Inhibition of RPTPβ/ζ blocks ethanol-induced conditioned place preference in pleiotrophin knockout mice

Abstract

Pleiotrophin (PTN) and Midkine (MK) are neurotrophic factors that are upregulated in the prefrontal cortex after alcohol administration and have been shown to reduce ethanol drinking and reward. PTN and MK are endogenous inhibitors of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. Interestingly, pharmacological inhibition of RPTPβ/ζ reduces ethanol consumption and blocks ethanol-induced conditioned place preference (CPP) in wild type mice. Since PTN-knockout (Ptn^-/-) mice are more sensitive to the conditioning effects of alcohol, we aimed to test the effects of MY10, a small-molecule inhibitor of RPTPβ/ζ, on ethanol-induced CPP in Ptn^-/- mice. The data presented here demonstrate for the first time that a regular dose of MY10, known to block ethanol consumption and reward in wild type mice, also blocks the rewarding effects of ethanol in the more vulnerable individuals lacking PTN, the endogenous inhibitor of RPTPβ/ζ. In addition, since MY10 readily penetrates the blood brain barrier (BBB), we tested its effects in a series of behavioural tests in Ptn^+/+ and Ptn^-/- mice. The data indicate that MY10 does not cause gross behavioural effects in wild type mice. However, MY10 tended to induce anxiolytic effects in Ptn^-/- mice in the elevated plus maze paradigm. Overall, the data indicate that MY10 rescues Ptn^-/- mice from their increased susceptibility to the conditioning effects of ethanol and may induce anxiolytic effects in individuals with reduced or absent PTN functions. Further studies are needed to confirm the potential of pharmacological inhibition of RPTPβ/ζ as a new therapeutic strategy in the treatment of anxiety-related disorders.

Keywords: ALK; Addiction; Alcohol; Conditioned place preference; Fyn; Midkine; Pleiotrophin.