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Nylander, Ingrid
Publications (10 of 122) Show all publications
Comasco, E., Schijven, D., de Maeyer, H., Vrettou, M., Nylander, I., Sundström-Poromaa, I. & Olivier, J. D. A. (2019). Constitutive serotonin transporter reduction resembles maternal separation with regard to stress-related gene expression. ACS Chemical Neuroscience, 10(7), 3132-3142
Open this publication in new window or tab >>Constitutive serotonin transporter reduction resembles maternal separation with regard to stress-related gene expression
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2019 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, no 7, p. 3132-3142Article in journal (Refereed) Published
Abstract [en]

Interactive effects between allelic variants of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) and stressors on depression symptoms have been documented, as well as questioned, by meta-analyses. Translational models of constitutive 5-htt reduction and experimentally controlled stressors often led to inconsistent behavioral and molecular findings and often did not include females. The present study sought to investigate the effect of 5-htt genotype, maternal separation, and sex on the expression of stress-related candidate genes in the rat hippocampus and frontal cortex. The mRNA expression levels of Avp, Pomc, Crh, Crhbp, Crhr1, Bdnf, Ntrk2, Maoa, Maob, and Comt were assessed in the hippocampus and frontal cortex of 5-htt± and 5-htt+/+ male and female adult rats exposed, or not, to daily maternal separation for 180 min during the first 2 postnatal weeks. Gene- and brain region-dependent, but sex-independent, interactions between 5-htt genotype and maternal separation were found. Gene expression levels were higher in 5-htt+/+ rats not exposed to maternal separation compared with the other experimental groups. Maternal separation and 5-htt+/− genotype did not yield additive effects on gene expression. Correlative relationships, mainly positive, were observed within, but not across, brain regions in all groups except in non-maternally separated 5-htt+/+ rats. Gene expression patterns in the hippocampus and frontal cortex of rats exposed to maternal separation resembled the ones observed in rats with reduced 5-htt expression regardless of sex. These results suggest that floor effects of 5-htt reduction and maternal separation might explain inconsistent findings in humans and rodents.

Keywords
Frontal cortex, hippocampus, maternal separation, serotonin transporter, gene expression
National Category
Neurosciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-381818 (URN)10.1021/acschemneuro.8b00595 (DOI)000476685400012 ()30614673 (PubMedID)
Funder
Swedish Society of Medicine, SLS-411161Fredrik och Ingrid Thurings StiftelseLars Hierta Memorial FoundationSwedish Research Council, K2012-61X-22090-01-3Swedish Research Council, VR: 2015-00495EU, FP7, Seventh Framework Programme, INCA 600398Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-09-20Bibliographically approved
Bendre, M., Granholm, L., Drennan, R., Meyer, A., Yan, L., Nilsson, K. W., . . . Comasco, E. (2019). Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.. Alcohol, 79, 7-16
Open this publication in new window or tab >>Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
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2019 (English)In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 79, p. 7-16Article in journal (Refereed) Published
Abstract [en]

Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.

Keywords
Alcohol, DNA methylation, Gene expression, Maoa, Maternal separation, Stress
National Category
Psychiatry Neurosciences
Identifiers
urn:nbn:se:uu:diva-368636 (URN)10.1016/j.alcohol.2018.11.001 (DOI)000483450600002 ()30414913 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-0627Fredrik och Ingrid Thurings StiftelseLars Hierta Memorial FoundationThe Swedish Brain Foundation, PS2013-0052Swedish Research Council, K2012-61X-22090-01-3Swedish Research Council, VR: 2015-00495EU, FP7, Seventh Framework Programme, INCA 600398Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2019-10-17Bibliographically approved
Vrettou, M., Nilsson, K. W., Tuvblad, C., Rehn, M., Åslund, C., Andershed, A.-K., . . . Comasco, E. (2019). VGLUT2 rs2290045 genotype moderates environmental sensitivity to alcohol-related problems in three samples of youths. European Child and Adolescent Psychiatry, 28(10), 1329-1340
Open this publication in new window or tab >>VGLUT2 rs2290045 genotype moderates environmental sensitivity to alcohol-related problems in three samples of youths
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2019 (English)In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 28, no 10, p. 1329-1340Article in journal (Refereed) Published
Abstract [en]

