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Activation of GABA(B) receptors in central amygdala attenuates activity of PKC delta plus neurons and suppresses punishment-resistant alcohol self-administration in rats
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Univ Camerino, Italy.ORCID iD: 0000-0001-5726-4814
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-5029-341x
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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. Vol. 48, p. 1386-1395
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Neurosciences
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URN: urn:nbn:se:liu:diva-191971DOI: 10.1038/s41386-023-01543-1ISI: 000926088900001PubMedID: 36739350OAI: oai:DiVA.org:liu-191971DiVA, id: diva2:1739949
Available from: 2023-02-28 Created: 2023-02-28 Last updated: 2024-03-05Bibliographically approved

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Wiskerke, JoostCoppola, AndreaHolm, LovisaAugier, EricHeilig, Markus

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Domi, EsiXu, LiToivainen Eloff, SanneWiskerke, JoostCoppola, AndreaHolm, LovisaAugier, EricPetrella, MicheleHeilig, Markus
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Center for Social and Affective NeuroscienceFaculty of Medicine and Health SciencesPsykiatriska kliniken i LinköpingCenter for Medical Image Science and Visualization (CMIV)
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