The role of lymphocytic CD5 in the effects of ethanol on mesolimbic circuitry and ethanol consumption behavior.

Cluster of differentiation 5 (CD5) is a negative regulatory molecule that alters lymphocyte activation pathways and is expressed on the surface of T cells, a subset of B cells (B1 cells), and dendritic cells. CD5 expression is sensitive to ethanol (EtOH) exposure, as the number of CD5+ B cells is reduced during chronic EtOH use. Given the apparent sensitivity of these cells to chronic EtOH consumption and the role of some lymphocytes in regulating the development of inhibitory GABA synapses, we assessed the impact of a murine CD5 genetic knockout (CD5KO) on measures related to EtOH reward, sedation, and consumption. We identified a sex difference in baseline firing rate of VTA GABA neurons in wild type (WT) C57BL/6J mice that is absent in CD5KO mice. We also showed that VTA GABA neurons in CD5KO mice display resistance to GABA(A) receptor-mediated inhibition when compared to WT controls. CD5KO mice did not exhibit any genotypic changes to electrically-evoked DA release at baseline or when exposed to EtOH. The CD5KO mice were resistant to cocaine-induced increases in DA paired-pulse ratio, suggesting downregulation of the DA transporter (DAT), which was supported by reduced expression of DAT RNA in the NAc. Additionally, CD5KO mice showed lower baseline locomotor activity, resistance to the EtOH-mediated decrease in locomotor activity, and decreased time spent in the center of the chamber at low doses (0.5 - 2.0 g/kg) and resistance to EtOH-induced sedation at high doses (4.0 g/kg) than their WT counterparts. Importantly, CD5KO mice drank less EtOH compared with age-matched WT controls in a 24-hour access two-bottle-choice drinking paradigm. Together, these results suggest that CD5 plays a greater role in the acute effects of EtOH than previously understood, including how EtOH impacts mesolimbic DA reward circuitry.