Novel in vivo electrophysiological assay for the effects of cocaine and putative "cocaine antagonists" on dopamine transporter activity of substantia nigra and ventral tegmental area dopamine neurons.
The aim of these studies was to establish a rapid in vivo assay for evaluating potential "cocaine antagonists," i.e., drugs postulated to block cocaine binding to the dopamine transporter (DAT) without corresponding blockade of dopamine reuptake. The assay is based on the ability of dopamine, and drugs that elevate synaptic dopamine levels, to inhibit the extracellular single unit activities of midbrain dopamine neurons in chloral hydrate-anesthetized 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 tegmental area (VTA) dopamine neurons, but had a significantly higher potency on VTA than nigral dopamine cells (ED(50)'s 1.2 and 8.8 mg/kg, respectively). VTA 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 GBR12909, a piperazine analog promoted as a "cocaine antagonist" because of its ability to bind with high affinity to the DAT, while only modestly elevating extracellular dopamine levels. The agonist- and antagonist-like properties of GBR12909 were evaluated on only VTA dopamine cells since these neurons were more fully inhibited by cocaine and have been implicated in its rewarding effects. Given alone, GBR12909 exhibited modest "cocaine-like" activity 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 firing only slightly, resulted in a >2-fold rightward shift in the dose-response curve to cocaine (ED(50) 2.6 mg/kg). We conclude that electrophysiological testing 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 behave as functional cocaine antagonists in the dopamine reward system.
Hinerth
M A
MA
Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
Collins
H A
HA
Baniecki
M
M
Hanson
R N
RN
Waszczak
B L
BL
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; C493216:Slc6a3 protein, rat; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine