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Early Environment, Adolescent Alcohol Drinking and Neurobiological Responses to Drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction & Behaviour)
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 190
Keyword [en]
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
URN: urn:nbn:se:uu:diva-229992ISBN: 978-91-554-9011-9OAI: diva2:740329
Public defence
2014-10-10, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2014-09-19 Created: 2014-08-18 Last updated: 2015-01-22
List of papers
1. Effects of Rearing Conditions on Behaviour and Endogenous Opioids in Rats with Alcohol Access during Adolescence
Open this publication in new window or tab >>Effects of Rearing Conditions on Behaviour and Endogenous Opioids in Rats with Alcohol Access during Adolescence
2013 (English)In: PLoS ONE, 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.

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
urn:nbn:se:uu:diva-198667 (URN)10.1371/journal.pone.0076591 (DOI)000325434500075 ()
Available from: 2013-04-22 Created: 2013-04-22 Last updated: 2015-01-22Bibliographically approved
2. Dopamine Release Dynamics Change during Adolescence and after Voluntary Alcohol Intake
Open this publication in new window or tab >>Dopamine Release Dynamics Change during Adolescence and after Voluntary Alcohol Intake
2014 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 5, e96337- p.Article in journal (Refereed) Published
Abstract [en]

Adolescence is associated with high impulsivity and risk taking, making adolescent individuals more inclined to use drugs. Early drug use is correlated to increased risk for substance use disorders later in life but the neurobiological basis is unclear. The brain undergoes extensive development during adolescence and disturbances at this time are hypothesized to contribute to increased vulnerability. The transition from controlled to compulsive drug use and addiction involve long-lasting changes in neural networks including a shift from the nucleus accumbens, mediating acute reinforcing effects, to recruitment of the dorsal striatum and habit formation. This study aimed to test the hypothesis of increased dopamine release after a pharmacological challenge in adolescent rats. Potassium-evoked dopamine release and uptake was investigated using chronoamperometric dopamine recordings in combination with a challenge by amphetamine in early and late adolescent rats and in adult rats. In addition, the consequences of voluntary alcohol intake during adolescence on these effects were investigated. The data show a gradual increase of evoked dopamine release with age, supporting previous studies suggesting that the pool of releasable dopamine increases with age. In contrast, a gradual decrease in evoked release with age was seen in response to amphetamine, supporting a proportionally larger storage pool of dopamine in younger animals. Dopamine measures after voluntary alcohol intake resulted in lower release amplitudes in response to potassium-chloride, indicating that alcohol affects the releasable pool of dopamine and this may have implications for vulnerability to addiction and other psychiatric diagnoses involving dopamine in the dorsal striatum.

National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-227196 (URN)10.1371/journal.pone.0096337 (DOI)000335510600094 ()
Available from: 2014-06-26 Created: 2014-06-24 Last updated: 2015-01-22Bibliographically approved
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4. Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats
Open this publication in new window or tab >>Risk-assessment and risk-taking behavior predict potassium- and amphetamine-induced dopamine response in the dorsal striatum of rats
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2014 (English)In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, Vol. 8, 236- p.Article in journal (Refereed) Published
Abstract [en]

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

National Category
urn:nbn:se:uu:diva-229989 (URN)10.3389/fnbeh.2014.00236 (DOI)000339022400001 ()25076877 (PubMedID)
Available from: 2014-08-18 Created: 2014-08-18 Last updated: 2015-01-22Bibliographically approved

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