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Individual differences in behavior, neurochemistry and pharmacology associated with voluntary alcohol intake
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University. (Neuropharmacology, Addiction and Behavior)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alcohol use disorder is a worldwide public health problem and is a disorder with substantial individual variation. There are suggested links between various behavioral traits, comorbid psychiatric diseases and excessive alcohol consumption. Moreover, the endogenous opioid system is involved in alcohol reward and reinforcement, and implicated in the action of alcohol. However, less is known about the complex associations between individual differences in behavior, alcohol consumption, pharmacotherapy response and related neurochemical mechanisms. Experimental animal models are critical for understanding the neurobiological underpinnings of alcohol use disorder.

The overall aims of this thesis were: i) to study the association between behavior and voluntary alcohol intake in outbred rats; ii) to study the association of voluntary alcohol intake, behavior, opioid receptor density and response to naltrexone; and iii) to obtain detailed behavioral characterizations of the animals on the basis of their voluntary alcohol intake.

The results revealed that the multivariate concentric square fieldTM (MCSF) test was a complementary method for understanding mechanisms underlying various mental states. The MCSF broadened the perspective on risk-related behaviors, including aspects of risk assessment. Individual differences in alcohol intake using the modified intermittent access paradigm enabled analyses of drinking patterns in high and low alcohol-drinking rats. There was an alcohol deprivation effect in high-drinking animals only. The behavior profiling of high alcohol drinking- rats before and after alcohol access suggested that this subgroup was consuming alcohol for its anxiolytic properties. Long-lasting changes were found in the mu and the delta opioid receptors after long-term, intermittent voluntary alcohol intake; some of these changes are in line with findings in humans. The voluntary alcohol consumption and the concomitant response to naltrexone were different for Wistar rats from different suppliers. Moreover, the Rcc Wistar rats may be more suitable for studies of alcohol use disorders due to increasing alcohol intake and the presence of a high-drinking subpopulation with increasing alcohol intake over time. The high-drinking subpopulation showed pronounced effects of naltrexone on alcohol intake.

In conclusion, studies of individual differences increase understanding of variability in behavior, pharmacotherapy response and factors involved in vulnerability of alcohol use disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 205
Keyword [en]
intermittent access, multivariate concentric square field, open field, risk assessment, risk taking, individual difference, behavior, strain variation, endogenous opioid system, naltrexone
National Category
Basic Medicine
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-264584ISBN: 978-91-554-9378-3 (print)OAI: oai:DiVA.org:uu-264584DiVA: diva2:861042
Public defence
2015-12-04, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-11-12 Created: 2015-10-15 Last updated: 2015-11-13
List of papers
1. Individual differences in risk-related behaviors and voluntary alcohol intake in outbred Wistar rats
Open this publication in new window or tab >>Individual differences in risk-related behaviors and voluntary alcohol intake in outbred Wistar rats
2014 (English)In: Behavioural Pharmacology, ISSN 0955-8810, E-ISSN 1473-5849, Vol. 25, no 3, 206-215 p.Article in journal (Refereed) Published
Abstract [en]

