MODULATION OF BRAIN OPIOIDS AND TACHYKININS BY PSYCHOACTIVE DRUGS

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The objectives of this project were: 1) to understand the basic biosynthetic process of opioid and tachykinin systems by employing molecular biological and immunochemical techniques, 2) to elucidate how the classical neurotransmitter systems such as dopamine (DA) interact with opioid peptides and tachykinins in the basal ganglia following the perturbation of dopaminergic transmission. The methods used include the quantitation of specific mRNA and the precursor content as well as the steady state peptide concentration. Long-term blockade of DA receptors with a DA antagonist, haloperidol (an antipsychotic drug), caused interesting changes in the expression of neuropeptides in the striatum: increases in (Met5)-enkephalin (ME) but decreases in tachykinin. This finding not only suggests that the DA system exerts important regulation on these two peptide systems, but also raises an interesting concept that gene expression of neuropeptide systems may be a potential site of action for antipsychotic drugs. The effects of haloperidol on these two peptides were mimicked by intranigral injection of 6- hydroxydopamine which selectively destroys the nigral-striatal DA pathway. These results add further credence to the concept that DA plays an important role in regulating the metabolism of ME and tachykinin. To determine if enhancement of dopaminergic transmission would produce opposite effects on these peptides, apomorphine, a DA agonist, was employed. Repeated injections of apomorphine increased the abundance of mRNA and peptide content of tachykinin and dynorphin, but failed to alter ME content in the basal ganglia. This finding plus the aforementioned results strongly suggest the following: 1) DA exerts strong inhibitory influence on the biosynthesis of ME and this tonic inhibitory effect is maximal under physiological conditions, 2) DA enhances the biosynthesis of tachykinin and dynorphin and this tonic excitatory effect is not maximal under physiological conditions. Striatal cell cultures will be employed to determine the subcellular events which link the DA receptor activation to gene expression of opioid peptides and tachykinins.