Inhibition of RPTP?/? reduces chronic ethanol intake in adolescent mice and modulates ethanol effects on hippocampal neurogenesis and glial responses in a sex-dependent manner

Pleiotrophin (PTN) is a cytokine that modulates ethanol drinking and reward and regulates glial responses in different contexts. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) beta/zeta. Inhibition of RPTP beta/zeta reduces binge-like drinking in adult male mice. Whether inhibition of RPTP beta/zeta is effective in reducing ethanol consumption during adolescence and in both sexes remained to be studied. In this work, male and female adolescent mice underwent an intermittent access to ethanol (IAE) 2-bottle choice protocol. Treatment with MY10 (60 mg/kg, i.g.), a small-molecule RPTP beta/zeta inhibitor, reduced chronic 3-week ethanol consumption only in male mice. We detected an ethanol-induced overall decrease in hippocampal GFAPir and Iba1ir, indepen-dently of the treatment received, suggesting that RPTP beta/zeta is not key in the regulation of IAE-induced glial re-sponses. However, we found a significant negative correlation between the size of microglial cells and the number of hippocampal neuronal progenitors only in male mice after IAE. This correlation was disrupted by treatment with MY10 before each drinking session, which may be related to the ability of MY10 to regulate the intensity of the perineuronal nets (PNNs) in the hippocampus in a sex-dependent manner. The data show for the first time that inhibition of RPTP beta/zeta reduces chronic voluntary ethanol consumption in adolescent mice in a sex-dependent manner. In addition, we show evidence for sex-specific differences in the effects of IAE on glial re-sponses and hippocampal neurogenesis, which may be related to different actions of the RPTP beta/zeta signalling pathway in the brains of male and female mice.