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Unique response to antipsychotic drugs is due to absence of terminal autoreceptors in mesocortical dopamine neurones

Naturevolume 296pages444446 (1982) | Download Citation



A projection of dopamine (DA) neurones has been identified which runs from the rat midbrain ventral tegmental area to the cerebral cortex1. Relative to other cortical areas, the prefrontal cortex is enriched in DA2,3, tyrosine hydroxylase3, DA uptake2,3, DA-sensitive adenylate cyclase2 and DA-responsive neurones4. Lesions of the prefrontal cortex or selective lesions of the prefrontal cortical DA innervation induce functional deficits, including detrimental effects on delayed response tasks, a difficulty in suppressing attention to irrelevant stimuli and a diminution in affective and social behaviour (for a review, see ref. 5). Recent studies have shown that this mesocortical DA system differs from other DA systems (such as the nigrostriatal and mesolimbic DA systems) in terms of drug responsiveness. For example, the acute administration of antipsychotic drugs (for example, haloperidol) greatly accelerates DA turnover in the nigrostriatal and mesolimbic DA systems through multiple sites of action, but only modestly accelerates mesocortical DA turnover. Following the chronic administration of moderate doses of antipsychotic drugs, tolerance to the effects of a haloperidol challenge dose is generally seen in the striatum and olfactory tubercle but not in the frontal cortex6–8. Similar results obtained in experiments involving primates have led to the suggestion that the frontal cortex may be the site of therapeutic action of the antipsychotic agents9,10. In light of the recent finding that rat mesocortical DA neurones lack terminal autoreceptors11, we have investigated the possible role of nerve terminal DA autoreceptors in mediating the varied responses seen in different brain regions following acute and chronic antipsychotic drug treatment. The results, reported here, suggest that both the relatively small activation of the mesocortical DA system in response to a haloperidol challenge, and the lack of tolerance to haloperidol following chronic treatment, may be related to the absence of nerve terminal autoreceptors.

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

    • M. J. Bannon
    • , J. F. Reinhard Jr
    • , E. B. Bunney
    •  & R. H. Roth


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