Synaptic encoding of in vivo ethanol experience in the nucleus accumbens

The nucleus accumbens (NAc) is a critical component of the brain reward system and neuroadaptations in the NAc are thought to underlie the development and persistence of addiction. The NAc is composed of two subregions, the core and shell, in which medium spiny neurons (MSNs) are the primary cell type. There are two distinct subtypes of MSNs in the NAc depending on the dopamine receptor expression: D1 dopamine receptor expressing (D1+) MSNs and D2 dopamine receptor expressing MSNs (D1-). We conducted whole-cell patch clamp recordings using transgenic mice to selectively record from D1+ and D1- MSNs in the NAc and found that chronic intermittent ethanol (CIE) vapor exposure resulted in cell type specific alterations in the intrinsic properties and expression of plasticity. To detect changes in plasticity of AMPA receptor (AMPAR) mediated currents we used a well described form of NMDAR-dependent long-term depression (LTD) that is induced by pairing low frequency stimulation with postsynaptic depolarization. Similar to previous findings from our lab we found that LTD was expressed exclusively in D1+ MSNs of ethanol naïve mice. In slices prepared from CIE treated mice, the induction protocol instead resulted in long-term potentiation (LTP) in D1+ MSNs. The expression of LTP in D1+ MSNs was accompanied by an increase in excitability as well as an increase in the frequency of spontaneous EPSCs. Interestingly, CIE exposure uncovered the expression of LTD in D1- MSNs. To further our understanding as to how these neuroadaptations contribute to maladaptive ethanol drinking behaviors we used CIE vapor exposure to induce an increase in voluntary ethanol consumption. Electrophysiological experiments were conducted in the core and shell to determine if excitatory signaling and plasticity is differentially modulated between the two subregions. CIE induced an increase in ethanol drinking and resulted in the long-lasting disruption of LTD in D1+ MSNs of the NAc shell with no changes in the core. In addition we found that AMPAR conductance was significantly reduced at positive holding potentials suggesting the presence of GluA2-lacking AMPARs. These findings may constitute important neuroadaptations that underlie alcohol dependence and excessive alcohol consumption.