Adenylate cyclase (EC 4.6 Many antipsychotic drugs produce an extrapyramidal syndrome indistinguishable from Parkinson's disease (1, 2). There is considerable evidence that suggests that these extrapyramidal side effects may arise from the demonstrated ability of these drugs to antagonize the "dopamine receptor" of the caudate nucleus (3, 4), which many investigators have indirectly characterized in an extensive series of physiological, biochemical, and behavioral studies. Recently, a dopaminesensitive adenylate cyclase was demonstrated in homogenates of the caudate nucleus of the rat brain (5). It was suggested (5) that an intimate association exists between this dopaminesensitive adenylate cyclase and the "dopamine receptor" of the caudate nucleus, since the biochemical and pharmacological properties of this enzyme were similar to the reported properties of the caudate "dopamine receptor." A variety of evidence suggests that dopamine may serve as a neurotransmitter in several other regions of the mammalian nervous system, in addition to the caudate nucleus. Both the nucleus accumbens and the olfactory tubercle, two anatomical structures associated with the limbic system, are among the regions recently identified (6) as receiving dopaminergic innervation. Furthermore, biochemical measurements have shown the occurrence of relatively high levels of dopamine and 1113 its metabolites in these regions (refs. 7 and 8; 0. Hornykiewicz, personal communication; A. Carlsson, personal communication).The evidence that the extrapyramidal syndrome produced by the antipsychotic drugs is attributable to the ability of these drugs to block caudate dopamine receptors, together with the evidence that dopamine occurs in several other regions of the nervous system, has focused attention (e.g., refs. 9-11) on the twin hypotheses (a) that the antipsychotic drugs may achieve their therapeutic effects by virtue of blocking dopamine receptors in the brain and (b) that a hyperactivity of dopaminergic pathways in the brain may be involved in the pathophysiology of schizophrenia. The mesolimbic dopaminergic system of the brain, which projects to the olfactory tubercle and the nucleus accumbens, has figured prominently in such speculations concerning the pathophysiology of schizophrenia and the site of action of the antipsychotic drugs (11).The results presented in this communication are consistent with a model in which the dopamine receptor of neural tissue is intimately associated with a dopamine-sensitive adenylate cyclase. The results are also compatible with the possibility that inhibition of this enzyme may provide an explanation, at the molecular level, for the therapeutic effects, as well as for the side effects, of some widely used antipsychotic agents. MATERIALS AND METHODSATP, cyclic AMP, l-norepinephrine, and EGTA were purchased from Sigma; 3-hydroxytyramine (dopamine) was from CalBiochem^; inorganic salts were all reagent grade. All phenothiazines and related compounds were obtained, in high purity, from their commercia...

Abstract— An adenylate cyclase present in the caudate nucleus of rat brain, which is selectively stimulated by low concentrations of dopamine, and which is believed to mediate dopaminergic synaptic transmission, has been characterized with respect to several properties. The parameters studied included temperature, pH, ATP concentration, Mg/ATP ratio, and metal ion specificity. The effects of other compounds, including EGTA, NaF and several guanosine nucleotides, were also tested on the dopa‐mine‐sensitive adenylate cyclase. In addition, the subcellular distribution of the enzyme was studied. The highest specific activity was found in subcellular fractions enriched in nerve endings. A half‐maximal increase in the activity of the enzyme in a subcellular fraction occurred in the presence of 4 × 10−6 M dopamine. Fluphenazine, a dopamine antagonist, competitively inhibited the activity of the enzyme in this fraction, with a calculated inhibition constant (Ki) of 8 × 10−9M.

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