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

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.

Fig. 1

Chemical structures for lobeline, lobelane, and GZ-793A

Fig. 2

Acute effects of GZ-793A on METH self-administration, cocaine self-administration, and food-maintained responding. a Relative to SAL control, GZ-793A treatment (s.c.) dose-dependently decreased METH infusions, n=6. b GZ-793A treatment (s.c.) dose-dependently decreased cocaine infusions, n=7. c GZ-793A treatment (s.c.) did not alter pellets earned, n=12. Asterisk denotes significant difference relative to SAL control

Fig. 3

Effect of repeated GZ-793A on METH self-administration and food-maintained responding. Top panel Relative to saline control, repeated GZ-793A (15 mg/kg; s.c.) treatment significantly decreased METH infusions, without the development of tolerance, n=4/group. Bottom panel Repeated GZ-793A (15 mg/kg; s.c.) treatment significantly increased pellets earned, n=6/group. Asterisk denotes significance relative to saline control

Fig. 4

GZ-793A time course. GZ-793A (15 mg/kg; s.c.) treatment significantly reduced METH infusions throughout the last session of repeated treatment (session 7), n=4. Asterisk denotes significance relative to saline control

Fig. 5

Effect of GZ-793A on METH dose-effect. The reduction in METH infusions following GZ-793A treatment (15 mg/kg; s.c.) was not surmounted by increasing the self-administered METH unit dose, n=10. Asterisk denotes significance relative to no pretreatment

Fig. 6

GZ-793A substitution. Rats did not differentially self-administer GZ-793A (0.01–0.3 mg/kg/infusion) relative to saline control. Baseline infusions represent self-administration of METH (0.03 mg/kg/infusion); sessions 1–21 represent substitution of varying unit doses of GZ-793A or saline; sessions 22–26 represent reinstatement of METH (0.03 mg/kg/infusion) self-administration, n=7/group

Fig. 7

Effect of GZ-793A on METH CPP. Treatment with GZ-793A (15 mg/kg; s.c.) blocked METH CPP, while GZ-793A treatment alone had no effect (no preference or aversion), n=7/group. Asterisks indicate significance relative to SAL-SAL control