Actions of cocaine on central monoamine neurons: intracellular recordings in vitro.

Intracellular recordings from monoaminergic neurons in brain slice preparations have been used to study the action of cocaine. The firing rate of noradrenergic neurons in the locus coeruleus, serotonergic neurons of dorsal raphe and dopaminergic neurons from substantia nigra zona compacta is reduced or inhibited by the transmitter substance that they produce. This process, which can be brought about by release of the transmitter from either dendrites or axon collaterals in the vicinity of the cell bodies, has been referred to as 'autoinhibition'. In each case, the inhibition results from a membrane hyperpolarization caused by an increased conductance to potassium ions. In each of the nuclei, cocaine caused a decrease in spontaneous firing through a membrane hyperpolarization. This action of cocaine was blocked by the respective 'autoreceptor' antagonist. In the locus coeruleus and dorsal raphe cocaine prolonged an inhibitory postsynaptic potential caused by the release of noradrenaline and 5-HT respectively. The concentration-response curve for the exogenously applied agonist in each of the three nuclei was shifted to the left in the presence of cocaine. These observations indicate that the activity of these aminergic neurons was affected by cocaine through an inhibition of the reuptake of endogenously release transmitter. The blockade of reuptake increased the extracellular level of noradrenaline, 5-HT and dopamine in the respective nuclei to concentrations which caused electrophysiologically detectable effects. This suggests that the reuptake process is a primary mechanism for termination of the response. In addition, this action of cocaine occurs at behaviorally relevant concentrations. The fact that all monoaminergic transmission can be affected by cocaine may contribute to the complexity of its behavioral actions.