Abstract

Cocaine is a potent central nervous system (CNS) stimulant whose primary mechanism of action is reuptake inhibition of the monoamines at presynaptic transporter sites. Drug-induced stereotypic motor effects may be due to actions within the dorsal striatum and associated structures while reinforcing properties have been attributed to action in the ventral striatal terminal fields of the mesolimbic system. Recent metabolic mapping studies have revealed activation of a limited number of CNS structures. However, because of the pharmacokinetic properties of cocaine, brief duration of action and complex behavioral actions, regional cerebral blood flow (rCBF), a rapid marker of neuronal activity, was used to identify structures involved in different temporal aspects of its pharmacologic profile. Conscious rats were injected i.v. with either 0, 0.1, 0.5, 0.75, 1.0 or 5.0 mg/kg cocaine, 1 min before administration of [14C]iodoantipyrene. A dose-related increase in rCBF was seen in specific terminal fields of the mesolimbic system such as the basolateral and corticomedial nuclei of the amygdala, ventral pallidum, olfactory tubercle and medial prefrontal cortex. Additional structures became activated at successively higher doses, including the nucleus accumbens and ventral pallidum. Biphasic responses were seen in several structures manifest as increased blood flow at 0.1 mg/kg and a decrease or no effect at the mid doses only to increase again after the two highest doses. Thus, rCBF appears to be a sensitive measure of the neuronal effects of cocaine and, as a brief temporal marker of neuronal activity, has identified activation of several novel CNS structures.