The importance of Vesicular Glutamate Transporter 2 (VGLUT2)-mediated neurotransmission has been highlighted in studies on addiction-related phenotypes. The single nucleotide polymorphism rs2290045 in VGLUT2 has been associated with alcohol dependence, but it is unknown whether or how this association is affected by environmental factors. The present study determined whether the association of alcohol-related problems with the rs2290045 in the VGLUT2 gene was modified by negative and positive environmental factors. Three samples were included: a clinical sample of 131 adolescents followed from age 17 to 22; a general population sample of 1794 young adults; and a general population sample of 1687 adolescents followed from age 14 to 17. DNA was extracted from saliva and the rs2290045 (T/C) was genotyped. Alcohol-related problems were assessed using the Alcohol Use Disorders Identification Test. Stressful life events (SLE) and parenting were assessed by questionnaires. Gene-environment interactions were investigated using a dual statistical approach. In all samples (effect sizes 0.6-6.2%), and consistent with the differential susceptibility framework, T carriers exposed to SLE reported more alcohol-related problems if they had experienced poor parenting, and lower alcohol-related problems if they had received supportive parenting. T carriers not exposed to SLE reported higher alcohol-related problems if they had received supportive parenting and lower alcohol-related problems if they had received poor parenting. Among CC carriers, alcohol-related problems did not vary as a function of negative and positive environmental factors. In conclusion, in three samples of youths, alcohol-related problems were associated with an interaction of VGLUT2 rs2290045, SLE, and parenting.

Keywords
Adolescents, Alcohol, Gene, Glutamate, Stress, VGLUT2
National Category
Psychiatry Medical Genetics
Identifiers
urn:nbn:se:uu:diva-381816 (URN)10.1007/s00787-019-01293-w (DOI)000489301800006 ()30805764 (PubMedID)
Funder
The Swedish Brain Foundation, PS2013-0052Åke Wiberg Foundation, M15-0239Forte, Swedish Research Council for Health, Working Life and Welfare, 2015-00897Swedish Research Council, 2013-4657Swedish Research Council, 2014-3804Swedish Research Council, VR: 2015-00495
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-11-06Bibliographically approved
Granholm, L., Segerström, L. & Nylander, I. (2018). Episodic Ethanol Exposure in Adolescent Rats Causes Residual Alterations in Endogenous Opioid Peptides. Frontiers in Psychiatry, 9, Article ID 425.
Open this publication in new window or tab >>Episodic Ethanol Exposure in Adolescent Rats Causes Residual Alterations in Endogenous Opioid Peptides
2018 (English)In: Frontiers in Psychiatry, ISSN 1664-0640, E-ISSN 1664-0640, Vol. 9, article id 425Article in journal (Refereed) Published
Abstract [en]

Adolescent binge drinking is associated with an increased risk of substance use disorder, but how ethanol affects the central levels of endogenous opioid peptides is still not thoroughly investigated. The aim of this study was to examine the effect of repeated episodic ethanol exposure during adolescence on the tissue levels of three different endogenous opioid peptides in rats. OutbredWistar rats received orogastric (i.e., gavage) ethanol for three consecutive days per week between 4 and 9 weeks of age. At 2 h and 3 weeks, respectively, after the last exposure, beta-endorphin, dynorphin B and Met-enkephalin-Arg(6)Phe(7) (MEAP) were analyzed with radioimmunoassay. Beta-endorphin levels were low in the nucleus accumbens during ethanol intoxication. Remaining effects of adolescent ethanol exposure were found especially for MEAP, with low levels in the amygdala, and high in the substantia nigra and ventral tegmental area three weeks after the last exposure. In the hypothalamus and pituitary, the effects of ethanol on beta-endorphin were dependent on time from the last exposure. An interaction effect was also found in the accumbal levels of MEAP and nigral dynorphin B. These results demonstrate that repeated episodic exposure to ethanol during adolescence affected opioid peptide levels in regions involved in reward and reinforcement as well as stress response. These alterations in opioid networks after adolescent ethanol exposure could explain, in part, the increased risk for high ethanol consumption later in life.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
beta-endorphin, dynorphin B, enkephalin, rat model, developing brain, alcohol
National Category
Pharmaceutical Sciences Substance Abuse
Identifiers
urn:nbn:se:uu:diva-364234 (URN)10.3389/fpsyt.2018.00425 (DOI)000444118600001 ()30250435 (PubMedID)
Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2018-10-24Bibliographically approved
Lundberg, S., Martinsson, M., Nylander, I. & Roman, E. (2017). Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats. Hormones and Behavior, 87, 137-144
Open this publication in new window or tab >>Altered corticosterone levels and social play behavior after prolonged maternal separation in adolescent male but not female Wistar rats
2017 (English)In: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 87, p. 137-144Article in journal (Refereed) Published
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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-316957 (URN)10.1016/j.yhbeh.2016.11.016 (DOI)000392905500016 ()27884596 (PubMedID)
Funder
Swedish Research Council, K2012-61 x-22090-01-3
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-11-29Bibliographically approved
Vrettou, M., Granholm, L., Todkar, A., Nilsson, K. W., Wallén-Mackenzie, Å., Nylander, I. & Comasco, E. (2017). Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress. Addiction Biology, 22(2), 369-380
Open this publication in new window or tab >>Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress
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2017 (English)In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, no 2, p. 369-380Article in journal (Refereed) Published
Abstract [en]

