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  • 1.
    Aniruddha, Todkar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hodgins, Sheilagh
    Nilsson W., Kent
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effect of early life stress and ethanol consumption on Pomc and Avp expression in rat hypothalamus2014In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 48, no 2, p. 193-193Article in journal (Other academic)
  • 2.
    Bendre, Megha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nillson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Granholm, Linnea
    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.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Maoa Methylation: A Molecular Mechanism Behind The Effect Of Early Life Stress And Voluntary Alcohol Consumption On Maoa Expression In Wistar Rats2017In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 52Article in journal (Other academic)
  • 3.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hodgins, Sheilagh
    Rehn, Mattias
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Kent W.
    Clinical and experimental evidence of a link between adrenergic genes, early life stress and alcohol-related phenotypes2014In: Alcohol, ISSN 0741-8329, E-ISSN 1873-6823, Vol. 48, no 2, p. 184-184Article in journal (Other academic)
  • 4.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alpha 2a-Adrenoceptor Gene Expression and Early Life Stress-Mediated Propensity to Alcohol Drinking in Outbred Rats2015In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 12, no 7, p. 7154-7171Article in journal (Refereed)
    Abstract [en]

    Stressful events early in life, later high alcohol consumption and vulnerability to alcohol use disorder (AUD) are tightly linked. Norepinephrine is highly involved in the stress response and the alpha 2A-adrenoceptor, which is an important regulator of norepinephrine signalling, is a putative target in pharmacotherapy of AUD. The aim of the present study was to investigate the effects of early-life stress and adult voluntary alcohol drinking on the alpha 2A-adrenoceptor. The relative expression and promoter DNA methylation of the Adra2a gene were measured in the hypothalamus, a key brain region in stress regulation. A well-characterized animal model of early-life stress was used in combination with an episodic voluntary drinking in adulthood. Alcohol drinking rats with a history of early-life stress had lower Adra2a expression than drinking rats not exposed to stress. Alcohol intake and Adra2a gene expression were negatively correlated in high-drinking animals, which were predominantly rats subjected to early-life stress. The results provide support for a link between early-life stress, susceptibility for high alcohol consumption, and low Adra2a expression in the hypothalamus. These findings can increase our understanding of the neurobiological basis for vulnerability to initiate risk alcohol consumption and individual differences in the response to 2A-adrenoceptor agonists.

  • 5.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    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.
    Gene-set-based expression and DNA methylation in hypothalamus and pituitary of rats exposed to early life stress and ethanol drinking2014In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no Suppl. 2, p. S663-Article in journal (Other academic)
  • 6.
    Comasco, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Mujtaba, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    EXPERIMENTAL EVIDENCE OF A LINK BETWEEN THE alpha 2A-ADRENERGIC RECEPTOR GENE, EARLY LIFE STRESS, AND ETHANOL DRINKING2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50Article in journal (Other academic)
  • 7.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurobiological Consequences of Social Conditions and Alcohol Exposure in Adolescent rats2015Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Adolescence represents a time of extensive reorganisation and maturation of brain circuits involved in emotions, motivation and cognition and it is a period particular sensitive for external stimuli. External stimuli can be both socio-environmental factors and exposure to exogenous compounds such as drugs of abuse (e.g. alcohol). If these stimuli are of an adverse nature the probability of develop neuropsychiatric diseases or addiction is increased. To study the neurobiological consequences of adverse events during adolescence animal models are crucial since they give the opportunity of providing an environment where the exposure of the stimuli is controlled and also enable a detailed analysis of the effects in the brain. The overall aim of in this thesis was to investigate how environmental factors, social conditions or alcohol exposure, during adolescence affect the brain and/or drug-taking in rats. Rats are very sensitive for dis- turbances in their social conditions and to induce an adverse social environment, early adolescent rats where single-housed for either a short or prolonged time. A short period of single housing induced an acute stress response and increased levels of nociceptin/orphanin FQ in brain areas associated with stress. Prolonged single housing reduced the levels of Met-enkephalin-Arg6Phe7 in several brain areas. Rats exposed to alcohol during adolescence had an altered dopamine response in dorsal striatum after an am- phetamine challenge but displayed similar amphetamine intake-behaviour as water controls. However, animals exposed to a combination of adolescent alcohol exposure and subsequent amphetamine intake had a more efficient removal of dopamine in dorsal striatum after an amphetamine challenge. This thesis demonstrates how two different environmental stimuli are able to alter the neurobiology in adolescent rats. The results further support the notion that environmental conditions are of importance for normal brain maturation and provide new evidence that endogenous opioids are severely affected by social dis- turbances during adolescence. Furthermore, additional information is provided to the existing literature of how alcohol exposure during adolescence affects dopamine dynamics and drug-taking behaviour. In the literature, the majority of the studies of adolescent alcohol exposure have focused on the nucleus accum- bens, a brain area important in the processing of rewards. The results herein provide evidence that dorsal striatum, a brain area involved in the transition into habitual drug use is also affected by adolescent alco- hol exposure. An altered drug response in dorsal striatum may affect habit formation and contribute to a heightened susceptibility for high drug consumption later in life.

