Ethanol Experience Enhances Glutamatergic Ventral Hippocampal Inputs to D1 Receptor-Expressing Medium Spiny Neurons in the Nucleus Accumbens Shell.

A growing number of studies implicate alterations in glutamatergic signaling within the reward circuitry of the brain during alcohol abuse and dependence. A key integrator of glutamatergic signaling in the reward circuit is the nucleus accumbens, more specifically, the dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) within this region, which have been implicated in the formation of dependence to many drugs of abuse including alcohol. D1-MSNs receive glutamatergic input from several brain regions; however, it is not currently known how individual inputs onto D1-MSNs are altered by alcohol experience. Here, we investigate input-specific adaptations in glutamatergic transmission in response to varying levels of alcohol experience. Virally mediated expression of Channelrhodopsin in ventral hippocampal (vHipp) glutamate neurons of male mice allowed for selective activation of vHipp to D1-MSN synapses. Therefore, we were able to compare synaptic adaptations in response to low and high alcohol experience in vitro and in vivo Alcohol experience enhanced glutamatergic activity and abolished LTD at vHipp to D1-MSN synapses. Following chronic alcohol experience, GluA2-lacking AMPARs, which are Ca permeable, were inserted into vHipp to D1-MSN synapses. These findings support the reversal of alcohol-induced insertion of Ca-permeable AMPARs and the enhancement of glutamatergic activity at vHipp to D1-MSNs as potential targets for intervention during early exposure to alcohol.SIGNIFICANCE STATEMENT Given the roles of the nucleus accumbens (NAc) in integrating cortical and allocortical information and in reward learning, it is vital to understand how inputs to this region are altered by drugs of abuse such as alcohol. The strength of excitatory inputs from the ventral hippocampus (vHipp) to the NAc has been positively associated with reward-related behaviors, but it is unclear whether or how ethanol affects these inputs. Here we show that vHipp-NAc synapses indeed are altered by ethanol exposure, with vHipp glutamatergic input to the NAc being enhanced following chronic ethanol experience. This work provides insight into ethanol-induced alterations of vHipp-NAc synapses and suggests that, similarly to drugs such as cocaine, the strengthening of these synapses promotes reward behavior.