title: The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Psychology, College of Arts and Sciences, University of Kentucky, 741 S. Limestone, BBSRB, Room B343, Lexington, KY 40536-0509, USA. joshua.beckmann@uky.edu
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Emily D
authors.initials: ED
authors.lastname: Denehy
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D005502:Food; D008120:Lobeline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D012646:Self Administration; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: C573789:N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine; D014179:Neurotransmitter Uptake Inhibitors; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D008120:Lobeline; D003042:Cocaine