Effects of cocaine on release and uptake of dopamine in vivo: differentiation by mathematical modeling.

Although considerable effort has been invested trying to distinguish between the effects of cocaine on dopamine (DA) uptake and release in both in vitro and in vivo experiments, disagreement over the specific actions of cocaine remains. The results obtained by combining experimental extracellular DA data with a mathematical model of the dopaminergic neuron allow examination of the cocaine uptake inhibition/release question. The extracellular DA concentration profile observed following a 30 mg/kg IP cocaine injection can be modeled if both pre- and postsynaptic uptake are competitively inhibited by cocaine with or without an enhanced DA release effect. However, if cocaine elicits enhanced DA release, modeling predicts a 40% increase over basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and a 30% increase in homovanillic acid (HVA) at 60 minutes following a 30 mg/kg IP cocaine injection. Reported DOPAC and HVA data for similar cocaine doses indicate little change in either DOPAC or HVA. These data agree best with modeled metabolite predictions for little or no cocaine-enhanced DA release.