Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala.
The endogenous cannabinoids (eCBs) influence the acute response to ethanol and the development of tolerance, dependence and relapse. Chronic alcohol exposure alters eCB levels and Type 1 cannabinoid receptor (CB1 ) expression and function in brain regions associated with addiction. CB1 inhibits GABA release, and GABAergic dysregulation in the central nucleus of the amygdala (CeA) is critical in the transition to alcohol dependence. We investigated possible disruptions in CB1 signaling of rat CeA GABAergic transmission following intermittent ethanol exposure. In the CeA of alcohol-naive rats, CB1 agonist WIN 55,212-2 (WIN) decreased the frequency of spontaneous and miniature GABAA receptor-mediated inhibitory postsynaptic currents (s/mIPSCs). This effect was prevented by CB1 antagonism, but not Type 2 cannabinoid receptor (CB2 ) antagonism. After 2-3 weeks of intermittent ethanol exposure, these WIN inhibitory effects were attenuated, suggesting ethanol-induced impairments in CB1 function. The CB1 antagonist AM251 revealed a tonic eCB/CB1 control of GABAergic transmission in the alcohol-naive CeA that was occluded by calcium chelation in the postsynaptic cell. Chronic ethanol exposure abolished this tonic CB1 influence on mIPSC, but not sIPSC, frequency. Finally, acute ethanol increased CeA GABA release in both naive and ethanol-exposed rats. Although CB1 activation prevented this effect, the AM251- and ethanol-induced GABA release were additive, ruling out a direct participation of CB1 signaling in the ethanol effect. Collectively, these observations demonstrate an important CB1 influence on CeA GABAergic transmission and indicate that the CeA is particularly sensitive to alcohol-induced disruptions of CB1 signaling.
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
Florence P
FP
Varodayan
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.
Neeraj
N
Soni
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
Michal
M
Bajo
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
George
G
Luu
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
Samuel G
SG
Madamba
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
Paul
P
Schweitzer
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
Loren H
LH
Parsons
Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute (TSRI), La Jolla, CA, USA.
Marisa
M
Roberto
D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects* / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects
D002492:Central Nervous System Depressants; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D000431:Ethanol
Alcohol; GABA; amygdala; cannabinoid; endocannabinoid CB1 receptor