Daily monitoring of dopamine efflux reveals a short-lasting occlusion of the dopamine agonist properties of d-amphetamine by dopamine transporter blockers GBR 12909 and methylphenidate.

The abuse potential of psychostimulant drugs such as amphetamine (AMPH) and cocaine is attributed to their actions as indirect dopamine (DA) agonists at presynaptic sites on the terminal regions of the mesocorticolimbic DA system.1,2 Compelling evidence for the links between the rewarding properties of psychostimulants and DA neurotransmission is provided by direct measurement of dramatic elevation in DA efflux into the extracellular compartment following intravenous (i.v.) self-administration of these drugs by animals as measured by the combined techniques of in vivo brain microdialysis and high-pressure liquid chromatography (HPLC) with electrochemical detection.3−7 Given the tremendous harm inflicted on personal health and the well-being of society, there is an urgent need to develop new medications that are effective in reducing addiction to psychostimulants. One approach to this challenge has focused on a specific group of compounds that serve as highly effective and selective DA uptake inhibitors. For a comprehensive review of this approach to the development of “agonist” therapy candidates, see Rothman et al.8 Rothman and colleagues have championed the use of compounds within the aryl-1,4-dial(en)ylpiperazine class, specifically GBR 12909 (1-(2-[bis-(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine), as potential medication for the treatment of psychostimulant drug addiction.9−11 The neuropharmacological of properties of GBR 12909 are distinct from other DA reuptake inhibitors such as cocaine. Specifically, GBR 12909 has a much slower onset and markedly longer duration of action,12−14 the latter characteristic being consistent with the indication that GBR 12909 and close analogues may bind irreversibly to the DAT.15,16 In preclinical studies, GBR 12909 treatment attenuated cocaine self-administration in rats.17,18 Pretreatment with a depot formulation of the drug, GBR-decanoate, selectively blocked operant responding for cocaine self-administration for up to a month, without affecting lever-pressing behavior for food reward.19 Initial in vivo microdialysis studies reported an elevation in DA efflux following systemic administration of GBR 12909,12,20 sufficient to attenuate cocaine-induced increases in DA efflux.21,22 Importantly, in rats treated with GBR-decanoate, elevation of DA efflux was observed up to 2 weeks later and furthermore, significantly antagonized the increase in DA efflux induced by i.v. doses (0.3 and 1.0 mg/kg) of methamphetamine.23 A different in vivo measure of the DA agonist effects of AMPH involves monitoring changes in [11C]raclopride binding as measured by PET. In a study with nonhuman primates, increased raclopride displacement of DA confirmed that GBR 12909 attenuated amphetamine-induced increase in striatal DA release.24 An alternate strategy to the development of medication for psychostimulant addiction based on highly selective DAT blockers as represented by GBR 12909 proposes the use of compounds that target multiple receptors or uptake sites.8,25 Although methylphenidate (MPH) is an effective DAT blocker, its inhibitory effects extend to the serotonin and norepinephrine transporters.26,27 Administration of MPH, both systemically and by reverse-dialysis, is associated with robust increases in extracellular levels of DA, serotonin and norepinephrine.28−31 The present study compared the effects of pretreatment with two DAT inhibitors, GBR 12909 and MPH, which differ in binding affinity and specificity for the DAT, on d-AMPH-induced DA efflux in the NAc. In light of the indication that GBR 12909 interaction with the DAT may be long-lasting,15 which raises the possibility of prolonged elevation of extracellular DA, microdialysis experiments in the present study were extended past the typical 3–4 h monitoring to 4 days. This permitted the assessment of both the acute and delayed effects of pretreatment with either DAT inhibitor on the DA agonist properties of d-AMPH on the first and last day of the experiment. In addition, monitoring basal DA efflux at 24 h intervals allowed a comparison of the longer-term action of these two DAT blockers on basal DA efflux.