offspring subjected to MS may, at least in part, be mediated by variations in maternal behavior and the amount of maternal care provided by the dam. The aim of this study was to investigate how daily short (15 min; MS15) and prolonged (360 min; MS360) periods of MS affects the dam by examining postpartum behavioral profiles using the multivariate concentric square field (MCSF) test. The dams were tested on postpartum days 24-25, i.e., just after the end of the separation period and weaning. The results reveal a lower exploratory drive and lower risk-assessment behavior in MS15 dams relative to MS360 or animal facility reared dams. The present results contrast some of the previously reported findings and provide new information about early post-weaning behavioral characteristics in a multivariate setting. Plausible explanations for the results are provided including a discussion how the present results fit into the maternal mediation hypothesis.

  • 10.
    Daoura, Loudin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Qualitative differences in pup-retrieval strategies in a maternal separation paradigm2013In: Journal of Behavioral and Brain Science, ISSN 2160-5866, E-ISSN 2160-5874, Vol. 3, p. 603-616Article in journal (Refereed)
    Abstract [en]

    The rodent maternal separation (MS) paradigm is frequently used to investigate the impact of early-life conditions in the offspring. One critical issue is whether the effects seen in the offspring are a result of maternal contact deprivation and/or altered pup-directed maternal behavior. To address this question we used an innovative approach with a qualita-tive analysis of pup-retrieval strategies in a test situation related to risk for the pups. The dams were separated from their litters for 0 (MS0) or 360 (MS360) min, respectively. The pups were placed in a risk area in the multivariate con-centric square field™ test at two test occasions and the pup-retrieval strategies were recorded. No significant evident differences between MS0 and MS360 dams were found. However, there were clearly two different strategies, either removing the pups out of potential danger or into safety, and these strategies were represented in both MS groups. As compared to the MS0 dams, the MS360 dams did not change their strategies and left more pups in the risk area in both pup-retrieval tests. This implies different pup-retrieval strategies depending on early-life conditions.

  • 11.
    Granholm, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Single housing during early adolescence causes time-, area- and peptide-specific alterations in endogenous opioids of rat brain2015In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 172, no 2, p. 606-614Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: A number of experimental procedures require single housing to assess individual behaviour and physiological responses to pharmacological treatments. The endogenous opioids are closely linked to social interaction, especially early in life, and disturbance in the social environment may affect opioid peptides and thereby confound experimental outcome. The aim of the present study was to examine time-dependent effects of single housing on opioid peptides in rats.

    EXPERIMENTAL APPROACH: Early adolescent Sprague Dawley rats (post-natal day 22) were subjected to either prolonged (7 days) or short (30 min) single housing. Several brain regions were dissected and immunoreactive levels of Met-enkephalin-Arg(6) Phe(7) (MEAP), dynorphin B and nociception/orphanin FQ, as well as serum corticosterone were measured using RIA.

    KEY RESULTS: Prolonged single housing reduced immunoreactive MEAP in hypothalamus, cortical regions, amygdala, substantia nigra and periaqueductal grey. Short single housing resulted in an acute stress response as indicated by high levels of corticosterone, accompanied by elevated immunoreactive nociceptin/orphanin FQ in medial prefrontal cortex, nucleus accumbens and amygdala. Neither short nor prolonged single housing affected dynorphin B.

    CONCLUSIONS AND IMPLICATIONS: Disruption in social environmental conditions of rats, through single housing during early adolescence, resulted in time-, area- and peptide-specific alterations in endogenous opioids in the brain. These results provide further evidence for an association between early life social environment and opioids. Furthermore, the results have implications for experimental design; in any pharmacological study involving opioid peptides, it is important to distinguish between effects induced by housing and treatment.

  • 12.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stephansson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat2008In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 9, p. 43-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    The Adhesion G protein-coupled receptors (GPCRs) are membrane-bound receptors with long N termini. This family has 33 members in humans. Several Adhesion GPCRs are known to have important physiological functions in CNS development and immune system response mediated by large cell surface ligands. However, the majority of Adhesion GPCRs are still poorly studied orphans with unknown functions.

    RESULTS

    In this study we performed the extensive tissue localization analysis of the entire Adhesion GPCR family in rat and mouse. By applying the quantitative real-time PCR technique we have produced comparable expression profile for each of the members in the Adhesion family. The results are compared with literature data and data from the Allen Brain Atlas project. Our results suggest that the majority of the Adhesion GPCRs are either expressed in the CNS or ubiquitously. In addition the Adhesion GPCRs from the same phylogenetic group have either predominant CNS or peripheral expression, although each of their expression profile is unique.

    CONCLUSION

    Our findings indicate that many of Adhesion GPCRs are expressed, and most probably, have function in CNS. The related Adhesion GPCRs are well conserved in their structure and interestingly have considerable overlap in their expression profiles, suggesting similarities among the physiological roles for members within many of the phylogenetically related clusters.

  • 13.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Lindström, Anna-Karin
    Hanrieder, Jorg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arnerup, Gunnel
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neonatal Exposure to the Cyanobacterial Toxin BMAA Induces Changes in Protein Expression and Neurodegeneration in Adult Hippocampus2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 130, no 2, p. 391-404Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin -N-methylamino-l-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 910) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460mg/kg) also induced changes in the expression of S100, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.

  • 14.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Colombo, Giancarlo
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Low copulatory activity in selectively bred Sardinian alcohol-nonpreferring (sNP) relative to alcohol-preferring (sP) rats2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 181-189Article in journal (Refereed)
    Abstract [en]

    Background. There is a growing consensus that similar neural mechanisms are involved in the reinforcing properties of natural rewards, like food and sex, and drugs of abuse. Rat lines selectively bred for high and low oral alcohol intake and preference have been useful for understanding factors contributing to excessive alcohol intake and may constitute proper animal models for investigating the neurobiological basis of natural rewarding stimuli. Methods. The present study evaluated copulatory behavior in alcohol and sexually naive Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats in three consecutive copulatory behavior tests. Results. The main finding was that, under the conditions used in this study, sNP rats were sexually inactive relative to sP rats. To gain more information about the sexual behavior in sP rats, Wistar rats were included as an external reference strain. Only minor differences between sP and Wistar rats were revealed. Conclusions. The reason behind the low copulatory activity of sNP rats remains to be elucidated, but may in part be mediated by innate differences in brain transmitter systems. The comparison between sP and Wistar rats may also suggest that the inherent proclivity to excessive alcohol drinking in sP rats may mainly be dependent on its anxiolytic properties, as previously proposed, and not changes in the reward system.

  • 15.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wadensten, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurotoxin-Induced Neuropeptide Perturbations in Striatum of Neonatal Rats2013In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, no 4, p. 1678-1690Article in journal (Refereed)
    Abstract [en]

    The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) is suggested to play a role in neurodegenerative disease. We have previously shown that although the selective uptake of BMAA in the rodent neonatal striatum does not cause neuronal cell death, exposure during the neonatal development leads to cognitive impairments in adult rats. The aim of the present study was to characterize the changes in the striatal neuropeptide systems of male and female rat pups treated neonatally (postnatal days 9-10) with BMAA (40-460 mg/kg). The label-free quantification of the relative levels of endogenous neuropeptides using mass spectrometry revealed that 25 peptides from 13 neuropeptide precursors were significantly changed in the rat neonatal striatum. The exposure to noncytotoxic doses of BMAA induced a dose-dependent increase of neurosecretory protein VGF-derived peptides, and changes in the relative levels of cholecystokinin, chromogranin, secretogranin, MCH, somatostatin and cortistatin-derived peptides were observed at the highest dose. In addition, the results revealed a sex-dependent increase in the relative level of peptides derived from the proenkephalin-A and protachykinin-1 precursors, including substance P and neurokinin A, in female pups. Because several of these peptides play a critical role in the development and survival of neurons, the observed neuropeptide changes might be possible mediators of BMAA-induced behavioral changes. Moreover, some neuropeptide changes suggest potential sex-related differences in susceptibility toward this neurotoxin. The present study also suggests that neuropeptide profiling might provide a sensitive characterization of the BMAA-induced noncytotoxic effects on the developing brain.

  • 16.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindquist, Nils Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Selective Brain Uptake and Behavioral Effects of the Cyanobacterial Toxin BMAA (β-N-Methylamino-L-alanine) following Neonatal Administration to Rodents2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 109, no 2, p. 286-295Article in journal (Refereed)
    Abstract [en]

    Cyanobacteria are extensively distributed in terrestrial and aquatic environments all over the world. Most cyanobacteria can produce the neurotoxin ss-N-methylamino-L-alanine (BMAA), which has been detected in several water systems and could accumulate in food chains. The aim of the study was to investigate the transfer of BMAA to fetal and neonatal brains and the effects of BMAA on the development of behavioral characteristics during the brain growth spurt (BGS) in rodents Pregnant and neonatal mice were given an injection of (3)H-BMAA on gestational day 14 and postnatal day (PND) 10, respectively, and processed for tape-section autoradiography. The study revealed transplacental transfer of (3)H-BMAA and a significant uptake in fetal mouse. The radioactivity was specifically located in the hippocampus, striatum, brainstem, spinal cord and cerebellum of 10-day-old mice. The effect of repeated BMAA treatment (200 or 600 mg/kg sc) during BGS on rat behavior was also studied. BMAA treatment on PND 9-10 induced acute alterations, such as impaired locomotor ability and hyperactivity, in the behavior of neonatal rats. Furthermore, rats given the high dose of BMAA failed to habituate to the test environment when tested at juvenile age. In conclusion, the results demonstrated that BMAA was transferred to the neonatal brain and induced significant changes in the behavior of neonatal rats following administration during BGS. The observed behavioral changes suggest possible cognitive impairment. Increased information on the long-term effects of BMAA on cognitive function following fetal and neonatal exposure is required for assessment of the risk to children's health.

  • 17.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dose-dependent effects of alcohol administration on behavioral profiles in the MCSF test.2016In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 50, p. 51-56Article in journal (Refereed)
    Abstract [en]

    The acute effects of alcohol administration are age-, dose-, time- and task-dependent. Although generally considered to be a sedative drug, alcohol has both stimulatory and depressant effects on behavior, depending on dose and time. Alcohol-induced motor activating effects are consistently shown in mice but rarely demonstrated in adult, outbred rats using conventional behavioral tests. The aim of the present experiment was to study acute alcohol-induced effects on behavioral profiles in a more complex environment using the novel multivariate concentric square field™ (MCSF) test, designed for assessing different behaviors in the same trial including locomotor activity. Adult male Wistar rats (Sca:WI) were administered one intraperitoneal (i.p.) injection of alcohol (0.0 g/kg, 0.5 g/kg, 1.0 g/kg, or 1.5 g/kg) 5 min prior to the 30-min MCSF test. The two highest doses induced marked motor-suppressing effects. A significant interaction between group and time was found in general activity when comparing rats exposed to alcohol at 0.0 g/kg and 0.5 g/kg. In contrast to the 0.0 g/kg dose that increased the activity over time, animals administered the low dose (0.5 g/kg) demonstrated an initial high activity followed by a decline over time. No indications for acute alcohol-induced anxiolytic-like effects were found. The multivariate setting in the MCSF test appears to be sensitive for detecting motor-activating effects of low doses of alcohol as well as reduced locomotion at doses lower than in other behavioral tasks. The detection of subtle changes in behavior across time and dose is important for understanding alcohol-induced effects. This approach may be useful in evaluating alcohol doses that correspond to different degrees of intoxication in humans.

