The Roles of D1 and D2 dopamine receptors in mediating methamphetamine-induced changes in monoamine and substance P systems.

The amphetamine-like compounds have prominent effects on several neurotransmitter systems within the central nervous system. The administration of multiple doses of these stimulants produces profound and long-lasting decreases in neurochemical indices of dopamine and serotonergic systems as well as increases in the concentration of the neuropeptide, substance P, within various brain regions. The nonselective dopamine receptor antagonist, haloperidol, blocks these effects of methamphetamine on all three neurotransmitter systems. The purpose of the present investigations was to identify the dopamine receptor subtype(s) which mediate these actions of methamphetamine. Thus, selective D1 and D2 agonists and antagonists were administered alone or in combination with methamphetamine and the effects of these treatments on neurochemical parameters of the dopamine, serotonin, and substance P systems were evaluated. The results from these present studies suggest that methamphetamine-released dopamine actions on the D2 receptor mediate the effects of methamphetamine on the nigrostriatal dopamine and striatonigral substance P systems. In contrast, the effects of methamphetamine on serotonin systems appear to involve dopamine actions on the D1 receptor. A single administration of an amphetamine produces a rapid, but transient depression of serotonin synthesis. The coadministration of dopamine antagonists with methamphetamine did not modify the methamphetamine effect on tryptophan hydroxylase activity, the rate-limiting enzyme in serotonin synthesis. These findings suggest a different mechanism is involved in this acute, transient effect of methamphetamine versus the long-lasting effects observed after multiple administrations. Whereas D1 blockade attenuates the effects of methamphetamine on the serotonergic system in the multiple dosing paradigm, it does not afford protection against the acute effect.