Abstract

Cocaine is a popular and sometimes deadly drug of abuse. Its mechanisms of action have previously not been linked with receptors localized to presynaptic sites for the major central nervous system amino acid transmitters γ-aminobutyric acid (GABA) and glutamate. We demonstrate that, within the dorsolateral septal nucleus of in vitrobrain slices from animals that had received cocaine chronicallyin vivo for 14 or 28, but not 7, days, control of both inhibitory (GABA) and excitatory (glutamate) amino acid transmission is impaired, due to the combined diminished effectiveness of presynaptic GABA_B auto- and heteroreceptors. As a result, disinhibition of inhibitory and excitatory transmitters occurs, with enhanced transmitter release. Although the involvement of postsynaptic GABA_B receptors has been suggested in the chronic actions of cocaine at other central nervous system nuclei, we do not see any change in the effectiveness of the postsynaptic GABA_Breceptors within the dorsolateral septal nucleus. Modulation of presynaptic GABA_B receptors at central nervous system nerve terminals after chronic cocaine administration has not been reported previously. Our findings demonstrate that chronic intermittent cocaine administration for at least 14 days induces a persistent change in neuronal activity that involves both inhibitory and excitatory amino acid-mediated transmission within the dorsolateral septal nucleus. These results suggest that nerve terminal GABA_B receptors have been overlooked as playing a role in either the etiology and treatment of chronic cocaine addiction or cocaine toxicity.