Oral administration of GZ-793A, a VMAT2 inhibitor, decreases methamphetamine self-administration in rats.
Despite the high prevalence of use of methamphetamine (METH), there is no FDA-approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30-240 mg/kg) on intravenous METH self-administration and food-maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20-180 min pretreatment) of oral administration of GZ-793A on METH self-administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240 mg/kg) producing an 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120 mg/kg) lasted at least 180 min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration support the feasibility of developing VMAT2 inhibitors as treatments for METH abuse.
Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, KY, United States.
Carrie E
CE
Wilmouth
Guangrong
G
Zheng
Peter A
PA
Crooks
Linda P
LP
Dwoskin
Michael T
MT
Bardo
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008120:Lobeline / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*
C573789:N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D008120:Lobeline
Dopamine; Methamphetamine; Self-administration; VMAT2