The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats

Joshua S. Beckmann, Emily D. Denehy, Guangrong Zheng, Peter A. Crooks, Linda P. Dwoskin, Michael T. Bardo

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Rationale Previous research suggests that the vesicular monoamine transporter-2 (VMAT2) is a novel target for the treatment of methamphetamine (METH) abuse. Objective The effects GZ-793A, a novel, selective, and potent lobelane analog, on the rewarding effects of METH, cocaine, and palatable food in rats were determined. Method GZ-793A (3-30 mg/kg, s.c.) was administered 20 min prior to each session in which the groups of rats pressed a lever for infusions of METH (0.03 mg/kg/ infusion), cocaine (0.3 mg/kg/infusion), or food pellets. Tolerance to repeated GZ-793A (15 mg/kg, s.c. for 7 days) on METH self-administration and food-maintained responding was determined. The ability of increasing doses of METH (0.001-0.56 mg/kg, i.v.) to surmount inhibition produced by GZ-793A (15 mg/kg, s.c.) was determined. Self-administration of GZ-793A (0.01-0.3 mg/kg/infusion, i.v.) was tested as a substitute for METH infusion. GZ-793A (15 mg/kg, s.c.) was administered 20 min prior to METH or saline conditioning in a place preference test. Results GZ-793A specifically decreased METH self-administration, without the development of tolerance. Increasing the unit dose of METH did not surmount the inhibition produced by GZ-793A on METH self-administration. GZ-793A did not serve as a substitute for self-administered METH. GZ-793A blocked METH-induced conditioned place preference (CPP) and did not induce CPP alone. Conclusions These results indicate that VMAT2 is a viable target for pharmacological inhibition of METH reward and that GZ-793A represents a new lead in the discovery of a treatment for METH abuse.

Original languageEnglish
Pages (from-to)395-403
Number of pages9
JournalPsychopharmacology
Volume220
Issue number2
DOIs
StatePublished - Mar 2012

Bibliographical note

Funding Information:
Acknowledgments We thank Kate Fischer for technical assistance. This work was supported by National Institutes of Health National Institute on Drug Abuse (R01 DA13519 and T32DA01617). The University of Kentucky holds patents on lobeline, lobelane, UKCP-110, and GZ-793A. A potential royalty stream to Dwoskin, Crooks, and Zheng may occur consistent with University of Kentucky policy.

Keywords

  • Abuse
  • Addiction
  • CPP
  • Lobelane
  • Lobeline
  • Methamphetamine
  • Self-administration
  • VMAT2

ASJC Scopus subject areas

  • Pharmacology

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