Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

Abstract

Significance Substance-use disorders damage individuals and communities, providing large societal costs. For stimulant-use disorders, there are no Food and Drug Administration-approved medications. Human genetic associations with common variants in the gene encoding the receptor-type protein tyrosine phosphatase D (PTPRD) make this cell-adhesion molecule/synaptic specifier gene an interesting target for new addiction therapeutic agents. We now report results of cocaine self-administration in heterozygous PTPRD-KO mice, discovery that 7-butoxy illudalic acid analog (7-BIA) inhibits PTPRD’s phosphatase with in vitro potency and specificity, and discovery that 7-BIA reduces cocaine reward in self-administration and conditioned place-preference models. PTPRD’s phosphatase is a target for antiaddiction medication development, and 7-BIA is a lead compound.