Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

Abstract

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 (GBRdecanoate) 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.

Evidence for the Involvement of Dopamine Transporters in Behavioral Stimulant Effects of Modafinil

“…The microdialysis findings with modafinil are much like our previous findings with GBR12909 and its analogspretreatment with these drugs substantially reduces DA release produced by intravenous amphetamine or METH (Baumann et al, 1994(Baumann et al, , 2002. Evidence indicates that GBR12909 and related compounds can prevent DA-releasing effects of METH by persistent occupation of DAT sites or internalization of DAT proteins (Kunko et al, 1997;Baumann et al, 2002). Arguably the most intriguing finding reported here is that modafinil pretreatment diminishes METH-induced ambulation.…”

“…For in vivo microdialysis studies, rats were anesthetized with sodium pentobarbital (60 mg/kg i.p. ), and then jugular catheters and intracerebral guide cannulae were implanted (Baumann et al, 2002). Guide cannulae were aimed at the n. accumbens according to coordinates ML, Ϫ1.7 mm and AP, ϩ1.6 mm relative to bregma, and DV, Ϫ6.0 mm relative to dura.…”

Monoaminergic Psychomotor Stimulants: Discriminative Stimulus Effects and Dopamine Efflux

“…For example, using self-administration procedures to study drug-maintained behavior and in vivo microdialysis procedures to measure the DA efflux, a close association between the reinforcing effects of COC or amphetamine and increases in extracellular DA levels from several different brain regions have been observed both in rodents (Pettit and Justice, 1989;Ranaldi et al, 1999;Di Chiara et al, 2004;Munzar et al, 2004) and nonhuman primates (Kimmel et al, 2005(Kimmel et al, , 2007Bradberry and Rubino, 2006). A similar association also has been reported between increased DA efflux and increased locomotor activity or frequency of observable stereotypic be-haviors in rats (Cadoni et al, 2000;Baumann et al, 2002;Di Chiara, 2002;Tanda et al, 2007). Finally, sensitization to abuse-related behavioral effects (i.e., motor, stereotypic, and self-administration behavior) of monoaminergic psychomotor stimulants seems to be accompanied by sensitization to their effects on DA efflux in rats (Cadoni et al, 2000;Di Chiara, 2002), although similar findings have not been reported in nonhuman primates (Bradberry, 2000;Bradberry and Rubino, 2006).…”

“…These latter three drugs were chosen to represent a monoaminereleasing compound (MA), a monoamine transport blocker (COC), and, with GBR 12909, a monoamine transport blocker that is generally considered to be DA-selective (Baumann et al, 2002;Howell and Kimmel, 2008). To evaluate the generality of such relationships across dissimilar drug discrimination procedures, two different groups of rats were trained to discriminate MA from saline using either a discrete-trial avoidance/escape procedure (Shannon and Holtzman, 1976;Holtzman, 2001) or a 20-response fixed-ratio (FR 20) schedule of food reinforcement to maintain behavior (Katz et al, 2004).…”

Variations in Nucleus Accumbens Dopamine Associated with Individual Differences in Maternal Behavior in the Rat

“…The DAT is a reuptake site that serves as a major source of clearance for DA from the synapse in the n. Acc (Wightman et al, 1988;Cass et al, 1993;Zahniser et al, 1999). Increased levels of DAT are commonly associated with reduced extracellular DA levels in the n. Acc (Baumann et al, 2002). Blockade of the DAT site with GBR 12909, a highly selective DAT blocker (Andersen, 1989), resulted in an increase in DA signal in the n. Acc and an enhanced level of pup LG in the low-LG mothers (Fig.…”