Psychopharmacology

, Volume 220, Issue 2, pp 395–403 | Cite as

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
Original Investigation

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.

Keywords

VMAT2 Methamphetamine Self-administration CPP Lobeline Lobelane Abuse Addiction 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Joshua S. Beckmann
    • 1
  • Emily D. Denehy
    • 1
  • Guangrong Zheng
    • 2
  • Peter A. Crooks
    • 2
  • Linda P. Dwoskin
    • 2
  • Michael T. Bardo
    • 1
  1. 1.Department of Psychology, College of Arts and SciencesUniversity of KentuckyLexingtonUSA
  2. 2.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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