The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats
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Previous research suggests that the vesicular monoamine transporter-2 (VMAT2) is a novel target for the treatment of methamphetamine (METH) abuse.
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.
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.
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.
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.
KeywordsVMAT2 Methamphetamine Self-administration CPP Lobeline Lobelane Abuse Addiction
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