  • 18.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berg, Anna-Lena
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-l-alanine) during the neonatal period2011In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 219, no 2, p. 310-320Article in journal (Refereed)
    Abstract [en]

    We have reported previously that exposure to the cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) during the neonatal period causes cognitive impairments in adult rats. The aim of this study was to investigate the long-term effects of neonatal BMAA exposure on learning and memory mechanisms and to identify early morphological changes in the neonatal brain. BMAA was injected subcutaneously in rat pups on postnatal days 9-10. BMAA (50 and 200mg/kg) caused distinct deficits in spatial learning and memory in adult animals but no morphological changes. No impairment of recognition memory was detected, suggesting that neonatal exposure to BMAA preferentially affects neuronal systems that are important for spatial tasks. Histopathological examination revealed early neuronal cell death as determined by TUNEL staining in the hippocampus 24h after a high dose (600mg/kg) of BMAA whereas no changes were observed at lower doses (50 and 200mg/kg). In addition, there was a low degree of neuronal cell death in the retrosplenial and cingulate cortices, areas that are also important for cognitive function. Taken together, these results indicate that BMAA is a developmental neurotoxin inducing long-term changes in cognitive function. The risk posed by BMAA as a potential human neurotoxin merits further consideration, particularly if the proposed biomagnifications in the food chain are confirmed.

  • 19.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brittebo, Eva B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term cognitive impairments in adult rats treated neonatally with beta-N-Methylamino-L-Alanine2009In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 112, no 1, p. 185-195Article in journal (Refereed)
    Abstract [en]

    Most cyanobacteria (blue-green algae) can produce the neurotoxin beta-N-methylamino-L-alanine (BMAA). Dietary exposure to BMAA has been suggested to be involved in the etiology of the neurodegenerative disease amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC). Little is known about BMAA-induced neurotoxicity following neonatal administration. Our previous studies have revealed an uptake of BMAA in the hippocampus and striatum of neonatal mice. Furthermore, rats treated with BMAA during the neonatal period displayed acute but transient motoric disturbances and failed to show habituation at juvenile age suggesting impairments in learning functions. In the present study, the aim was to investigate long-term behavioral effects of BMAA administration in neonatal rats. BMAA was administered on postnatal days 9-10 (200 or 600 mg/kg; subcutaneous injection). Spatial learning and memory was investigated in adulthood using the radial arm maze test. The results revealed impaired learning but not memory in BMAA-treated animals. The observed impairments were not due to alterations in motoric capacity, general activity, or behavioral profiles, as assessed in the multivariate concentric square field (MCSF) and open field tests. An aversive stimulus in the MCSF test revealed impairments in avoidance learning and/or memory. There was no difference in basal serum corticosterone levels in BMAA-treated animals, indicating that the observed long-term effects were not secondary to an altered basal hypothalamic-pituitary-adrenal axis function. The present data demonstrated long-term learning impairments following neonatal BMAA administration. Further studies on biochemical effects in various brain regions and subsequent behavioral alterations are needed to elucidate the mechanisms of BMAA-induced developmental neurotoxicity.

  • 20.
    Lundberg, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Abelson, Klas
    Univ Copenhagen, Dept Expt Med, Copenhagen, Denmark.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Few long-term consequences after prolonged maternal separation in female Wistar rats2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190042Article in journal (Refereed)
    Abstract [en]

    Environmental factors during the early-life period are known to have long-term consequences for the adult phenotype. An intimate interplay between genes and environment shape the individual and may affect vulnerability for psychopathology in a sex-dependent manner. A rodent maternal separation model was here used to study the long-term effects of different early-life rearing conditions on adult behavior, HPA axis activity and long-term voluntary alcohol intake. Litters were subjected to 15 (MS15) or 360 min (MS360) of daily maternal separation during postnatal day 1–21. In adulthood, the behavioral profiles were investigated using the multivariate concentric square field™ (MCSF) test or examined for HPA axis reactivity by cat-odor exposure with subsequent characterization of voluntary alcohol intake and associated changes in HPA axis activity. Adult female offspring showed mostly no, or only minor, effects of MS360 on behavior, HPA axis reactivity and long-term alcohol intake. Instead, more pronounced effects were found dependent on changes in the female’s natural hormonal cycle or by the choice of animal supplier. However, changes were revealed in corticosterone load after long-term alcohol access, as females subjected to MS360 had higher concentrations of fecal corticosterone. The present findings are in line with and expand on previous studies on the long-term effects of maternal separation and the sex-dependent effects, with regard to behavior and voluntary alcohol intake. Why female rats show increased resilience compared to males using the present experimental protocol for maternal separation remains to be further investigated.

  • 21.
    Lundberg, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Högman, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Adolescent Exploratory Strategies and Behavioral Types in the Multivariate Concentric Square Field (TM) Test2019In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 13, article id 41Article in journal (Refereed)
    Abstract [en]

    Adolescence is an important developmental phase with extensive changes in behavior due to remodeling of the brain and hormonal systems. Validation of animal behavioral tests in this age group is therefore of importance as differences to adult behavior are often not clarified. The aim of the present study was to investigate adolescent behavior in the multivariate concentric square field (TM) (MCSF) test and its relationship to other common behavioral tests as well as to a literature dataset of adult animals. Sixty adolescent male Wistar rats were tested in the MCSF and one of four reference tests; the elevated plus maze, the open field with or without start box, or the social play behavior test. Additionally, 12 animals were tested twice in the MCSF. When analyzing the first encounter with the MCSF test, a distinct grouping of the individuals into three behavioral types was observed. Approximately 20% of the animals had high levels of activity and an additional 20% had high levels of shelter seeking-behavior, these groups composed the outlying behavioral types named Explorers and Shelter seekers, respectively, which were distinct from the Main type of animals. When tested in the MCSF for a second time, the adolescent animals showed a recollection of the arena as they changed their behavior in relation to the first encounter. When comparing the MCSF performance to the reference tests, a relationship was found between the MCSF and the other behavioral test entailing forced exploration, while no relationship was found between the MCSF and social play. The adolescent behavioral profile was characterized by decreased risk assessment and a different activity profile than adults. In conclusion, the MCSF test is useful for profiling adolescent rats but the behavioral interpretation differs from that of adults due to differences in behavioral manifestation during adolescence and the presence of natural subgroups. Adolescent exploration shows a relationship across tests, but the MCSF gives more information than any of the other behavioral tests based on forced exploration. Further studies into the neurobiology behind the behavioral types and how different manipulations affect the distribution into the behavioral types are of interest.