    List of papers
    1. Single housing during early adolescence causes time-, area- and peptide-specific alterations in endogenous opioids of rat brain
    Open this publication in new window or tab >>Single housing during early adolescence causes time-, area- and peptide-specific alterations in endogenous opioids of rat brain
    2015 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 172, no 2, p. 606-614Article in journal (Refereed) Published
    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.

    National Category
    Neurosciences Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-241312 (URN)10.1111/bph.12753 (DOI)000346826500032 ()24821004 (PubMedID)
    Available from: 2015-01-09 Created: 2015-01-09 Last updated: 2018-03-16Bibliographically approved
    2. Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats
    Open this publication in new window or tab >>Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats
    Show others...
    2015 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 24, p. 4421-4431Article in journal (Refereed) Published
    Abstract [en]

    Adolescent binge drinking is common and associated with increased risk of substance use disorders. Transition from recreational to habitual ethanol consumption involves alterations in dorsal striatal function, but the long-term impact of adolescent ethanol exposure upon this region remains unclear. This study aimed to characterise and describe relationships between adolescent ethanol exposure, amphetamine self-administration and adult dopamine dynamics in dorsal striatum, including response to amphetamine challenge, in male Wistar rats. Ethanol (2 g/kg) or water was administered intragastrically in an episodic binge-like regimen (three continuous days/week) between 4 and 9 weeks of age (i.e. post-natal days 28-59). In adulthood, animals were divided into two groups. In the first, dorsal striatal potassium-evoked dopamine release was examined via chronoamperometry, in the basal state and after a single amphetamine challenge (2 mg/kg, i.v.). In the second, amphetamine self-administration behaviour was studied (i.e. fixed and progressive ratio) before chronoamperometric analysis was conducted as described above. Adolescent ethanol exposure suppressed locally evoked dopamine response after amphetamine challenge in adulthood, whereas in the basal state, no differences in dopamine dynamics were detected. Ethanol-exposed animals showed no differences in adult amphetamine self-administration behaviour but an abolished effect on dopamine removal in response to a single amphetamine challenge after self-administration. Amphetamine challenges in adult rats revealed differences in in vivo dopamine function after adolescent ethanol exposure. The attenuated drug response in ethanol-exposed animals may affect habit formation and contribute to increased risk for substance use disorders as a consequence of adolescent ethanol.

    Keywords
    Chronoamperometry, Operant self-administration, Alcohol, Rodents
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-270438 (URN)10.1007/s00213-015-4070-3 (DOI)000365186600004 ()26407601 (PubMedID)
    Funder
    Swedish Research Council, K2012-61X-22090-01-3
    Available from: 2016-02-08 Created: 2015-12-28 Last updated: 2018-03-16Bibliographically approved
  • 8.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Stress, Drugs and Neuroscience: Neurobiological Effects of Social Stressors and Drug Exposure in Young and Adolescent Rats2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Experiences early in life or during adolescence modulate neuronal networks in the immature brain and consequently lay the foundation for future susceptibility or resilience towards psychiatric disorders. The objective in this thesis is to understand, in part, how the surrounding environment shapes the brain of a young individual. Three types of negative life events were studied, in an animal model, for their effects on the brain reward system (i.e., endogenous opioids and dopamine) and voluntary drug intake. These were: disruption of maternal care, disruption of interaction with peers, and exposure to drugs. Stress, in the form of maternal separation, altered expression of opioid genes in the dorsal striatum and amygdala, and the response to subsequent alcohol intake on these genes was dependent on early life conditions. Basal levels of endogenous opioids were also dependent on how the animals were housed in early adolescence. Short single housing (30 minutes) caused an acute stress response as evidenced by increased serum corticosterone and nociceptin/orphanin FQ in brain areas associated with stress. A prolonged single housing resulted in a marked decrease of Met-Enk-Arg6-Phe7 (i.e., a marker of enkephalins) in several brain areas. The endogenous opioids were also affected by repeated exposure of ethanol during adolescence; ethanol intoxication increased the accumbal levels of Met-Enk-Arg6-Pheand decreased those of β-endorphin. Residual effects of the adolescent ethanol exposure were found in Met-Enk-Arg6-Phe7 levels in the amygdala, ventral tegmental area, and substantia nigra. Furthermore, rats exposed to ethanol as adolescents had alterations in the dopamine dynamics in the dorsal striatum. Both endogenous opioids and dopamine are essential in mediating rewarding properties. Alterations of these systems, caused by environmental disturbances and alcohol exposure, presented herein could explain, in part, the increased susceptibility for alcohol- and substance use disorders later in life.

