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Early Environment and Adolescent Ethanol Consumption : Effects on Endogenous Opioids and Behaviour in Rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction and Behaviour)
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 [en]
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: urn:nbn:se:uu:diva-198670ISBN: 978-91-554-8678-5 (print)OAI: oai:DiVA.org:uu-198670DiVA: diva2:618007
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
List of papers
1. Early Environmental Factors Differentially Affect Voluntary Ethanol Consumption in Adolescent and Adult Male Rats
Open this publication in new window or tab >>Early Environmental Factors Differentially Affect Voluntary Ethanol Consumption in Adolescent and Adult Male Rats
2011 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 35, no 3, 506-515 p.Article in journal (Refereed) Published
Abstract [en]

Background: Previous studies using the maternal separation (MS) model have shown that environmental factors early in life affect adult ethanol consumption. Prolonged MS is related to enhanced propensity for high adult ethanol intake when compared to short MS. Less is known about the environmental impact on adolescent ethanol intake. In this study, the aim was to compare establishment of voluntary ethanol consumption in adolescent and adult rats subjected to different rearing conditions. Methods: Wistar rat pups were separated from their mother 0 minutes (MS0), 15 minutes (MS15), or 360 minutes (MS360) daily during postnatal days (PNDs) 1 to 20. After weaning, the male rats were divided into two groups; rats were given free access to water, 5 and 20% ethanol at either PND 26 or 68. Ethanol was provided in 24-hour sessions three times per week for 5 weeks. Results: MS resulted in altered ethanol consumption patterns around the pubertal period but otherwise the rearing conditions had little impact on ethanol consumption in adolescents. In adults, the establishment of ethanol consumption was dependent on the rearing condition. The adult MS0 and MS15 rats had a stable ethanol intake, whereas the MS360 rats increased both their ethanol intake and preference over time. Conclusions: With the use of intermittent access to ethanol, new data were provided, which confirm the notion that MS360 represents a risk environment related to higher ethanol intake compared to MS15. The adolescent rats had higher ethanol intake than adult rats but the consumption was independent of rearing condition. Experiences during the first three postnatal weeks thus affect the establishment of voluntary ethanol consumption differently in adolescent and adult rats. Further studies are now warranted to examine the consequences of a combination of early environmental influence and high adolescent ethanol intake.

Keyword
Maternal Separation, Intermittent Access, Alcohol, Risk Factor, Protective Factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-149788 (URN)10.1111/j.1530-0277.2010.01367.x (DOI)000288143100014 ()21143247 (PubMedID)
Available from: 2011-03-23 Created: 2011-03-23 Last updated: 2017-12-11
2. 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, 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.

Keyword
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:nbn:se:uu:diva-198667 (URN)10.1371/journal.pone.0076591 (DOI)000325434500075 ()
Available from: 2013-04-22 Created: 2013-04-22 Last updated: 2017-12-06Bibliographically approved
3. The response to naltrexone in ethanol-drinking rats depends on early environmental experiences
Open this publication in new window or tab >>The response to naltrexone in ethanol-drinking rats depends on early environmental experiences
2011 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 99, no 4, 626-633 p.Article in journal (Refereed) Published
Abstract [en]

The opioid receptor antagonist naltrexone is currently used in the treatment of alcohol addiction. However, substantial individual differences have been reported for the efficacy of naltrexone. Genetic factors are known to contribute to these differences; however, little is known about the impact of early environmental influences. Based on previous findings that have suggested a link between ethanol, endogenous opioids and the early environment, it was hypothesised that early environmental factors affect naltrexone efficacy later in life. A population of Wistar rats was subjected to three different rearing conditions where the pups experienced a daily separation from the dam, for either 15 min or 360 min, or were just briefly handled. On postnatal day 26, the rats were given intermittent access to ethanol (5% and 20%) and water for six weeks before naltrexone (0.3mg/kg or 3.0mg/kg) or saline treatment using a randomised injection schedule with a one-week washout period between injections. Naltrexone reduced ethanol consumption, but there was high variability in the efficacy. In addition, there was an association between the rearing condition and the effectiveness of naltrexone. Naltrexone reduced ethanol intake in rats experiencing postnatal conditions that contrasted normal wildlife conditions, i.e., prolonged absence or continuous presence of the dam, and naltrexone had no effect on the total ethanol consumption in rats reared under naturalistic conditions, i.e., short absences of the dam. These rats reduced their intake of 5% ethanol but increased their preference for 20% ethanol. We conclude that rats with a history of early adversity responded well to naltrexone treatment, whereas rats reared in a social context similar to that found in nature did not benefit from treatment. The present study highlights the importance of not only considering genetics but also environmental factors when identifying individual responses to naltrexone.

Keyword
Individual variability, Alcohol, Maternal separation, Ethanol intake, Volountary drinking, Rearing environment
National Category
Neurosciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-159550 (URN)10.1016/j.pbb.2011.06.004 (DOI)000294880100015 ()21689677 (PubMedID)
Available from: 2011-10-04 Created: 2011-10-04 Last updated: 2017-12-08
4. Postpartum Behavioral Profiles in Wistar Rats Following Maternal Separation: Altered Exploration and Risk-Assessment Behavior in MS15 Dams
Open this publication in new window or tab >>Postpartum Behavioral Profiles in Wistar Rats Following Maternal Separation: Altered Exploration and Risk-Assessment Behavior in MS15 Dams
Show others...
2010 (English)In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 4, 37Article in journal (Refereed) Published
Abstract [en]

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

Keyword
handling, maternal deprivation, animal facility rearing, non-handling, stress, multivariate concentric square field™ test, principal component analysis, trend analysis
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-133566 (URN)10.3389/fnbeh.2010.00037 (DOI)000208454700039 ()20617189 (PubMedID)
Available from: 2010-11-11 Created: 2010-11-11 Last updated: 2017-12-12Bibliographically approved
5. Qualitative differences in pup-retrieval strategies in a maternal separation paradigm
Open this publication in new window or tab >>Qualitative differences in pup-retrieval strategies in a maternal separation paradigm
2013 (English)In: Journal of Behavioral and Brain Science, ISSN 2160-5866, E-ISSN 2160-5874, Vol. 3, 603-616 p.Article in journal (Refereed) Published
Abstract [en]

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

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-214125 (URN)10.4236/jbbs.2013.38064 (DOI)
Available from: 2014-01-07 Created: 2014-01-07 Last updated: 2017-12-06Bibliographically approved

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