The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats.

RATIONALE: The vesicular monoamine transporter 2 (VMAT2) has been identified as a potential target for the treatment of methamphetamine (METH) abuse. GZ-793A is a potent and selective VMAT2 inhibitor that has been shown to block the primary and conditioned reinforcing effects of METH, while demonstrating no abuse liability when given alone.
OBJECTIVES: The aim of the current study was to determine if GZ-793A attenuates METH- or cue-induced reinstatement of METH-seeking after a period of extinction. The effect of acute GZ-793A on locomotor activity also was assessed.
METHODS: After a period of extinction, rats were administered GZ-793A (15 mg/kg, s.c.) 15 min prior to a priming injection of METH or re-exposure to cues associated with METH infusions. GZ-793A also was administered 20 min prior to an injection of METH (0.5 mg/kg, s.c.) or saline to determine its effect on locomotor behavior.
RESULTS: Pretreatment with GZ-793A (15 mg/kg) decreased cue-induced reinstatement, without demonstrating any response suppressive effects when administered in the absence of reinstating stimuli. GZ-793A also decreased methamphetamine-induced reinstatement; however, response suppressant effects of GZ-793A were obtained when the compound was presented alone. In this latter experiment, GZ-793A may have reduced responding for the conditioned reinforcing effects of the contingently available cues rather than having nonspecific effects on baseline responding. GZ-793A had no effect on locomotor activity when administered alone or with METH.
CONCLUSIONS: GZ-793A and related VMAT2 inhibitors may be promising leads for reducing the risk of relapse to METH use following exposure to drug-associated cues.