  • 22.
    Lundberg, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Martinsson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats2017In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 87, p. 137-144Article in journal (Refereed)
    Abstract [en]

    Early-life socio-environmental factors are crucial for normal developmental processes; adverse experiences early in life can therefore lead to detrimental effects in several physiological systems. The aim of this study was to examine short-term effects of early adverse experiences in a maternal separation (MS) rodent model. In this study two separation conditions were used: daily 15-(MS15) or 360-min (MS360) separation of the litter from the dam during postnatal day 1-21. In early adolescence, male and female offspring were subjected to a single-isolation procedure with analysis of corticosterone levels prior to and after isolation. In addition, social play behavior was assessed during mid-adolescence. There was a clear difference between male and female offspring in both tests performed. There was no difference in corticosterone levels between the female MS groups, whereas MS360 males showed higher baseline and recovery corticosterone levels than MS15 males. The amount of pinning, a specific social play behavior, was affected by rearing with MS360 males having a higher frequency than MS15 males, while there was no difference between the female MS groups. The observation that males but not females are affected by MS360 has previously been reported for adult animals, and herein we show that this difference is present already in adolescence. Changes in corticosterone levels and social behavior following early-life adversity have been associated with adult behavioral alterations, and our results confirm that these changes emerge already within adolescence.

  • 23.
    Mackenzie, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fejgin, Kim
    Lagerström, Malin C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lindhe, Örjan
    Emilsson, Lina
    Svensson, Lennart
    Långström, Bengt
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    VGLUT2 is essential in neuronal circuitry of cognitive and emotional behavior2008In: Society for Neuroscience Abstract Viewer and Itinerary Planner, Vol. 38Article in journal (Other academic)
  • 24. Magara, Salvatore
    et al.
    Holst, Sarah
    Lundberg, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindskog, Maria
    Altered explorative strategies and reactive coping style in the FSL rat model of depression2015In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 9, article id 89Article in journal (Refereed)
    Abstract [en]

    Modeling depression in animals is based on the observation of behaviors interpreted as analogue to human symptoms. Typical tests used in experimental depression research are designed to evoke an either-or outcome. It is known that explorative and coping strategies are relevant for depression, however these aspects are generally not considered in animal behavioral testing. Here we investigate the Flinders Sensitive Line (FSL), a rat model of depression, compared to the Sprague-Dawley (SD) rat in three independent tests where the animals are allowed to express a more extensive behavioral repertoire. The multivariate concentric square field T (MCSF) and the novel cage tests evoke exploratory behaviors in a novel environment and the home cage change test evokes social behaviors in the re-establishment of a social hierarchy. In the MCSF test, FSL rats exhibited less exploratory drive and more risk-assessment behavior compared to SD rats. When re-exposed to the arena, FSL, but not SD rats, increased their exploratory behavior compared to the first trial and displayed risk-assessment behavior to the same extent as SD rats. Thus, the behavior of FSL rats was more similar to that of SDs when the rats were familiar with the arena. In the novel cage test FSL rats exhibited a reactive coping style, consistent with the reduced exploration observed in the MCSF. Reactive coping is associated with less aggressive behavior. Accordingly, FSL rats displayed less aggressive behavior in the home cage change test. Taken together, our data show that FSL rats express altered explorative behavior and reactive coping style. Reduced interest is a core symptom of depression, and individuals with a reactive coping style are more vulnerable to the disease. Our results support the use of FSL rats as an animal model of depression and increase our understanding of the FSL rat beyond the behavioral dimensions targeted by the traditional depression-related tests.

  • 25. Marmendal, M
    et al.
    Roman, Erika
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eriksson, PCJ
    Nylander, Ingrid
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fahlke, C
    Maternal separation alters maternal care, but has minor effects on behavior and brain opioid peptides in adult offspring.2004In: Dev Psychobiol, Vol. 45, p. 140-152Article in journal (Refereed)
  • 26.
    Meyerson, Bengt J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Augustsson, Hanna
    Berg, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The Concentric Square Field: A multivariate test arena for analysis of explorative strategies2006In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 168, no 1, p. 100-113Article in journal (Refereed)
    Abstract [en]

    In this study, we describe the behavior of laboratory rats in a recently developed observation arena, the Concentric Square Field (CSF). The CSF contains a number of areas designed to provoke exploration and behaviors associated with risk assessment, risk taking and security seeking in an environment not previously experienced. The model includes sheltered, open and elevated areas, a hole board device, areas with different light conditions, and wall-enclosed corridors. The rationale behind the CSF is to meet the demand for multivariate test situations that are not predictive in the sense of previous definition of a specific purpose of measuring a certain mental state. We define multivariate as being a free choice of where to stay in areas of different qualities. In the present study, identification of risky as opposed to safe areas is based on the retrieval behavior in lactating females and hoarding of food pellets in food-deprived males. Furthermore, we describe the effects of pre-trial food deprivation, immobilization, social stress, strain differences (Sprague–Dawley, Wistar and Lister Hooded males), sex differences (Sprague–Dawley) and repeated testing. Besides the conventional statistics, a principal component analysis (PCA) helped to discriminate between the various categories tested. Our conclusion is that the multivariate and non-predictive test situation (CSF) and the use of PCA provide a good tool for ethoexperimental analysis.

  • 27.
    Meyerson, Bengt J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Jurek, Betty
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Rank-Order Procedure Applied to an Ethoexperimental Behavior Model—The Multivariate Concentric SquareField™ (MCSF) Test2013In: Journal of Behavioral and Brain Science, ISSN 2160-5866, E-ISSN 2160-5874, Vol. 3, no 4, p. 350-361Article in journal (Refereed)
    Abstract [en]

    Designing relevant animal models in order to investigate the neurobiological basis for human mental disorders is an important challenge. The need for new tests to be developed and traditional tests to be improved has recently been em-phasized. The authors propose a multivariate test approach, the multivariate concentric square fieldTM (MCSF) test. To measure and evaluate variation in the behavioral traits, we here put forward a statistical procedure of which the working title is “trend analysis”. Low doses of the benzodiazepine agonist diazepam (DZP; 1.0, 1.5, or 2.0 mg/kg) were used for exploring the use of the trend analysis in combination with multivariate data analysis for assessment of MCSF per-formance in rats. The commonly used elevated plus maze (EPM) test was used for comparison. The trend analysis comparing vehicle and the DZP1.5 groups revealed significantly higher general activity and risk-taking behavior in the DZP1.5 rats relative to vehicle rats. This finding was supported by multivariate data analysis procedures. It is concluded that the trend analysis together with multivariate data analysis procedures offers possibilities to extract information and illustrates effects obtained in the MCSF test. Diazepam in doses that have no apparent increase in open arm activity in the EPM was effective to alter the behavior in the MCSF test. The MCSF test and the use of multivariate data analysis and the proposed trend analysis may be useful alternatives to behavioral test batteries and traditionally used tests for the understanding of mechanisms underlying various mental states. Finally, the impact of an ethological reasoning and multivariate measures enabling behavioral profiling of animals may be a useful complementary methodology when phenotyping animals in behavioral neuroscience.

