Preclinical evaluation of GBR12909 decanoate as a long-acting medication for methamphetamine dependence

Methamphetamine (METH) abuse is a growing health problem, and no treatments for METH dependence have been identified. The powerful addictive properties of METH are mediated by release of dopamine (DA) from nerve terminals in mesolimbic reward pathways. METH stimulates DA release by acting as a substrate for DA transporter (DAT) proteins, thereby triggering efflux of DA from cells into the synapse. We have shown that blocking DAT activity with high-affinity DA uptake inhibitors, like GBR12909, can substantially reduce METH-evoked DA release in vitro, suggesting GBR12909 may have potential as a pharmacotherapy for METH dependence. The purpose of the present study was to examine the neurobiological effects of a long-acting oil-soluble preparation of GBR12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate, or GBR-decanoate). Male rats received GBR-decanoate (480 mg/kg, i.m.) or its oil vehicle, and were tested using a variety of methods one and two weeks later. Ex vivo autoradiography showed that GBR-decanoate decreases DAT binding in DA-rich brain regions. In vivo microdialysis in the nucleus accumbens revealed that GBR-decanoate elevates baseline levels of extracellular DA and antagonizes the ability of METH to evoke DA release. The dopaminergic effects of GBR-decanoate were sustained, lasting for at least two weeks. Rats pretreated with GBR-decanoate displayed enhanced locomotor responses to novelty at one week, but not two weeks, postinjection. Administration of the D(2)/D(3) receptor agonist quinpirole (10 and 100 microg/kg, s.c.) decreased locomotor activity and suppressed plasma prolactin levels; quinpirole-induced responses were not altered by GBR-decanoate. Thus, GBR-decanoate is able to elevate basal synaptic DA levels and block METH-evoked DA release in a persistent manner, without significant perturbation of DA receptor function. The findings suggest that GBR-decanoate, or similar long-acting agents, should be evaluated further as potential treatment adjuncts in the management of METH addiction in humans.