The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

Abstract

The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggest a role for the endocannabinoid (eCB) system in ethanol binging and dependence. We used the slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, prior superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA where the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol.

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

“…This indicates that CB1 receptors are tonically activated under such conditions, and blockade of CB1 receptor relieves the continuous CB1 receptor-mediated suppression of neurotransmitter. The extent of tonic CB1 receptor-mediated inhibition appears to be stronger on GABAergic than on glutamateric terminals and has been more frequently described on GABAergic terminals (Roberto et al, 2010;Slanina and Schweitzer, 2005). Consistent with this notion is the proposition that the CB1 receptor on glutamatergic terminals acts as a stout guard when excessive glutamate transmission occurs and CB1 receptor will consequently be activated and suppress glutamatergic transmission (Marsicano et al, 2003;Katona and Freund, 2008).…”

“…In vitro experiments revealed that the application of CB1 receptor antagonist can enhance inhibitory and excitatory postsynaptic potentials, depending on the type of synapse (Roberto et al, 2010;Slanina and Schweitzer, 2005). The CB1 receptor antagonists used in these studies (SR141716 and AM251) were shown to promote also inverse agonist actions.…”

Neurochemical and Neurostructural Plasticity in Alcoholism

“…43 Alcohol also modulates endocannabinoid signaling in the central nucleus of the amygdala (CeA), another region implicated in alcohol dependence. 44 Consistent with the notion of alcohol-induced increases in endocannabinoid transmission, various studies have shown that chronic alcohol exposure down-regulates levels of CB 1 receptors well as desensitizes cannabinoid-activated signal transduction various brain regions. 45,46 Pharmacological evidence also suggests that the endocannabinoid system regulates alcohol intake, as numerous studies have shown that CB 1 receptor activation increases alcohol consumption in rodents, whereas CB 1 receptor antagonism or genetic deletion decreases alcohol consumption and/or preference.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…More recently, ethanol-induced increase in firing rates of subpopulations of CeA neurons has been shown to be mediated by CRF 1 receptors and tonic GABA currents, with the network effect being increased output neuron activity to the BNST (Herman et al, 2013), a brain region involved in sustained anxiety and relapse. Furthermore, the ethanol-induced increase in GABA release and IPSC amplitudes in the CeA slices can be blocked by activation of presynaptic CB 1 receptors (Roberto et al, 2010a), demonstrating multiple presynaptic mechanisms being involved in ethanol modulation of amygdala activity.…”