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Effects of Rearing Conditions on Behaviour and Endogenous Opioids in Rats with Alcohol Access during Adolescence
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction and Behaviour)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction and Behaviour)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction and Behaviour)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction and Behaviour)
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, e76591- p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2013. Vol. 8, no 10, e76591- p.
Keyword [en]
male Wistar rats; behavioural ontogeny; endogenous opioids; intermittent ethanol access; maternal separation; multivariate concentric square field™ test
National Category
Pharmaceutical Sciences Neurosciences
Research subject
Pharmaceutical Pharmacology
Identifiers
URN: urn:nbn:se:uu:diva-198667DOI: 10.1371/journal.pone.0076591ISI: 000325434500075OAI: oai:DiVA.org:uu-198667DiVA: diva2:617229
Available from: 2013-04-22 Created: 2013-04-22 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Early Environment and Adolescent Ethanol Consumption : Effects on Endogenous Opioids and Behaviour in Rats
Open this publication in new window or tab >>Early Environment and Adolescent Ethanol Consumption : Effects on Endogenous Opioids and Behaviour in Rats
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Excessive and compulsive ethanol drinking is one of the most serious public health issues. Therefore, it is vital to increase the knowledge about risks and protection for alcohol use disorders (AUD) to optimize prevention and treatment strategies. Ethanol consumption commonly initiates during adolescence when extensive neuronal maturation and development also occurs. Early exposure to ethanol is a risk factor for AUD, but the effects of adolescent drinking and the basis for the individual susceptibility to AUD are not fully understood. The interactions between genotype and environmental factors determine the individual risk for AUD and this thesis aimed to examine the environmental impact. The specific aims were to investigate 1) how early-life conditions affect adolescent voluntary ethanol drinking, behavioural profiles, endogenous opioids and response to treatment with an opioid antagonist (naltrexone), and 2) whether alterations detected in the offspring may be mediated by variations in maternal behaviour. A rodent maternal separation (MS) model was used to mimic a protective and risk-inducing early-life environment, respectively, with the use of 15 min (MS15) or 360 min (MS360) of daily MS. The main findings were 1) the MS360, but not the MS15 rats, responded to naltrexone following adolescent ethanol drinking; all adolescent rats had a high voluntary ethanol intake independent of early environmental conditions whereas in the adult groups the MS360, but not the MS15 rats, increased their ethanol intake and preference over time; adolescent ethanol exposure resulted in higher dynorphin levels in hippocampus and higher Met-enkephalin-Arg6Phe7 in the amygdala, independently of rearing conditions, 2) behavioural profiling using the multivariate concentric square field™ test showed: the young MS360 rats had increased risk assessment and risk taking behaviour compared to the young MS15 rats; the young MS15 rats increased, whereas the young MS360 rats decreased, their risk assessment and risk taking behaviour over time; differences in pup-retrieval strategies where the MS360 dams retrieved some pups into a safe area but as compared to MS15 rats they left more pups in a risk area; increased risk assessment behaviour in the MS360 dams immediately after weaning. Taken together, early-life environmental conditions alter adult but not adolescent drinking, the response to naltrexone, and behaviour in dams and offspring. Adolescent rats consumed more ethanol independent of rearing conditions and displayed increased opioid levels in brain areas related to cognition and addiction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 91 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 171
Keyword
Alcohol, intermittent ethanol access, maternal separation, multivariate concentric square field™ test, maternal behavior, ultrasonic vocalization, adolescent, neonatal handling
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Pharmacology
Identifiers
urn:nbn:se:uu:diva-198670 (URN)978-91-554-8678-5 (ISBN)
Public defence
2013-06-14, B22, BMC, Husargatan, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-05-24 Created: 2013-04-22 Last updated: 2014-04-23Bibliographically approved
2. Early Environment, Adolescent Alcohol Drinking and Neurobiological Responses to Drugs
Open this publication in new window or tab >>Early Environment, Adolescent Alcohol Drinking and Neurobiological Responses to Drugs
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genes and environment interact to determine an individual’s vulnerability or resilience to several psychiatric disorders, including alcohol use disorder (AUD). Alcohol use is often initiated during adolescence and early onset drinking is associated with increased risk for later AUD. Childhood and adolescence are periods of extensive brain maturation, which makes young individuals more susceptible to environmental influence. However, little is known about early environmental influence on reward pathways and behaviors involved in the development of AUD. Changes in the endogenous opioid and dopamine systems, as well as individual differences in risk behaviors are all believed to play important roles in the increased vulnerability seen after adverse early life events and early onset drinking. The overall aim of the thesis was therefore to investigate the influence of early environmental factors on adolescent alcohol intake, endogenous opioids, dopamine dynamics and alcohol-induced effects in rats to increase our knowledge of neurobiological factors underlying vulnerability to AUD. Furthermore, individual behavioral differences and their correlation to basal and drug-induced neurobiological responses in rats were also investigated. Animal models of different early environments, e.g. maternal separation and social vs. single housing, and adolescent alcohol consumption have been used to study effects on behavior, endogenous opioid peptides and dopamine dynamics. The results identified the amygdala and dorsal striatum as interesting brain regions in which endogenous opioids and dopamine, respectively, are impacted by early environmental factors. The amygdala and the dorsal striatum are both hypothesized to be involved in the shift from initial drug use to compulsive use and changes in these areas may be underlying environmentally increased vulnerability to AUD. Furthermore, behavioral phenotypes in relation to individual neurobiological responses were identified. High risk-taking behavior was associated with a more pronounced response to amphetamine, but the inherent dopamine response was instead associated with risk-assessment behavior. In conclusion, several brain regions of interest for future research were identified. Furthermore, the results contribute to increased understanding of factors involved in the development of vulnerability for AUD in adolescents and young adults.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 99 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 190
Keyword
adolescence, beta-endorphin, dopamine, dynorphin, endogenous opioids, enkephalin, high-speed chronoamperometry, housing conditions, maternal separation, multivariate concentric square field™ test, open field test, radioimmunoassay, voluntary alcohol intake, Wistar rats
National Category
Neurosciences Pharmacology and Toxicology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-229992 (URN)978-91-554-9011-9 (ISBN)
Public defence
2014-10-10, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-09-19 Created: 2014-08-18 Last updated: 2015-01-22

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