Novel in vivo electrophysiological assay for the effects of cocaine and putative "cocaine antagonists" on dopamine transporter activity of substantianigra and ventral tegmental area dopamine neurons

The aim of these studies was to establish a rapid in vivo assay for evaluat ing potential "cocaine antagonists," i.e., drugs postulated to block cocain e binding to the dopamine transporter (DAT) without corresponding blockade of dopamine reuptake. The assay is based on the ability of dopamine, and dr ugs that elevate synaptic dopamine levels, to inhibit the extracellular sin gle unit activities of midbrain dopamine neurons in chloral hydrate-anesthe tized rats. As expected, cocaine itself (0.06-16 mg/kg, i.v.) caused a dose -dependent inhibition of firing of both substantia nigra and ventral tegmen tal area (VTA) dopamine neurons, but had a significantly higher potency on VTA than nigral dopamine cells (ED50's 1.2 and 8.8 mg/kg, respectively). VT A cells were also inhibited to a greater extent (to 4.7 +/- 4.5% vs. 41.3 /- 6.3% of baseline rates at 16 mg/kg, respectively). We next evaluated GBR 12909, a piperazine analog promoted as a "cocaine antagonist" because of it s ability to bind with high affinity to the DAT, while only modestly elevat ing extracellular dopamine levels. The agonist- and antagonist-like propert ies of GBR12909 were evaluated on only VTA dopamine cells since these neuro ns were more fully inhibited by cocaine and have been implicated in its rew arding effects. Given alone, CBR12909 exhibited modest "cocaine-like" activ ity insofar as it partially inhibited VTA dopamine neurons (to 59.0 +/- 4.6 % of baseline at 8 mg/kg). However, consistent with an antagonist profile, pretreatment with a low (0.5 mg/kg) dose of GBR12909, which depressed firin g only slightly, resulted in a >2-fold rightward shift in the dose-response curve to cocaine (ED50 2.6 mg/kg). We conclude that electrophysiological t esting of putative "anti-cocaine" drugs for their abilities to inhibit the firing of VTA dopamine neurons, and to block their inhibitory responses to cocaine, may provide a rapid in vivo screen for compounds expected to behav e as functional cocaine antagonists in the dopamine reward system. (C) 2000 Wiley-Liss, Inc.