Repeated Cocaine Administration Results in Supersensitive Nigrostriatal D-2 Dopamine Autoreceptors

Abstract

Presynaptic D-2 dopamine (DA) receptors, or “autoreceptors”, are associated with both the cell bodies and terminals of the nigrostriatal and mesolimbic dopaminergic tracts. Those on the cell bodies regulate impulse flow, while those on the terminals modulate the stimulation-evoked release of DA, both in an inhibitory fashion. The activity of these D-2 autoreceptors appears to be very sensitive to the concentration of DA in the synapse. Cocaine increases the concentration of DA in the synaptic cleft by blocking high affinity DA uptake and thus stimulates dopaminergic systems by activating DA receptors indirectly. One might expect that both presynaptic and postsynaptic DA receptors would be regulated in response to repeated cocaine administration. In the striatum and nucleus accumbens, all of the D-1 DA receptors and the majority of the D-2 DA receptors are thought to be localized postsynaptically. The effects of repeated administration of cocaine on D-1 receptors has not been directly examined. In two early studies, chronic cocaine administration resulted in parallel increases in binding to striatal DA receptors, presumably D-2 receptors; stereotypy; and locomotor behavior (Borison et al., 1979; Taylor et al., 1979). Recently, however, Goeders and Kuhar (1987) found a decreased density of D-2 receptors in the striatum but an increased density in the nucleus accumbens following a similar dosage regimen. Therefore, there is a need to reconcile the D-2 receptor data and to investigate whether D-1 receptors are regulated following repeated cocaine administration.