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

Hot Off the Press – October 25, 2018.

There are currently no effective medications available for the treatment of psychostimulant addiction. Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule that has been associated with psychostimulant addiction in humans. In this research, we found that PTPRD gene mutation significantly reduced vulnerability to cocaine in animal models of addiction and identified a novel compound – a selective PTPRD inhibitor, that appears promising in treatment of cocaine addiction in mice.

Publication Information

Uhl, George R; Martinez, Maria J; Paik, Paul; Sulima, Agnieszka; Bi, Guo-Hua; Iyer, Malliga R; Gardner, Eliot; Rice, Kenner C; Xi, Zheng-Xiong

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

In: Proc Natl Acad Sci U S A, 2018, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking).

Abstract | Links

@article{Uhl:2018aa,

title = {Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist.},

author = {George R Uhl and Maria J Martinez and Paul Paik and Agnieszka Sulima and Guo-Hua Bi and Malliga R Iyer and Eliot Gardner and Kenner C Rice and Zheng-Xiong Xi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30348770},

doi = {10.1073/pnas.1720446115},

issn = {1091-6490 (Electronic); 0027-8424 (Linking)},

year  = {2018},

date = {2018-10-22},

urldate = {2018-10-22},

journal = {Proc Natl Acad Sci U S A},

address = {Neurology and Research Services, New Mexico VA Healthcare System, Albuquerque, NM 87108; George.Uhl@va.gov.},

abstract = {Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule/synaptic specifier that has been implicated in addiction vulnerability and stimulant reward by human genomewide association and mouse cocaine-conditioned place-preference data. However, there have been no reports of effects of reduced expression on cocaine self-administration. There have been no reports of PTPRD targeting by any small molecule. There are no data about behavioral effects of any PTPRD ligand. We now report (i) robust effects of heterozygous PTPRD KO on cocaine self-administration (These data substantially extend prior conditioned place-preference data and add to the rationale for PTPRD as a target for addiction therapeutics.); (ii) identification of 7-butoxy illudalic acid analog (7-BIA) as a small molecule that targets PTPRD and inhibits its phosphatase with some specificity; (iii) lack of toxicity when 7-BIA is administered to mice acutely or with repeated dosing; (iv) reduced cocaine-conditioned place preference when 7-BIA is administered before conditioning sessions; and (v) reductions in well-established cocaine self-administration when 7-BIA is administered before a session (in WT, not PTPRD heterozygous KOs). These results add to support for PTPRD as a target for medications to combat cocaine use disorders. 7-BIA provides a lead compound for addiction therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}