  • 28.
    Momeni, Shima
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Individual Differences In Risk-Related Behaviors And Voluntary Alcohol Intake In Wistar Rats2014In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 38, no Suppl. 1, p. 242A-242AArticle in journal (Other academic)
  • 29.
    Momeni, Shima
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Subgroup-dependent effects of voluntary alcohol intake on behavioral profiles in outbred Wistar rats2014In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 275, p. 288-296Article in journal (Refereed)
    Abstract [en]

    Experimental animal models are critical for understanding the genetic, environmental and neurobiological underpinnings of alcohol use disorders. Limited studies investigate alcohol-induced effects on behavior using free-choice paradigms. The aims of the present experiment were to study voluntary alcohol intake using a modified intermittent access paradigm, investigate the effects of voluntary alcohol intake on behavioral profiles in water- and alcohol-drinking rats, and select extreme low- and high-drinking animals for a more detailed behavioral characterization. Sixty outbred male Wistar rats were randomized into water and alcohol groups. Behavioral profiles in the multivariate concentric square field (TM) (MCSF) test were assessed prior to and after voluntary alcohol intake. The animals had intermittent access to 20% alcohol and water for three consecutive days per week for seven weeks. The results revealed increased alcohol intake over time. No major alcohol-induced differences on behavior profiles were found when comparing water- and alcohol-drinking animals. The high-drinking animals displayed an alcohol deprivation effect, which was not found in the low-drinking animals. High-drinking rats had lower risk-taking behavior prior to alcohol access and lower anxiety-like behavior after voluntary alcohol intake compared to low-drinking rats. In conclusion, the modified intermittent access paradigm may be useful for pharmacological manipulation of alcohol intake. With regard to behavior, the present findings highlights the importance of studying subgroup-dependent differences and add to the complexity of individual differences in behavioral traits of relevance to the vulnerability for excessive alcohol intake.

  • 30.
    Momeni, Shima
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Segerström, Lova
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats2015In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 9, article id 424Article in journal (Refereed)
    Abstract [en]

    Alcohol use disorder (AUD) is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHan™:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI) were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for 6 weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over 4 weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHan™:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier-dependent differences in the effect of naltrexone that were dose- and time-dependent; evident differences in high-drinking RccHan™:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHan™:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to naltrexone and further highlight the inherent heterogeneity of the Wistar strain. The overall results put focus on the importance of thoroughly considering the animals used to aid in study design and for comparison of reported results.

  • 31.
    Momeni, Shima
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sharif, Mana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ågren, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Individual differences in risk-related behaviors and voluntary alcohol intake in outbred Wistar rats2014In: Behavioural Pharmacology, ISSN 0955-8810, E-ISSN 1473-5849, Vol. 25, no 3, p. 206-215Article in journal (Refereed)
    Abstract [en]

    Some personality traits and comorbid psychiatric diseases are linked to a propensity for excessive alcohol drinking. The objective of this study was to investigate the association between individual differences in risk-related behaviors, voluntary alcohol intake and preference. Outbred male Wistar rats were tested in a novel open field, followed by assessment of behavioral profiles using the multivariate concentric square field (MCSF) test. Animals were classified into high risk taking and low risk taking on the basis of open-field behavior and into high risk-assessing (HRA) and low risk-assessing (LRA) on the basis of the MCSF profile. Finally, voluntary alcohol intake was investigated using intermittent access to 20% ethanol and water for 5 weeks. Only minor differences in voluntary alcohol intake were found between high risk taking and low risk taking. Differences between HRA and LRA rats were more evident, with higher intake and increased intake over time in HRA relative to LRA rats. Thus, individual differences in risk-assessment behavior showed greater differences in voluntary alcohol intake than risk taking. The findings may relate to human constructs of decision-making and risk taking associated with a predisposition to rewarding and addictive behaviors. Further studies are needed to clarify the relationship between risk-related behaviors, including risk-assessment behavior, and liability for excessive alcohol intake.

  • 32.
    Mustafa, Arshi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Winberg: Behavioral Neuroendocrinology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Thörnqvist, Per-Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Winberg: Behavioral Neuroendocrinology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Winberg: Behavioral Neuroendocrinology.
    The aggressive spiegeldanio, carrying a mutation in the fgfr1a gene, has no advantage in dyadic fights with zebrafish of the AB strain2019In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 370, article id 111942Article in journal (Refereed)
    Abstract [en]

    Zebrafish which carries a mutation in the fibroblast growth factor receptor 1A (fgfr1a), also known as spiegeldanio (spd), has previously been reported to be bolder and more aggressive than wildtype (AB) zebrafish. However, in previous studies aggression has been quantified in mirror tests. In dyadic fights the behavior of the combatants is modified by the behavior of their opponent, and fighting a mirror has been reported to have different effects on brain gene expression and brain monoaminergic systems. In the present study aggression was quantified in fgfr1a mutants and AB zebrafish using a mirror test after which the fish were allowed to interact in pairs, either consisting of two fgfr1a mutants or one AB and one fgfr1a mutant fish. Following dyadic interaction aggressive behavior was again quantified in individual fish in a second mirror test after which the fish were sacrificed and brain tissue analyzed for monoamines and monoamine metabolites. The results confirm that fgfr1a mutants are more aggressive than AB zebrafish in mirror tests. However, fgfr1a mutant fish did not have any advantage in fights for social dominance, and agonistic behavior of fgfr1a mutants did not differ from that of AB fish during dyadic interactions. Moreover, as the AB fish, fgfr1a mutant fish losing dyadic interactions showed a typical loser effect and social subordination resulted in an activation of the brain serotonergic system in fgfr1a mutants as well as in AB fish. Overall the effects of dyadic interaction were similar in fgfr1a mutant fish and zebrafish of the AB strain.

