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

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.

Fig. 1.

Numbers of 1-mg/kg cocaine infusions self-administered during 3-h sessions by WT (solid line, closed symbols) and heterozygous PTPRD-KO mice (dashed line, open circles) on experimental days shown. (Top) FR1 (1 mg/kg per infusion) and (Bottom) progressive-ratio schedules. Mice received 1-mg/kg cocaine infusions after completing 2, 4, 6, 9, and 12 lever presses on days 1–5, respectively (*P < 0.05, t test).

Fig. 2.

Synthetic scheme and structures, including structure for the illudalic acid analog PRPRD phosphatase inhibitor 7-BIA (i.e., 14; further detail provided in SI Appendix).

Fig. 3.

Concentration-dependent inhibition of the phosphatase activity of recombinant human PTPRD (solid line) and PTPRS (dashed line) D1 phosphatase domain fusion proteins by 16-min preincubation with 7-BIA at concentrations shown (log10 × 10⁻⁶ M; note that phosphatase assays diluted 7-BIA 10-fold; SI Appendix).

Fig. 4.

(Top) Cocaine-conditioned place preference in mice with vehicle (black) and 7-BIA (gray; >6 mg/kg) pretreatment before each conditioning session (*P = 0.03, t test; n = 12; Values normalized. 1 represents time (+/− SEM) in seconds spent (during postconditioning–preconditioning test sessions) in control mice which were pretreated prior to each conditioning session with saline vehicle for cocaine and DMSO vehicle for 7-BIA). (Bottom) Well-established cocaine self-administration is reduced significantly by 7-BIA pretreatments (90 min before session start) in WT but not in PTPRD heterozygous KO mice (n = 12–126 sessions; 13 WT and 6 heterozygous KO mice; *P < 0.05).