Chronic alcohol exposure disrupts CB₁ regulation 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 CB1 activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here we investigated the potential disruption of eCB/CB1 signaling on GABAergic transmission in BLA pyramidal neurons of rats exposed to 2–3 weeks intermittent ethanol. In the naïve rat BLA, the CB1 agonist WIN 55,212-2 (WIN) decreased GABA release and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity. This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system. In contrast, acute ethanol increased GABAergic transmission similarly in naïve and chronic ethanol exposed rats, via both pre- and postsynaptic mechanisms. Notably, CB1 activation impaired ethanol’s facilitation of GABAergic transmission across both groups, but the AM251- and ethanol-induced facilitation of GABA release were additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic transmission that is dysregulated by chronic ethanol exposure and thus, may contribute to the alcohol dependent state.

P/Q-type voltage-gated calcium channels mediate the ethanol and CRF sensitivity of central amygdala GABAergic synapses

“…Other G protein-coupled receptors (GPCRs) have also been implicated in alcohol-induced CeA GABA release, including the type 1 cannabinoid receptor (CB 1 ) (Roberto et al, 2010a; Varodayan et al, 2016), δ-opioid receptor (Kang-Park et al, 2009) and neuropeptide Y receptor (Gilpin et al, 2011). Additionally, CB 1 and GABA B receptors mediate alcohol’s potentiation of GABA release in the BLA and cerebellum (Kelm et al, 2011; Talani and Lovinger, 2015; Varodayan et al, 2017a), while in the VTA, μ-opioid and 5HT-2C receptors are involved (Theile et al, 2009). Therefore, alcohol’s actions on CeA GABA release via CRF 1 do not occur in isolation, and future studies must identify which alcohol-induced GPCR pathways interact and predominate, and whether they are dysregulated after chronic ethanol exposure.…”

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

“…Furthermore, CIE in rats has been shown to inhibit retrograde tonic eCB/CB 1 signalling in the BLA. However, acute alcohol exposure enhances GABAergic transmission equally in naïve and chronic alcohol‐exposed rats through both presynaptic and postsynaptic mechanisms (Varodayan et al, ). Together, these findings demonstrate the dynamic regulation of the CeA and BLA eCB systems by acute and chronic alcohol exposure.…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…Chronic non-contingent alcohol exposure has been shown to eliminate eCB-dependent LTD at corticostriatal synapses in rodents (Xia et al, 2006; DePoy et al, 2013), and similar effects were observed following alcohol drinking (Adermark et al, 2011). Inhibition of GABAergic synapses by CB1 is also decreased following chronic ethanol exposure in both BLA and CeA (Varodayan et al, 2016a,b). A single in vivo exposure to cocaine also eliminates eCB-dependent LTD in the NAc (Fourgeaud et al, 2004), and effects of cocaine self-administration on glutamatergic synapses in the NAc shell involves an eCB-mediated mechanism (Ortinski et al, 2012).…”