Dopamine-opiate interaction in the regulation of neostriatal and pallidal neuronal activity as assessed by opioid precursor peptides and glutamate decarboxylase messenger RNA expression

Neostriatal GABAergic neurons projecting to the globus pallidus synthesize the opioid peptide enkephalin, while those innervating the substantia nigra pars reticulata and the entopeduncular nucleus synthesize dynorphin. The d ifferential control exerted by dopamine on the activity of these two effere nt projections concerns also the biosynthesis of these opioid peptides. Usi ng in situ hybridization histochemistry, we investigated the role of opioid co-transmission in the regulation of neostriatal and pallidal activity. Th e expression of the messenger RNAs encoding glutamate decarboxylase-the bio synthetic enzyme of GABA-and the precursor peptides of enkephalin (preproen kephalin) and dynorphin (preprodynorphin) were measured in rats after a sus tained blockade of opioid receptors by naloxone (s.c. implanted osmotic min ipump, eight days, 3 mg/kg per h), and/or a subchronic blockade of D-2 dopa mine receptors by haloperidol (one week, 1.25 mg/kg s.c. twice a day). The density of mu opioid receptors in the neostriatum and globus pallidus was d etermined by autoradiography. Naloxone treatment resulted in a strong up-re gulation of neostriatal and pallidal mu opioid receptors that was not affec ted by the concurrent administration of haloperidol. Haloperidol alone prod uced a moderate down-regulation of neostriatal and pallidal mu opioid recep tors. Haloperidol strongly stimulated the expression of neostriatal preproe nkephalin and preprodynorphin messenger RNAs. This effect was partially att enuated by naloxone, which alone produced moderate increases in preproenkep halin and preprodynorphin messenger RNA levels. In the neostriatum, naloxon e did not affect either basal or haloperidol-stimulated glutamate decarboxy lase messenger RNA expression. A strong reduction of glutamate decarboxylas e messenger RNA expression was detected over pallidal neurons following eit her naloxone or haloperidol treatment, but concurrent administration of the two antagonists did not result in a further decrease. The amplitude of the variations of mu opioid receptor density and of prepro enkephalin and preprodynorphin messenger RNA levels suggests that the regul ation of neostriatal and pallidal mu opioid receptors is more susceptible t o a direct opioid antagonism, while the biosynthesis of opioid peptides in the neostriatum is more dependent on the dopaminergic transmission. The dow n-regulation of mu opioid receptors following haloperidol represents probab ly an adaptive change to increased enkephalin biosynthesis and release. The haloperidol-induced increase in neostriatal preprodynorphin messenger RNA expression might result from an indirect, intermittent stimulation of neost riatal D-1 receptors. The haloperidol-induced decrease of pallidal glutamat e decarboxylase messenger RNA expression suggests, in keeping with the curr ent functional model of the basal ganglia, that the activation of the stria topallidal projection produced by the interruption of neostriaral dopaminer gic transmission reduces the GABAergic output of the globus pallidus. The reduction of pallidal glutamate decarboxylase messenger RNA expression following opioid receptor blockade indicates an indirect, excitatory influe nce of enkephalin upon globus pallidus neurons and, consequently, a functio nal antagonism between the two neuroactive substances (GABA and enkephalin) of the striatopallidal projection in the control of globus pallidus output . Through this antagonism enkephalin could partly attenuate the GABA-mediat ed effects of a dopaminergic denervation on pallidal neuronal activity. (C) 1999 IBRO. Published by Elsevier Science Ltd.