The major goal was to characterize dopaminergic control over neuropeptide homeostasis in the basal ganglia, by manipulating dopaminergic tone. Early studies from our laboratory demonstrated that long-term blockade of dopaminergic transmission by daily injections of haloperidol, an antipsychotic drug which selectively blocks dopamine receptors, caused a large increase in the level of enkephalin in those brain areas enriched with dopamine innervation, such as the striatum and nucleus accumbens. Subsequently, we undertook studies which showed that chronic haloperidol treatment also elevated the levels of precursor and mRNA encoding proenkephalin in the striatum. Based on these results, we concluded that long-term blockade of dopaminergic transmission by haloperidol accelerated the biosynthesis of enkephalin. This conclusion was further supported by our findings in rats treated with 6-hydroxydopamine. Changes of enkephalin and its mRNA after 6-hydroxydopamine lesion were identical to those obtained from the haloperidol experiment. Results from these two experiments present strong evidence for a tonic inhibitory influence o DA on the biosynthesis of striatal enkephalin. Studies were extended to characterize dopaminergic control over striatal dynorphin and substance P systems. In contrast to enkephalin, our data showed that dopamine exerted a tonic excitatory influence on the biosynthesis of both peptides, as dopaminergic blockade reduced the levels of these peptides and their respective mRNA. Another series of experiments examined the influence of enhancement of dopaminergic transmission (phasic control) on the turnover of opioid peptides and substance P. Results indicated that dopamine exerted phasic excitatory influence on the turnover of dynorphin and substance P, but not on enkephalin. The phasic regulation of dopamine on dynorphin and substance P may have some relevance to conditions where animals are under stress and nigrostriatal dopaminergic transmission is enhanced.
