MODULATION OF BRAIN OPIOIDS AND TACHYKININS BY NEUROTRANSMITTER SYSTEM

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The objectives of this project were: 1) to understand the basic biosynthetic process of opioid peptide(enkephalin and dynorphin) and tachykinin (substance P) systems, 2) to elucidate how the classical neurotransmitter systems, such as dopamine (DA) interact with opioid peptides and tachykinins in the basal ganglia. Previous works have shown that blockade of dopaminergic transmission increases the biosynthesis of enkephalins, but decreases that of dynorphins and tachykinins in the basal ganglia. This study examined the effects of enhanced dopaminergic transmission on the expression of opioid peptide and tachykinin genes. For this purpose, apomorphine, a DA receptor agonist, and D-amphetamine, a DA releaser were employed. Repeated injections of either DA agonist increased the abundance of mRNA and the peptide content of substance P and dynorphin, but not enkephalin in the striatum. To determine whether the effects of repeated injections of DA agonists or antagonists on the peptides were a direct action on the nigrostriatal DA pathway or an indirect effect through other brain regions, a unilateral nigral 6-hydroxydopamine (6-DHDA) lesion model was used. Degeneration of nigrostriatal DA neurons prevented the D-amphetamine-induced increase in the levels of dynorphin and substance P in the basal ganglia. In contrast, the apomorphine-induced increase in the levels of these two peptides were greatly enhanced in the lesioned side as compared with the contralateral unlesioned side, presumably due to the supersensitivity of the DA receptors. It is interesting to note that the potentiation of apomorphine-induced increases in dynorphin and substance P only occurred in rats with more than 90% depletion of DA in the striatum. This phenomenon can be interpreted by our recent finding that the release of striatal DA measured by microdialysis procedure remained almost normal in rats with less than 90% depletion of striatal DA by 6-DHDA lesion. These results demonstrate the unusual great plasticity of the nigrostriatal pathway to maintain its transmission function.