title: Striatal-enriched protein tyrosine phosphatase controls responses to aversive stimuli: implication for ethanol drinking.
abstract: The STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase whose dysregulation in expression and/or activity is associated with several neuropsychiatric disorders. We recently showed that long-term excessive consumption of ethanol induces a sustained inhibition of STEP activity in the dorsomedial striatum (DMS) of mice. We further showed that down-regulation of STEP expression in the DMS, and not in the adjacent dorsolateral striatum, increases ethanol intake, suggesting that the inactivation of STEP in the DMS contributes to the development of ethanol drinking behaviors. Here, we compared the consequence of global deletion of the STEP gene on voluntary ethanol intake to the consumption of an appetitive rewarding substance (saccharin) or an aversive solution (quinine or denatonium). Whereas saccharin intake was similar in STEP knockout (KO) and wild type (WT) littermate mice, the consumption of ethanol as well as quinine and denatonium was increased in STEP KO mice. These results suggested that the aversive taste of these substances was masked upon deletion of the STEP gene. We therefore hypothesized that STEP contributes to the physiological avoidance towards aversive stimuli. To further test this hypothesis, we measured the responses of STEP KO and WT mice to lithium-induced conditioned place aversion (CPA) and found that whereas WT mice developed lithium place aversion, STEP KO mice did not. In contrast, conditioned place preference (CPP) to ethanol was similar in both genotypes. Together, our results indicate that STEP contributes, at least in part, to the protection against the ingestion of aversive agents.
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Rémi
authors.initials: R
authors.lastname: Legastelois
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wegner
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lombroso
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D001348:Aversive Therapy; D003213:Conditioning, Psychological; D017353:Gene Deletion; D018021:Lithium Chloride; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D012439:Saccharin / Q000494:pharmacology
chemical_list: D000644:Quaternary Ammonium Compounds; D011803:Quinine; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse; D012439:Saccharin; D018021:Lithium Chloride