Some personality traits and comorbid psychiatric diseases are linked to a propensity for excessive alcohol drinking. The objective of this study was to investigate the association between individual differences in risk-related behaviors, voluntary alcohol intake and preference. Outbred male Wistar rats were tested in a novel open field, followed by assessment of behavioral profiles using the multivariate concentric square field (MCSF) test. Animals were classified into high risk taking and low risk taking on the basis of open-field behavior and into high risk-assessing (HRA) and low risk-assessing (LRA) on the basis of the MCSF profile. Finally, voluntary alcohol intake was investigated using intermittent access to 20% ethanol and water for 5 weeks. Only minor differences in voluntary alcohol intake were found between high risk taking and low risk taking. Differences between HRA and LRA rats were more evident, with higher intake and increased intake over time in HRA relative to LRA rats. Thus, individual differences in risk-assessment behavior showed greater differences in voluntary alcohol intake than risk taking. The findings may relate to human constructs of decision-making and risk taking associated with a predisposition to rewarding and addictive behaviors. Further studies are needed to clarify the relationship between risk-related behaviors, including risk-assessment behavior, and liability for excessive alcohol intake.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-224079 (URN)10.1097/FBP.0000000000000036 (DOI)000335578800003 ()24776488 (PubMedID)
Available from: 2014-05-02 Created: 2014-05-02 Last updated: 2017-12-05Bibliographically approved
2. Subgroup-dependent effects of voluntary alcohol intake on behavioral profiles in outbred Wistar rats
Open this publication in new window or tab >>Subgroup-dependent effects of voluntary alcohol intake on behavioral profiles in outbred Wistar rats
2014 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 275, 288-296 p.Article in journal (Refereed) Published
Abstract [en]

Experimental animal models are critical for understanding the genetic, environmental and neurobiological underpinnings of alcohol use disorders. Limited studies investigate alcohol-induced effects on behavior using free-choice paradigms. The aims of the present experiment were to study voluntary alcohol intake using a modified intermittent access paradigm, investigate the effects of voluntary alcohol intake on behavioral profiles in water- and alcohol-drinking rats, and select extreme low- and high-drinking animals for a more detailed behavioral characterization. Sixty outbred male Wistar rats were randomized into water and alcohol groups. Behavioral profiles in the multivariate concentric square field (TM) (MCSF) test were assessed prior to and after voluntary alcohol intake. The animals had intermittent access to 20% alcohol and water for three consecutive days per week for seven weeks. The results revealed increased alcohol intake over time. No major alcohol-induced differences on behavior profiles were found when comparing water- and alcohol-drinking animals. The high-drinking animals displayed an alcohol deprivation effect, which was not found in the low-drinking animals. High-drinking rats had lower risk-taking behavior prior to alcohol access and lower anxiety-like behavior after voluntary alcohol intake compared to low-drinking rats. In conclusion, the modified intermittent access paradigm may be useful for pharmacological manipulation of alcohol intake. With regard to behavior, the present findings highlights the importance of studying subgroup-dependent differences and add to the complexity of individual differences in behavioral traits of relevance to the vulnerability for excessive alcohol intake.

Keyword
Anxiety, Alcohol, Multivariate concentric square field (MCSF), Intermittent access, Individual difference, Alcohol deprivation effect
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-238391 (URN)10.1016/j.bbr.2014.08.058 (DOI)000344431100037 ()25200519 (PubMedID)
Available from: 2014-12-22 Created: 2014-12-12 Last updated: 2017-12-05Bibliographically approved
3. Intermittent voluntary alcohol intake and long-term modulation of brain 3H-DAMGO and 3H-DPDPE binding in outbred Wistar rats
Open this publication in new window or tab >>Intermittent voluntary alcohol intake and long-term modulation of brain 3H-DAMGO and 3H-DPDPE binding in outbred Wistar rats
(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-264581 (URN)
Available from: 2015-10-15 Created: 2015-10-15 Last updated: 2015-11-13
4. Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats
Open this publication in new window or tab >>Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats
2015 (English)In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 9, 424Article in journal (Refereed) Published
Abstract [en]

Alcohol use disorder (AUD) is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHan™:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI) were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for 6 weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over 4 weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHan™:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier-dependent differences in the effect of naltrexone that were dose- and time-dependent; evident differences in high-drinking RccHan™:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHan™:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to naltrexone and further highlight the inherent heterogeneity of the Wistar strain. The overall results put focus on the importance of thoroughly considering the animals used to aid in study design and for comparison of reported results.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-264582 (URN)10.3389/fnins.2015.00424 (DOI)000366717200001 ()26594143 (PubMedID)
Available from: 2015-10-15 Created: 2015-10-15 Last updated: 2017-12-01Bibliographically approved

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