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


OBJECTIVE
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.
Department of Psychology, University of Kentucky, 106b Kastle Hall, Lexington, KY 40506, USA.
Kristin M
KM
Alvers
Joshua S
JS
Beckmann
Guangrong
G
Zheng
Peter A
PA
Crooks
Linda P
LP
Dwoskin
Michael T
MT
Bardo
D019969:Amphetamine-Related Disorders / Q000188:drug therapy*; D000818:Animals; D058999:Drug-Seeking Behavior / Q000187:drug effects; D013287:Illicit Drugs / Q000494:pharmacology*; D008120:Lobeline / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*
D013287:Illicit Drugs; C573789:N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D008120:Lobeline