RT Journal Article
SR Electronic
T1 Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1190
OP 1197
DO 10.1124/jpet.301.3.1190
VO 301
IS 3
A1 Michael H. Baumann
A1 Mario A. Ayestas
A1 Lawrence G. Sharpe
A1 David B. Lewis
A1 Kenner C. Rice
A1 Richard B. Rothman
YR 2002
UL http://jpet.aspetjournals.org/content/301/3/1190.abstract
AB Methamphetamine abuse is a serious global health problem, and no effective treatments for methamphetamine dependence have been developed. In animals, the addictive properties of methamphetamine are mediated via release of dopamine (DA) from nerve terminals in mesolimbic reward circuits. At the molecular level, methamphetamine promotes DA release by a nonexocytotic diffusion-exchange process involving DA transporter (DAT) proteins. We have shown that blocking DAT activity with high-affinity DA uptake inhibitors, such as 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR12909), can substantially reduce amphetamine-induced DA release in vivo. In the present study, we examined the ability of a long-acting depot formulation of GBR12909 decanoate (GBR-decanoate) to influence neurochemical actions of methamphetamine in the nucleus accumbens of rats. Rats received single injections of GBR-decanoate (480 mg/kg i.m.) and were subjected to in vivo microdialysis testing 1 and 2 weeks later. Pretreatment with GBR-decanoate produced modest elevations in basal extracellular levels of DA, but not 5-hydroxytryptamine (5-HT), at both time points. GBR-decanoate nearly eliminated the DA-releasing ability of methamphetamine (0.3 and 1.0 mg/kg i.v.) for 2 weeks, whereas methamphetamine-induced 5-HT release was unaffected. Autoradiographic analysis revealed that GBR-decanoate caused long-term decreases in DAT binding in the brain. Our data suggest that GBR-decanoate, or similar agents, may be useful adjuncts in treating methamphetamine dependence. This therapeutic strategy would be especially useful for noncompliant patient populations. U.S. Government