title: Chronic alcohol exposure disrupts CB1regulation of GABAergic transmission in the rat basolateral amygdala.
abstract: The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse. The endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB1is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here, we investigated the potential disruption of eCB/CB1signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2-3 weeks intermittent ethanol. In the naïve rat BLA, the CB1agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity. This retrograde tonic eCB/CB1signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1system. In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms. Notably, CB1activation impaired ethanol's facilitation of GABAergic transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB1influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
authors.forename: Florence P
authors.initials: FP
authors.lastname: Varodayan
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Bajo
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.|Faculty of Health and Medical Sciences, University of Copenhagen (UCPH), Denmark.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Soni
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Luu
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Madamba
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Schweitzer
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
mesh_terms: D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D066272:Basolateral Nuclear Complex / Q000187:drug effects* / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000633:toxicity; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000187:drug effects*
chemical_list: D002492:Central Nervous System Depressants; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; D005680:gamma-Aminobutyric Acid
keywords: Basolateral amygdala; GABA; endocannabinoid (eCB); ethanol; type 1 cannabinoid receptor (CB1); whole cell recordings