  • 33.
    Nordenankar, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Birgner, Carolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lagerström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fejgin, Kim
    Department of Pharmacology, Gothenburg University.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Altered expression of Vglut2 affects behavior in a gender-dependent mannerManuscript (preprint) (Other academic)
  • 34.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Daoura, Loudin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Palm, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Endogenous opioid peptides as mediators of the early environmental influence on ethanol consumption2011In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 45, no 3, p. 284-284Article in journal (Other academic)
  • 35.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Palm, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Daoura, Loudin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rowley, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Early Life Stress Causes Long Term Effects On Neuropeptides, Alcohol Consumption And Behaviour: Results From A Translational Initiative2014In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 38, p. 355A-355AArticle in journal (Other academic)
  • 36.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Palm, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Daoura, Loudin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rowley, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurobiological and behavioural studies on early life stress and adolescent alcohol drinking in a translational initiative2014In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 48, no 2, p. 160-161Article in journal (Other academic)
  • 37.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption?2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 229, no 4, p. 555-569Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Early-life events can cause long-term neurobiological and behavioural changes with a resultant effect upon reward and addiction processes that enhance risk to develop alcohol use disorders. Maternal separation (MS) is used to study the mediating mechanisms of early-life influences in rodents. In MS studies, the pups are exposed to maternal absence during the first postnatal weeks. The outcome of MS experiments exhibits considerable variation and questions have been raised about the validity of MS models.

    OBJECTIVES: This short review aims to provide information about experimental conditions that are important to consider when assessing the impact of early-life environment on voluntary ethanol consumption.

    RESULTS: The results from currently used MS protocols are not uniform. However, studies consistently show that longer separations of intact litters predispose for higher ethanol consumption and/or preference in adult male rats as compared to shorter periods of MS. Studies using individual pup MS paradigms, other controls, low ethanol concentrations, adult females or examining adolescent consumption reported no differences or inconsistent results.

    CONCLUSIONS: There is no "a rodent MS model", there are several models and they generate different results. The compiled literature shows that MS is a model of choice for analysis of early-life effects on voluntary ethanol consumption but there are examples of MS paradigms that are not suitable. These studies emphasize the importance to carefully designed MS experiments to supply the optimal conditions to definitely test the research hypothesis and to be particulate in the interpretation of the outcome.

  • 38.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neuropeptides as mediators of the early-life impact on the brain: implications for alcohol use disorders2012In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 5, no Article 77Article in journal (Refereed)
    Abstract [en]

    The brain is constantly exposed to external and internal input and to function in an ever-changing environment we are dependent on processes that enable the brain to adapt to new stimuli. Exposure to postnatal environmental stimuli can interfere with vital adaption processes and cause long-term changes in physiological function and behavior. Early-life alterations in brain function may result in impaired ability to adapt to new situations, in altered sensitivity to challenges later in life and thereby mediate risk or protection for psychopathology such as alcohol use disorders (AUD). In clinical research the studies of mechanisms, mediators, and causal relation between early environmental factors and vulnerability to AUD are restricted and attempts are made to find valid animal models for studies of the early-life influence on the brain. This review focuses on rodent models and the effects of adverse and naturalistic conditions on peptide networks within the brain and pituitary gland. Importantly, the consequences of alcohol addiction are not discussed but rather neurobiological alterations that can cause risk consumption and vulnerability to addiction. The article reviews earlier results and includes new data and multivariate data analysis with emphasis on endogenous opioid peptides but also oxytocin and vasopressin. These peptides are vital for developmental processes and it is hypothesized that early-life changes in peptide networks may interfere with neuronal processes and thereby contribute the individual vulnerability for AUD. The summarized results indicate a link between early-life rearing conditions, opioids, and ethanol consumption and that the ethanol-induced effects and the treatment with opioid antagonists later in life are dependent on early-life experiences. Endogenous opioids are therefore of interest to further study in the early-life impact on individual differences in vulnerability to AUD and treatment outcome.

  • 39.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Daoura, Loudin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Behavioral profiling before and after adolescent ethanol intake in rats subjected to different early-life conditions2011Conference paper (Other academic)
    Abstract [en]

    Causal links between the early-life environment and later psychiatric dysfunction are difficult to study in a clinical setting. Animal studies have therefore provided valuable insights into the basis of early-life impact on disorders later in life. For instance, repeated periods of short or prolonged maternal separation differentially affect behavior and voluntary ethanol intake in adult rats. This study examined the behavioral consequences of adolescent voluntary ethanol intake in rats subjected to different rearing environments.Rat pups were subjected to daily separation from the dams for 15 min (MS15) or 360 min (MS360) during the first 21 postnatal days. At 4 weeks of age their behavior was profiled using the multivariate concentric square field™ (MCSF) test. This test has an ethological foundation and is designed to provoke exploration and behaviors associated with risk assessment, risk taking and shelter seeking. At 5 weeks of age they were given intermittent access to 20% ethanol in a two-bottle free-choice paradigm. During a deprivation period after 9 weeks of access they were again tested in the MCSF. Water drinking MS15 and MS360 rats, and animal facility reared rats were included in the profiling.A principal component analysis (PCA) indicated large individual differences in behavioral profiles within the two MS groups. A trend analysis also revealed differences between the MS15 and the MS360 in risk assessment. The median ethanol intake in the MS groups was approximately 3 g/kg/day and did not differ between groups or change over time, whereas the ethanol preference increased significantly to 30%. Thus, in line with previous findings, adolescent access to ethanol abolishes differences in intake between MS groups. Examination of the behavior before ethanol access showed that parameters correlated with initial intake differed between MS15 and MS360 rats. The effects on behavior over time also differed depending on the early environment and ethanol access. The PCA for the second MCSF test revealed that ethanol intake in the MS360 group resulted in a more homogenous behavioral profile as compared to the first trial. Correlations between ethanol intake and the profiles from the second MCSF trial were also found in different parameters depending on the rearing environment.The results show that the early environment has effects on behavior in early adolescence, as well as differential effects on adult behavior after ethanol access. Furthermore, the behavioral profiles given by the MCSF tests makes it possible to follow an individual over time in order to look at causal links between behavior and voluntary ethanol intake.

