STUDY OF DRUG-ACTION ON NORMAL AND DENERVATED STRIATAL MECHANISMS

Apomorphine, N-n-propylnorapomorphine, N,N-di-n-propyldopamine, 1-aza-7,8-dihydroxy-1-a-1,2,3,4,4a,9, 10,10a-octahydrophenanthrene (CS-224) and 2-di-n-propylamino-5,6-dihydroxytetralin each caused ipsilateral circling (with respect to the side of electrolesion) in mice with electrolesions of the striatum or electrolesions combined with 6-hydroxydopamine (6-OHDA) lesions of the contralateral straitum. All agents were more potent (2-4 fold) in the latter model: the shift of the dose response curves to the left was approximately parallel (indicating increased dopamine receptor sensitivity on the side of 6-OHDA injection) except where stereotypy development interfered with circling. In contrast to these dopamine agonists, 1-aza-7,8-dihydroxy-1-1-propyl-1,2, 3,4,4a,9,10,10a-octahydrophenanthrene (TL-140-III) was more potent in the single electrolesion model: the action of this agent was abolished by α-methyl-p-tyrosine similarly to d-amphetamine but unlike the directly acting dopamine agonists. Haloperidol, fluphenazine, sulpiride, thioridazine, clozapine and metoclopramide each reduced/abolished the circling induced by apomorphine in mice with electrolesions or combined 6-OHDA/ electrolesions of the striatum. Doses required appeared the same for both models, or the neuroleptic was a maximum of 2× more active in the combined lesioned model. In contrast, tiapride and oxiperomide were 8× and 4× more active in mice with combined 6-OHDA/electrolesion than in animals with a single electrolesion. The α- and β-adrenergic blocking agents, aceperone and propranolol, were inactive in both circling models. Biochemical determinations showed that 6-OHDA depleted striatal dopamine content by 85% whilst failing to cause any significant depletions in mesolimbic (nucleus accumbens and tuberculum olfactorium) dopamine or noradrenaline. The possibility that tiapride may be more effective as an antagonist at denervated dopamine mechanisms is discussed in terms of its known spectrum of activity as a dopamine antagonist both experimentally and clinically. © 1979.