Summary
An in vivo model for investigating the interaction of drugs with presynaptic receptors was used to study the effect of chronic treatment of rats with fluphenazine decanoate on the presynaptic dopamine receptors in the neostriatum and olfactory tubercle. In this model system dopaminergic impulse flow is inhibited pharmacologically with γ-butyrolactone (GBL). This results in an increase of apparent tyrosine hydroxylase activity, estimated by the accumulation of a dopa during the 30-min interval following administration of a dopa decarboxylase inhibitor. Dopamine agonists produce a dose-dependent blockade of the effect of GBL on dopa accumulation.
On days 12 through 21 after rats were injected with fluphenazine decanoate, 2 dopamine agonists-apomorphine (tested on days 12, 15, 17, and 21) and trivastal (ET 495; piribidel; tested on days 12, 14, and 19)-were more potent in blocking the GBL-induced increase of dopa accumulation in the striata of treated animals than in controls. Thirty days after the fluphenazine injection the effect of the dopamine agonists on dopa accumulation in the neostriatum returned to control levels. On Day 14 after fluphenazine decanoate injection the dose-response curve of apomorphine's inhibitory effect on the GBL-induced increase of dopa accumulation in the neostriatum was shifted to the left.
In control animals apomorphine was approximately 10-fold more potent in depressing the GBL-induced increase of dopa accumulation in the olfactory tubercles than in the neostriatum. Apomorphine was even more potent in the olfactory tubercle on day 14 after a single injection of fluphenazine decanoate. These results suggest that following chronic treatment of rats with a phenothiazine, presynaptic receptors on dopamine nerve terminals in the striatum and limbic system become supersensitive to dopamine agonists.
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Nowycky, M.C., Roth, R.H. Presynaptic dopamine receptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 247–254 (1977). https://doi.org/10.1007/BF00500967
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DOI: https://doi.org/10.1007/BF00500967