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Domi, E., Xu, L., Toivainen Eloff, S., Wiskerke, J., Coppola, A., Holm, L., . . . Heilig, M. (2023). Activation of GABA(B) receptors in central amygdala attenuates activity of PKC delta plus neurons and suppresses punishment-resistant alcohol self-administration in rats. Neuropsychopharmacology, 48, 1386-1395
Open this publication in new window or tab >>Activation of GABA(B) receptors in central amygdala attenuates activity of PKC delta plus neurons and suppresses punishment-resistant alcohol self-administration in rats
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2023 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, p. 1386-1395Article in journal (Refereed) Published
Abstract [en]

Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKC delta + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABA(B) receptors in CeA can attenuate the activity of PKC delta + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABA(B) agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 mu l/side) reduced the activity of PKC delta + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKC delta + neurons express the GABA(B) receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABA(B) receptors, and that lack these limitations, such as e.g., GABA(B) positive allosteric modulators (PAM:s).

Place, publisher, year, edition, pages
SPRINGERNATURE, 2023
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-191971 (URN)10.1038/s41386-023-01543-1 (DOI)000926088900001 ()36739350 (PubMedID)
Available from: 2023-02-28 Created: 2023-02-28 Last updated: 2024-03-05Bibliographically approved
Lguensat, A., Coppola, A. & Augier, E. (2023). Animal Models Used to Study Alcohol Use Disorder. In: Sebastian Mueller, Markus Heilig (Ed.), Alcohol and Alcohol-related Diseases: (pp. 665-685). Cham: Springer Nature
Open this publication in new window or tab >>Animal Models Used to Study Alcohol Use Disorder
2023 (English)In: Alcohol and Alcohol-related Diseases / [ed] Sebastian Mueller, Markus Heilig, Cham: Springer Nature, 2023, p. 665-685Chapter in book (Refereed)
Abstract [en]

For ethical and technical reasons, research in humans has some limitations and requires the support of animal models. Numerous animal models have been developed over the years to study alcohol consumption and model alcohol-related behaviors in several species, including non-human primates, rodents and more recently zebrafish, fruit flies and C. elegans. In this chapter, we provide an overview of the most commonly used animal models of alcohol use disorder (AUD) and discuss their pros and cons. We classify animal models of AUD into two main categories, operant and non-operant paradigms, which covers behavioral procedures developed to model several aspects of human addiction, including primary alcohol reinforcement, physical dependence, loss of control over alcohol intake, progressive choice of alcohol over healthy rewards and relapse. Finally, we will conclude and discuss about other important aspects of human addiction, including interindividual differences, sex differences and social factors, that need to be incorporated into preclinical models of AUD to improve their translational value.

Place, publisher, year, edition, pages
Cham: Springer Nature, 2023
Keywords
Alcohol use disorder, Animals, Preclinical models, Behavior, Reward, Motivation, Choice
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-200560 (URN)10.1007/978-3-031-32483-3_35 (DOI)9783031324826 (ISBN)
Available from: 2024-01-30 Created: 2024-01-30 Last updated: 2024-02-29Bibliographically approved
Augier, G., Schwabl, V., Lguensat, A., Atudorei, M., Iyere, O., Eriksson Solander, S. & Augier, E. (2023). Wistar rats choose alcohol over social interaction in a discrete-choice model. Neuropsychopharmacology, 48, 1098-1107
Open this publication in new window or tab >>Wistar rats choose alcohol over social interaction in a discrete-choice model
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2023 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 48, p. 1098-1107Article in journal (Refereed) Published
Abstract [en]

Animal models of substance use disorders have been criticized for their limited translation. One important factor behind seeking and taking that has so far been largely overlooked is the availability of alternative non-drug rewards. We recently reported that only about 15% of outbred Wistar rats will choose alcohol over a sweet solution of saccharin. It was also shown using a novel operant model of choice of drugs over social rewards that social interaction consistently attenuates self-administration and incubation of craving for stimulants and opioids. Whether this is also true for alcohol and choice of alcohol over a sweet reward translates to social rewards is currently unknown. We therefore evaluated choice between alcohol and a social reward in different experimental settings in both male and female Wistar rats. We found, in contrast to prior work that employed discrete choice of drugs vs. social reward, that rats almost exclusively prefer alcohol over social interaction, irrespective of the nature of the social partner (cagemate vs. novel rat), the length of interaction, housing conditions and sex. Alcohol choice was reduced when the response requirement for alcohol was increased. However, rats persisted in choosing alcohol, even when the effort required to obtain it was 10-16 times higher (for females and males respectively) than the one for the social reward. Altogether, these results indicate that the social choice model may not generalize to alcohol, pointing to the possibility that specific interactions between alcohol and social reward, not seen when a sweet solution is used as an alternative to the drug, may play a crucial role in alcohol vs. social choice experiments.

Place, publisher, year, edition, pages
SPRINGERNATURE, 2023
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-191030 (URN)10.1038/s41386-022-01526-8 (DOI)000906306600001 ()36587185 (PubMedID)
Note

Funding Agencies|Swedish Research Council, VR; Linkoeping University [2018-02320]

Available from: 2023-01-16 Created: 2023-01-16 Last updated: 2024-02-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5615-2973

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