Alcohol use disorder is the outcome of both genetic and environmental influences and their interaction via epigenetic mechanisms. The neurotransmitter glutamate is an important regulator of reward circuits and implicated in adaptive changes induced by ethanol intake. The present study aimed at investigating corticolimbic and corticostriatal genetic signatures focusing on the glutamatergic phenotype in relation to early-life stress (ELS) and consequent adult ethanol consumption. A rodent maternal separation model was employed to mimic ELS, and a free-choice paradigm was used to assess ethanol intake in adulthood. Gene expression levels of the Vesicular Glutamate Transporters (Vglut) 1, 2 and 3, as well as two key regulators of DNA methylation, DNA (cytosine-5)-methyltransferase 1 (Dnmt1) and methyl-CpG-binding protein 2 (Mecp2), were analyzed. Brain regions of interest were the ventral tegmental area (VTA), nucleus accumbens (Acb), medial prefrontal cortex (mPFC) and dorsal striatum (dStr), all involved in mediating aspects of ethanol reward. Region-specific Vglut, Dnmt1 and Mecp2 expression patterns were observed. ELS was associated with down-regulated expression of Vglut2 in the VTA and mPFC. Rats exposed to ELS were more sensitive to ethanol-induced changes in Vglut expression in the VTA, Acb, and dStr and in Dnmt1 and Mecp2 expression in the striatal regions. These findings suggest long-term glutamatergic and DNA methylation neuroadaptations as a consequence of ELS, and show an association between voluntary drinking in non-preferring, non-dependent, rodents and different Vglut, Dnmt1 and Mecp2 expression depending on early-life history.

Keywords
Alcohol, DNA methylation, glutamate, rats, stress, Vgluts
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-276528 (URN)10.1111/adb.12331 (DOI)000394988500008 ()26610727 (PubMedID)
Funder
Swedish Research Council, K2012-61X-22090-01-3 2013-4657 2014-3804Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-0627Lars Hierta Memorial FoundationThe Swedish Brain Foundation, PS2013-0052
Available from: 2016-02-15 Created: 2016-02-15 Last updated: 2018-09-04Bibliographically approved
Nylander, I., Todkar, A., Granholm, L., Vrettou, M., Bendre, M., Boon, W., . . . Comasco, E. (2017). Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans. Molecular Neurobiology, 54(8), 6225-6234
Open this publication in new window or tab >>Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans
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2017 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 54, no 8, p. 6225-6234Article in journal (Refereed) Published
Abstract [en]

