Binge Alcohol Drinking Alters the Differential Control of Cholinergic Interneurons over Nucleus Accumbens Medium Spiny Neurons

Abstract

Striatal cholinergic interneurons (ChIs) play a central role in basal ganglia function by regulating associative learning and reward processing. Drug addiction, such as alcoholism, is often described to hijack the natural reward system. In the nucleus accumbens (NAc), a brain region that mediates rewarding properties of substance of abuse, ChIs regulate glutamatergic, dopaminergic, and GABAergic neurotransmission. However, it is unclear how ChIs orchestrate the control of these neurotransmitters to determine the excitability of medium spiny neurons (MSNs), the NAc output neurons that translate accumbens electrical activity into behavior. Combining ex vivo electrophysiology, fast scan cyclic voltammetry and optogenetics approaches, I have demonstrated that stimulating NAc ChIs decreases the spontaneous excitatory postsynaptic currents (sEPSCs) frequency of both D1- and D2-MSNs through different mechanisms. While this effect in D1-MSNs was mediated by dopamine, it resulted from a direct control of glutamate release by ChIs in D2-MSNs. Interestingly, after two weeks of binge alcohol drinking, the effect of ChI stimulation on glutamate release was reversed in D1-MSNs, while its effect on D2-MSNs remained unchanged. Finally, in vivo optogenetic stimulation of NAc ChIs significantly increased alcohol consumption compared to unstimulated mice, but failed to alter mouse locomotor activity and saccharine or water consumption. Together, these results identify ChIs as a key modulator of NAc circuit activity and as a potential therapeutic target for alcohol use disorder.