    List of papers
    1. The expression of opioid genes in non-classical reward areas depends on early life conditions and ethanol intake
    Open this publication in new window or tab >>The expression of opioid genes in non-classical reward areas depends on early life conditions and ethanol intake
    Show others...
    2017 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1668, p. 36-45Article in journal (Refereed) Published
    Abstract [en]

    The young brain is highly sensitive to environmental influences that can cause long-term changes in neuronal function, possibly through altered gene expression. The endogenous opioid system continues to mature after birth and because of its involvement in reward, an inadequate maturation of this system could lead to enhanced susceptibility for alcohol use disorder. Recent studies show that the classical reward areas nucleus accumbens and ventral tegmental area are less affected by early life stress whereas endogenous opioids in non-classical areas, e.g. dorsal striatum and amygdala, are highly responsive. The aim was to investigate the interaction between early life conditions and adult voluntary ethanol intake on opioid gene expression. Male Wistar rats were exposed to conventional rearing, 15, or 360min of daily maternal separation (MS) postnatal day 1-21, and randomly assigned to ethanol or water drinking postnatal week 10-16. Rats exposed to early life stress (MS360) had increased opioid receptor gene (Oprm1, Oprd1 and Oprk1) expression in the dorsal striatum. Ethanol drinking was associated with lower striatal Oprd1 and Oprk1 expression solely in rats exposed to early life stress. Furthermore, rats exposed to early life stress had high inherent Pomc expression in the amygdala but low expression after ethanol intake. Thus, adverse events early in life induced changes in opioid gene expression and also influenced the central molecular response to ethanol intake. These long-term consequences of early life stress can contribute to the enhanced risk for excessive ethanol intake and alcohol use disorder seen after exposure to childhood adversity.

    National Category
    Neurosciences Neurology
    Identifiers
    urn:nbn:se:uu:diva-330917 (URN)10.1016/j.brainres.2017.05.006 (DOI)000404796300005 ()28511993 (PubMedID)
    Funder
    Swedish Research Council, K2012-61X-22090-01-3; VR: 2015-00495The Swedish Brain FoundationLars Hierta Memorial FoundationForte, Swedish Research Council for Health, Working Life and WelfareEU, European Research Council, INCA 600398
    Available from: 2017-10-06 Created: 2017-10-06 Last updated: 2018-03-16Bibliographically approved
    2. Single housing during early adolescence causes time-, area- and peptide-specific alterations in endogenous opioids of rat brain
    Open this publication in new window or tab >>Single housing during early adolescence causes time-, area- and peptide-specific alterations in endogenous opioids of rat brain
    2015 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 172, no 2, p. 606-614Article in journal (Refereed) Published
    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.

