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

Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11597-11602. doi: 10.1073/pnas.1720446115. Epub 2018 Oct 22.

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: Post-GWAS; addiction; cell adhesion molecule; drug discovery; stimulant use disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Catheters, Indwelling
  • Cocaine-Related Disorders / drug therapy*
  • Cocaine-Related Disorders / enzymology
  • Cocaine-Related Disorders / genetics
  • Cocaine-Related Disorders / physiopathology
  • Conditioning, Psychological
  • Coumarins / chemical synthesis
  • Coumarins / pharmacology*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Humans
  • Injections, Intravenous
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Narcotic Antagonists / chemical synthesis
  • Narcotic Antagonists / pharmacology*
  • Neurons / drug effects
  • Neurons / enzymology
  • Neurons / pathology
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / antagonists & inhibitors
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / deficiency
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics*
  • Reward*
  • Self Administration
  • Signal Transduction
  • Substance Abuse, Intravenous / drug therapy*
  • Substance Abuse, Intravenous / enzymology
  • Substance Abuse, Intravenous / genetics
  • Substance Abuse, Intravenous / physiopathology
  • Toxicity Tests, Acute
  • Toxicity Tests, Chronic

Substances

  • Coumarins
  • Ligands
  • Narcotic Antagonists
  • Ptprd protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2