The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats
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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.
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.
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.
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.
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.
KeywordsMethamphetamine Reinstatement Relapse GZ-793A VMAT2 Locomotor activity
This research was supported by the National Institute of Drug Abuse grants DA13519 and DA016176. We thank Emily Denehy for technical assistance. The University of Kentucky holds a patent on GZ-793A, and a potential royalty stream to LPD, GZ, and PAC may occur consistent with the University of Kentucky policy.
Conflict of interest
The other authors have no disclosures.
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