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

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

Uhl GR1,2,3,4,5,6,7,8,9, Martinez MJ10,5, Paik P9, Sulima A11, Bi GH12, Iyer MR11, Gardner E13, Rice KC11, Xi ZX12.

Author information

1
Neurology and Research Services, New Mexico VA Healthcare System, Albuquerque, NM 87108; George.Uhl@va.gov.
2
Department of Neurology, University of New Mexico, Albuquerque, NM 87131.
3
Department of Neuroscience, University of New Mexico, Albuquerque, NM 87131.
4
Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131.
5
Biomedical Research Institute of New Mexico, Albuquerque, NM 87108.
6
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
7
Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205.
8
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205.
9
Molecular Neurobiology, National Institute on Drug Abuse, Baltimore, MD 21224.
10
Neurology and Research Services, New Mexico VA Healthcare System, Albuquerque, NM 87108.
11
Drug Design and Synthesis, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892.
12
Addiction Biology, National Institute on Drug Abuse, Baltimore, MD 21224.
13
Neuropsychopharmacology, National Institute on Drug Abuse, Baltimore, MD 21224.

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

PMID:
30348770
PMCID:
PMC6233130
[Available on 2019-05-06]
DOI:
10.1073/pnas.1720446115

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