Molecular Pharmacology, Vol 12, 639-648, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Stimulation by Dopamine of Adenosine Cyclic 3',5'-Monophosphate Formation in Rat Caudate Nucleus: Effect of Lesions of the Nigro-neostriatal Pathway

¹ Departments of Pharmacology and Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510

Stimulation by dopamine of cyclic 3',5'-AMP formation in slices and homogenates of caudate nucleus was studied in rats that exhibited apomorphine-induced contralateral circling following unilateral lesions of the nigro-neostriatal system. Electrothermic lesions or 6-hydroxydopamine injections were made in the ascending dopaminergic pathway, and resulted in 93-95% depletion of endogenous dopamine in the ipsilateral caudate nucleus. An increase in the ability of submaximal concentrations of dopamine to stimulate cyclic AMP formation was observed, 3-30 days after placement of the lesions, in slices prepared from the caudate nucleus on the lesioned side. In contrast to the results obtained with slices, the stimulation by dopamine of adenylate cyclase activity in homogenates of caudate nucleus was the same on the lesioned as on the control side. The data suggest that contralateral circling, induced by dopamine agonists in animals with unilateral lesions in the nigro-neostriatal pathway, may be due to an increased ability of the dopamine agonists to stimulate cyclic AMP formation on the lesioned side. This increased ability of dopamine agonists to raise cyclic AMP levels appears to result primarily from the lesion-induced destruction of presynaptic dopamine-containing nerve terminals in the caudate nucleus rather than from a change in dopamine-sensitive adenylate cyclase in the postsynaptic cells. The stimulation by dopamine of cyclic AMP formation in slices of caudate nucleus may be a useful biochemical model for the study of denervation supersensitivity in the nigro-neostriatal pathway.

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ACKNOWLEDGMENTS We thank Janice Abele and Frank Wilson for excellent technical assistance.

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