    National Category
    Neurosciences Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-241312 (URN)10.1111/bph.12753 (DOI)000346826500032 ()24821004 (PubMedID)
    Available from: 2015-01-09 Created: 2015-01-09 Last updated: 2018-03-16Bibliographically approved
    3. Episodic Ethanol Exposure in Adolescent Rats - Effects on Endogenous Opioid Peptides
    Open this publication in new window or tab >>Episodic Ethanol Exposure in Adolescent Rats - Effects on Endogenous Opioid Peptides
    (English)Manuscript (preprint) (Other academic)
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-346150 (URN)
    Available from: 2018-03-14 Created: 2018-03-14 Last updated: 2018-03-16
    4. Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats
    Open this publication in new window or tab >>Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats
    Show others...
    2015 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 24, p. 4421-4431Article in journal (Refereed) Published
    Abstract [en]

    Adolescent binge drinking is common and associated with increased risk of substance use disorders. Transition from recreational to habitual ethanol consumption involves alterations in dorsal striatal function, but the long-term impact of adolescent ethanol exposure upon this region remains unclear. This study aimed to characterise and describe relationships between adolescent ethanol exposure, amphetamine self-administration and adult dopamine dynamics in dorsal striatum, including response to amphetamine challenge, in male Wistar rats. Ethanol (2 g/kg) or water was administered intragastrically in an episodic binge-like regimen (three continuous days/week) between 4 and 9 weeks of age (i.e. post-natal days 28-59). In adulthood, animals were divided into two groups. In the first, dorsal striatal potassium-evoked dopamine release was examined via chronoamperometry, in the basal state and after a single amphetamine challenge (2 mg/kg, i.v.). In the second, amphetamine self-administration behaviour was studied (i.e. fixed and progressive ratio) before chronoamperometric analysis was conducted as described above. Adolescent ethanol exposure suppressed locally evoked dopamine response after amphetamine challenge in adulthood, whereas in the basal state, no differences in dopamine dynamics were detected. Ethanol-exposed animals showed no differences in adult amphetamine self-administration behaviour but an abolished effect on dopamine removal in response to a single amphetamine challenge after self-administration. Amphetamine challenges in adult rats revealed differences in in vivo dopamine function after adolescent ethanol exposure. The attenuated drug response in ethanol-exposed animals may affect habit formation and contribute to increased risk for substance use disorders as a consequence of adolescent ethanol.

    Keywords
    Chronoamperometry, Operant self-administration, Alcohol, Rodents
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-270438 (URN)10.1007/s00213-015-4070-3 (DOI)000365186600004 ()26407601 (PubMedID)
    Funder
    Swedish Research Council, K2012-61X-22090-01-3
    Available from: 2016-02-08 Created: 2015-12-28 Last updated: 2018-03-16Bibliographically approved
  • 9.
    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.

  • 10.
    Granholm, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rowley, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ellgren, M.
    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.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 24, p. 4421-4431Article in journal (Refereed)
    Abstract [en]

    Adolescent binge drinking is common and associated with increased risk of substance use disorders. Transition from recreational to habitual ethanol consumption involves alterations in dorsal striatal function, but the long-term impact of adolescent ethanol exposure upon this region remains unclear. This study aimed to characterise and describe relationships between adolescent ethanol exposure, amphetamine self-administration and adult dopamine dynamics in dorsal striatum, including response to amphetamine challenge, in male Wistar rats. Ethanol (2 g/kg) or water was administered intragastrically in an episodic binge-like regimen (three continuous days/week) between 4 and 9 weeks of age (i.e. post-natal days 28-59). In adulthood, animals were divided into two groups. In the first, dorsal striatal potassium-evoked dopamine release was examined via chronoamperometry, in the basal state and after a single amphetamine challenge (2 mg/kg, i.v.). In the second, amphetamine self-administration behaviour was studied (i.e. fixed and progressive ratio) before chronoamperometric analysis was conducted as described above. Adolescent ethanol exposure suppressed locally evoked dopamine response after amphetamine challenge in adulthood, whereas in the basal state, no differences in dopamine dynamics were detected. Ethanol-exposed animals showed no differences in adult amphetamine self-administration behaviour but an abolished effect on dopamine removal in response to a single amphetamine challenge after self-administration. Amphetamine challenges in adult rats revealed differences in in vivo dopamine function after adolescent ethanol exposure. The attenuated drug response in ethanol-exposed animals may affect habit formation and contribute to increased risk for substance use disorders as a consequence of adolescent ethanol.

  • 11.
    Granholm, Linnea
    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.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Episodic Ethanol Exposure in Adolescent Rats Causes Residual Alterations in Endogenous Opioid Peptides2018In: Frontiers in Psychiatry, ISSN 1664-0640, E-ISSN 1664-0640, Vol. 9, article id 425Article in journal (Refereed)
    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.