  • 40.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Daoura, Loudin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of Rearing Conditions on Behaviour and Endogenous Opioids in Rats with Alcohol Access during Adolescence2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e76591-Article in journal (Refereed)
    Abstract [en]

    Abstract: Causal links between early-life stress, genes and later psychiatric diagnoses are not possible to fully address in human studies. Animal models therefore provide an important complement in which conditions can be well controlled and are here used to study and distinguish effects of early-life stress and alcohol exposure. The objective of this study was to investigate the impact of rearing conditions on behaviour in young rats and if these changes could be followed over time and to examine interaction effects between early-life environment and adolescent alcohol drinking on behaviour and immunoreactive levels of the opioid peptides dynorphin B, met-enkephalin-Arg(6)Phe(7) and beta-endorphin. We employed a rodent model, maternal separation, to study the impact of rearing conditions on behaviour, voluntary alcohol consumption and alcohol-induced effects. The consequences of short, 15 min (MS 15), and long, 360 min (MS 360), maternal separation in combination with adolescent voluntary alcohol consumption on behaviour and peptides were examined. A difference in the development of risk taking behaviour was found between the MS15 and MS360 while the development of general activity was found to differ between intake groups. Beta-endorphin levels in the pituitary and the periaqueductal gray area was found to be higher in the MS15 than the MS360. Adolescent drinking resulted in higher dynorphin B levels in the hippocampus and higher met-enkephalin-Arg(6)Phe(7) levels in the amygdala. Amygdala and hippocampus are involved in addiction processes and changes in these brain areas after adolescent alcohol drinking may have consequences for cognitive function and drug consumption behaviour in adulthood. The study shows that individual behavioural profiling over time in combination with neurobiological investigations provides means for studies of causality between early-life stress, behaviour and vulnerability to psychiatric disorders.

  • 41.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hävermark, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    When is a Wistar a Wistar?: Behavioral profiling of outbred Wistar rats from five different suppliers using the MCSF test2011In: Applied Animal Behaviour Science, ISSN 0168-1591, E-ISSN 1872-9045, Vol. 135, no 1-2, p. 128-137Article in journal (Refereed)
    Abstract [en]

    The same strain of rats purchased from different suppliers may exhibit behavioral differences that could give rise to variability and deficient repeatability. We have previously demonstrated that outbred Wistar rats from different suppliers display striking differences in voluntary alcohol intake. Using outbred male Wistar rats from five suppliers, four suppliers in Europe (Charles River, Taconic, Harlan and B&K Universal) and one in the United States (Harlan), the present study investigated the variability in behavioral profiles of the Wistar substrains. To this end, we used the multivariate concentric square field™ (MCSF) test. This test has an ethological foundation and is designed to provoke exploration and behaviors associated with risk assessment, risk taking and shelter seeking. The term “multivariate” refers to the test situation as well as the statistical analysis of the data. Our results demonstrate significant differences in body weight and behavioral profiles between the age-matched groups of Wistar rats. A principal component analysis clearly separated Harlan (US) and Charles River rats from the B&K Universal, Harlan (EU) and Taconic rats. The parameters important for this separation included activity and risk-taking performance. A trend analysis further confirmed this finding. The results emphasize the need for careful specification of the animals used in a given study. The utility of differences in explorative strategies and behavioral profiles among various outbred strains derived from a single strain is discussed. In conclusion, the data support differences between substrains of Wistar rats and illustrate the utility of using a multivariate strategy for behavioral profiling.

  • 42.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Momeni, Shima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lundberg, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats2014In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 8, p. 236-Article in journal (Refereed)
    Abstract [en]

    Certain personality types and behavioral traits display high correlations to drug use and an increased level of dopamine in the reward system is a common denominator of all drugs of abuse. Dopamine response to drugs has been suggested to correlate with some of these personality types and to be a key factor influencing the predisposition to addiction. This study investigated if behavioral traits can be related to potassium- and amphetamine-induced dopamine response in the dorsal striatum, an area hypothesized to be involved in the shift from drug use to addiction. The open field and multivariate concentric square field™ tests were used to assess individual behavior in male Wistar rats. Chronoamperometric recordings were then made to study the potassium- and amphetamine-induced dopamine response in vivo. A classification based on risk-taking behavior in the open field was used for further comparisons. Risk-taking behavior was correlated between the behavioral tests and high risk takers displayed a more pronounced response to the dopamine uptake blocking effects of amphetamine. Behavioral parameters from both tests could also predict potassium- and amphetamine-induced dopamine responses showing a correlation between neurochemistry and behavior in risk-assessment and risk-taking parameters. In conclusion, the high risk-taking rats showed a more pronounced reduction of dopamine uptake in the dorsal striatum after amphetamine indicating that this area may contribute to the sensitivity of these animals to psychostimulants and proneness to addiction. Further, inherent dopamine activity was related to risk-assessment behavior, which may be of importance for decision-making and inhibitory control, key components in addiction.