Alcohol misuse has been linked to dysregulation of stress, emotion, and reward brain circuitries. A candidate key mediator of this association is the FK506-binding protein (FKBP5), a negative regulator of the glucocorticoid receptor. The aim of the present study was to further understand the Fkbp5/FKBP5-related genetic underpinnings underlying the relationship between early life social relations and alcohol drinking. The effect of maternal separation and voluntary alcohol drinking on Fkbp5 expression was investigated in the brain of young adult rats, whereas the interaction effect of the functional FKBP5 single nucleotide polymorphism rs1360780 genotype and parent-child relationship on problematic drinking was examined in young adult humans. In rats, Fkbp5 expression in the nucleus accumbens and ventral tegmental area, core regions of the reward system, was affected in a region-dependent manner and in opposite direction by maternal separation and alcohol drinking. Fkbp5 expression in the cingulate cortex was affected by the combined effect of maternal separation and alcohol drinking. In humans, the TT genotype, in the presence of a poor relationship between the child and parents, was associated with problematic drinking behavior. The present findings suggest that Fkbp5 expression in mesocorticolimbic dopaminergic regions associates with early life stress-mediated sensitivity to alcohol drinking and that FKBP5 genotype interacts with parent-child relationship to influence alcohol drinking. These findings are the first to point to a role of FKBP5 in propensity to alcohol misuse and call for studies of the underlying molecular mechanisms to identify potential drug targets.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-309060 (URN)10.1007/s12035-016-0157-z (DOI)000409039000040 ()27709495 (PubMedID)
Funder
Lars Hierta Memorial FoundationThe Swedish Brain FoundationSwedish Research Council, K2012-61X-22090-01-3, 2015-00495Forte, Swedish Research Council for Health, Working Life and WelfareEU, FP7, Seventh Framework Programme, INCA 600398
Available from: 2016-12-02 Created: 2016-12-02 Last updated: 2018-01-03Bibliographically approved
Lundberg, S., Abelson, K., Nylander, I. & Roman, E. (2017). Few long-term consequences after prolonged maternal separation in female Wistar rats. PLoS ONE, 12(12), Article ID e0190042.
Open this publication in new window or tab >>Few long-term consequences after prolonged maternal separation in female Wistar rats
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190042Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
Keywords
Alcohol intake, behavior, estrus cycle, gonadal hormone, handling, HPA axis reactivity, maternal deprivation, multivariate concentric square field test, MCSF, resilience, sex differences, stress reactivity, supplier differences
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-322548 (URN)10.1371/journal.pone.0190042 (DOI)000418587400082 ()29267376 (PubMedID)
Funder
Swedish Research Council, K2012-61-22090-01-3, K2005-04X-12588-08AThe Swedish Brain FoundationAFA Insurance
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2018-02-15Bibliographically approved
Bendre, M., Nillson, K. W., Granholm, L., Nylander, I. & Comasco, E. (2017). Maoa Methylation: A Molecular Mechanism Behind The Effect Of Early Life Stress And Voluntary Alcohol Consumption On Maoa Expression In Wistar Rats. Alcohol and Alcoholism, 52
Open this publication in new window or tab >>Maoa Methylation: A Molecular Mechanism Behind The Effect Of Early Life Stress And Voluntary Alcohol Consumption On Maoa Expression In Wistar Rats
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2017 (English)In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 52Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
National Category
Substance Abuse
Identifiers
urn:nbn:se:uu:diva-345576 (URN)000417304100158 ()
Available from: 2018-03-09 Created: 2018-03-09 Last updated: 2018-03-09Bibliographically approved
Wood, C. M., Nicolas, C. S., Choi, S.-L., Roman, E., Nylander, I., Fernandez-Teruel, A., . . . Lodge, D. (2017). Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour.. Neuropharmacology, 115, 128-138
Open this publication in new window or tab >>Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour.
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2017 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 115, p. 128-138Article, review/survey (Refereed) Published
Abstract [en]

Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors.

Keywords
Metabotropic glutamate receptor; mGlu2; Grm2 mutation; Wistar rats; Han Wistar rats; Emotionality; Anxiety; Selectively bred rats; Alcohol preference
National Category
Neurosciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-318629 (URN)10.1016/j.neuropharm.2016.03.020 (DOI)000400218600013 ()26987983 (PubMedID)
Funder
Eli Lilly, PS1201341872-P (MINECO); 2014SGR-1587 (DGR)
Available from: 2017-03-27 Created: 2017-03-27 Last updated: 2018-01-13
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