  • 12.
    Granholm, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Todkar, Aniruddah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bergman, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nillson, Kent
    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.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The expression of opioid genes in non-classical reward areas depends on early life conditions and ethanol intake2017In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1668, p. 36-45Article in journal (Refereed)
    Abstract [en]

    The young brain is highly sensitive to environmental influences that can cause long-term changes in neuronal function, possibly through altered gene expression. The endogenous opioid system continues to mature after birth and because of its involvement in reward, an inadequate maturation of this system could lead to enhanced susceptibility for alcohol use disorder. Recent studies show that the classical reward areas nucleus accumbens and ventral tegmental area are less affected by early life stress whereas endogenous opioids in non-classical areas, e.g. dorsal striatum and amygdala, are highly responsive. The aim was to investigate the interaction between early life conditions and adult voluntary ethanol intake on opioid gene expression. Male Wistar rats were exposed to conventional rearing, 15, or 360min of daily maternal separation (MS) postnatal day 1-21, and randomly assigned to ethanol or water drinking postnatal week 10-16. Rats exposed to early life stress (MS360) had increased opioid receptor gene (Oprm1, Oprd1 and Oprk1) expression in the dorsal striatum. Ethanol drinking was associated with lower striatal Oprd1 and Oprk1 expression solely in rats exposed to early life stress. Furthermore, rats exposed to early life stress had high inherent Pomc expression in the amygdala but low expression after ethanol intake. Thus, adverse events early in life induced changes in opioid gene expression and also influenced the central molecular response to ethanol intake. These long-term consequences of early life stress can contribute to the enhanced risk for excessive ethanol intake and alcohol use disorder seen after exposure to childhood adversity.

  • 13.
    Granholm, Linnea
    et al.
    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, Neuro-psycho-pharmacology. 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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The Effects Of Early Environment And Adult Voluntary Drinking On Pomc Gene Expression In Rats2014In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 38, p. 153A-153AArticle in journal (Other academic)
  • 14.
    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)
  • 15.
    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)
  • 16.
    Nylander, Ingrid
    et al.
    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.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vrettou, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Bendre, Megha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Boon, Wout
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Andershed, Henrik
    Tuvblad, Catherine
    Nilsson, Kent W
    Centre for Clinical Research, Västerås Central Hospital, Västerås, Sweden.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats and Humans2017In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 54, no 8, p. 6225-6234Article in journal (Refereed)
    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.

  • 17.
    Rowley, Samuel C. S.
    et al.
    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.
    Ellgren, Maria
    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.
    Palm, Sara
    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.
    Impact Of Adolescent Alcohol Exposure And Adult Amphetamine Self-Administration On Evoked Striatal Dopamine Release In Rats2014In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 38, p. 83A-83AArticle in journal (Other academic)
  • 18.
    Todkar, Aniruddha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aljumah, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nilsson, Kent W.
    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.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Expression of Stress and DNA Methylation Regulatory Genes in the Hypothalamus and Pituitary of Rats Exposed to Early Life Stress and Adult Voluntary Ethanol Drinking2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50, no S1Article in journal (Other academic)
  • 19.
    Todkar, Aniruddha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Granholm, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aljumah, Mujtaba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nilsson, Kent W
    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.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing2016In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 8, article id 90Article in journal (Refereed)
    Abstract [en]

    The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation. Concluding, single housing is a confounding factor to be considered in voluntary ethanol drinking paradigms. ELS and ethanol drinking in adulthood exert independent effects on hypothalamic and pituitary related genes, however, in a manner dependent on the control group used.

  • 20.
    Todkar, Aniruddha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    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.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Hodgins, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nilsson, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Effect Of Early Life Stress And Ethanol Consumption On Pomc In Rat Hypothalamus2013In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 48, no Suppl. 1, p. 44-45Article in journal (Other academic)
  • 21.
    Vrettou, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Granholm, Linnea
    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, Neuro-psycho-pharmacology.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Wallen-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Ethanol Affects Limbic and Striatal Expression of Vesicular Glutamate Transporters in Outbred Rats Exposed to Early Life Stress2015In: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 50, article id P-03Article in journal (Other academic)
  • 22.
    Vrettou, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Granholm, Linnea
    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.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Wallén-Mackenzie, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress2017In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 22, no 2, p. 369-380Article in journal (Refereed)
    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.

1 - 22 of 22
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