REGULATION OF DOPAMINE AND SEROTONIN SYNTHESIS BY ACUTE ADMINISTRATION OF COCAINE

Because cacaine effectively increases extracellular levels of both dopamine (DA) and serotonin (5HT), it might be expected that this agent would inhibit transmitter biosynthesis in these monoamine neurons by activation of autoregulatory feedback pahwas. This possibility was tested by measuring the effect of cocaine on 3,4‐dihydroxyphenylalanine accumulation (DA synthesis) and 5‐hydroxytryptophan accmulation (5HT synthesis) in vivo and in vitro after inhibition of aromatic amino acid decarboxylase with NSD‐1015. In vivo, cocaine suppressed both Da and 5HT synthesis in a dose‐depentent (10–60 μmol/kg, i.p.) and time‐dependent fashion (maximum 60 min after administrationm, recovery by 120–150 min). Inhibition of Da and 5HT synthesis ranged from 35% to 60% depending on the brian region and was apparent in dopaminergic fields such as the medial prefrontal cortex, nucleus accumbens, piriform cortex, striatum, and in noradrenergic fields such as the hipocampus and temporal cortex. Inhibition of DA, but not 5HT, synthesis was blocked by the D2 antagonist sulpiride in brain areas containing DA nerve terminals. Procaine (30 μmol/kg) did not inhibit DA or 5HT synthesis and prior treatment with reserpine diminished the effectiveness of cocaine in the medial prefrontal cortex, but not in the striatum. Cocaine did not reverse the gamma‐butyrolactone‐induced increase in striatal DA synthesis nor did cocaine block the ability of the D2 agonist quinpirole to reverse the increase. In vitro, cocaine inhibited Da synthesis in depolarized (K+=30 mM) striatal brian slices, an effect that was reversed by the D2 antagonist eticlopride. These results suggest that DA and 5HT neurons compensate in situ for cocaine‐induced increases in synaptic transmitter levels by a transient inhibition of transmitter biosynthesis. Acute suppression of transmitter synthesis (and release) in mesoprefrontal DA neurcns may represent the principal compensatorty mechanism in this group of neurons. Copyright © 1990 Wiley‐Liss, Inc.