Chronic ethanol exposure decreases CB1 receptor function at GABAergic synapses in the rat central amygdala

    loading  Checking for direct PDF access through Ovid


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.

Central nucleus of the amygdala (CeA) GABAergic dysregulation is critical in the transition to ethanol dependence. While type 1 cannabinoid receptor (CB1) activation inhibits spontaneous CeA GABA release in naïve rats, CB1 activation was impaired after intermittent ethanol exposure. CB1 activation also blocks acute ethanol's effects, and CB1 antagonism revealed an endocannabinoid tone, but did not affect acute ethanol's effects. Thus, CB1 significantly influences CeA GABAergic transmission, revealing the CeA as particularly sensitive to alcohol-induced disruptions of CB1 signaling.

Related Topics

    loading  Loading Related Articles