  • 43.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differences in basal and ethanol-induced levels of opioid peptides in Wistar rats from five different suppliers2012In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 36, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    One major cause for discrepancies in results from animal experimental studies is the use of different animal strains and suppliers. We have previously reported that Wistar rats from five different suppliers display profound differences in ethanol intake and behavior. One of the neurobiological processes that could be underlying these differences is the endogenous opioid system, which has been implicated in the rewarding and reinforcing effects of alcohol. We therefore hypothesized that the differences between the supplier groups would also be evident in the endogenous opioid system. Radioimmunoassay was used to determine the levels of the opioid peptides Met-enkephalin-Arg(6)Phe(7) and dynorphin B in several brain areas of ethanol-drinking and ethanol naive Wistar rats from five different suppliers. In the ethanol naive animals, differences between the supplier groups were found in the pituitary gland, hypothalamus, frontal cortex, dorsal striatum and hippocampus. In the ethanol-drinking rats, differences were found in the same structures, with the addition of medial prefrontal cortex and substantia nigra. Correlations between ethanol intake and peptide levels were also found in several of the areas examined. The structures in which differences were found have all been implicated in the transition from drug use to addiction and these differences may lead to different propensities and vulnerability to this transition. Because the endogenous opioids have been suggested to be involved in a number of neurobiological disorders the results do not only have implications for research on alcohol or drug addiction, but many other fields as well.

  • 44.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differences in voluntary ethanol consumption in wistar rats from five different breeders2010In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 34, no Suppl. 3, p. 96A-96A, article id P025Article in journal (Other academic)
  • 45.
    Palm, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Differences in voluntary ethanol consumption in Wistar rats from five different suppliers2011In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 45, no 6, p. 607-614Article in journal (Refereed)
    Abstract [en]

    Understanding the mechanism of action of ethanol and the neurobiological substrates for alcohol use disorders is challenging. In search of this knowledge, it is imperative to use valid animal experimental models. The Wistar rat is one example of a commonly used strain that also exert foundation stock for several rat lines selectively bred for high and low voluntary ethanol intake. Different studies report varying ethanol intake in Wistar rats posing the question of whether this is because of the methodological differences or the rat strain. The purpose of this study was therefore to compare voluntary ethanol intake in Wistar rats from five different suppliers. Rats from B&K Universal, UK (BK); Charles River, Germany; Harlan Laboratories, IN (Hsd); Harlan Laboratories, The Netherlands (RccHan™); and Taconic, Denmark were exposed to a three-bottle free-choice paradigm with intermittent 24h access to 5 and 20% ethanol and water three times per week for 6 weeks. A general finding was that the RccHan™ rats differed significantly from the other groups. At the end of the experiment, the RccHan™ group had the highest median ethanol intake of 3.85g/kg/24h, whereas the BK rats had the lowest intake of 1.84g/kg/24h. The preference for ethanol was also different throughout the experiment. At the end of the experiment, the RccHan™ rats had the highest preference of approximately 80%, whereas the BK rats had the lowest preference around 25%. During the 6-week drinking period, only the Hsd rats increased their ethanol intake, as evidenced by a significant increase of 5% ethanol intake. Although all rats are of Wistar origin, they display profound differences in voluntary ethanol consumption depending on the supplier. The choice of Wistar can therefore have implications for the outcome and make comparisons between studies difficult. The present findings highlight the supplier as an important parameter to consider when planning and performing preclinical animal studies in the field of alcohol research.

  • 46.
    Ploj, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergstrom, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effects of neonatal handling on nociceptin/orphanin FQ and opioid peptide levels in female rats2001In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 69, no 1-2, p. 173-179Article in journal (Refereed)
    Abstract [en]

    Animals exposed to short periods of handling during the critical period of development, i.e., the first 21 days of life in rats, show attenuated neuroendocrine responses to stress in adult life. We have previously reported long-term changes in brain dynorphin (DYN) peptide levels in male Sprague-Dawley rats after neonatal handling. The purpose of this study was to investigate whether neonatal handling, 15-min individual separation from the mother during postnatal days 1-21, can induce long-term changes in DYNB, Met-enkephalin Arg(6)Phe(7) (MEAP) and nociceptin/orphanin FQ (N/OFQ) immunoreactive (ir) levels in female Sprague-Dawley rats. The peptides were measured in brain and pituitary gland 2 months after the handling procedure. The results reveal that handled (H) rats had increased ir levels of N/OFQ, DYNB and MEAP in the periaqueductal gray (PAG) as compared to nonhandled (NH) controls. Furthermore, H rats had decreased ir levels of DYNB in the frontal cortex and in the amygdala. In contrast to previous findings in male rats, DYNB levels were unaffected in areas related to the hypothalamo - pituitary - adrenal (HPA)-axis. The results indicate that a manipulation early in life can induce persistent neurochemical changes in the N/OFQ and opioid peptide system in female Sprague-Dawley rats.

  • 47.
    Ploj, Karolina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors in male Wistar rats.2003In: Neuroscience, no 121, p. 787-799Article in journal (Other (popular scientific, debate etc.))
  • 48.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Djurexperimentell metodik2015In: Beroendemedicin / [ed] Johan Franck och Ingrid Nylander, Studentlitteratur AB, 2015, 2, p. 77-89Chapter in book (Refereed)
  • 49.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The multivariate concentric square field test for behavioral profiling in rodents2007In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 42Article in journal (Other academic)
  • 50.
    Roman, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Arborelius, Lotta
    Male but not female Wistar rats show increased anxiety-like behaviour in response to bright light in the defensive withdrawal test2009In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 202, no 2, p. 303-307Article in journal (Refereed)
    Abstract [en]

    The defensive withdrawal test (DWT) is used to model anxiety-like behaviour in rats. The aim of this study was to investigate whether an aversive stimulus, bright light, affects the behaviour in this test. Additionally, the effect of habituation to the apparatus was studied. Both male and female Wistar rats were used to study whether sex differences exist in the DWT, as reported for other tests of anxiety. On day 1 half of the rats were tested under low light and half under bright light. Two to seven days after trial one the same rats were repeatedly tested under the same light condition for five consecutive days. The male rats showed a higher degree of anxiety-like behaviour when tested under bright light than under low light. In contrast, the behaviour of the female rats was not affected by changes in illumination. Male rats also exhibited elevated anxiety-like behaviour compared to female rats under bright light, whereas under low light conditions no sex difference was seen. Males in low light habituated much faster than males tested under bright light, whereas in females there was little difference in habituation between low and bright light. In summary, we found that bright light is aversive for male but not female Wistar rats in the DWT. Whether this is due to sex differences in light sensitivity or if females respond with a different behavioural strategy in response to bright light, which could not be detected in the DWT, remains to be elucidated.

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