Effects produced by acute and chronic treatment with granisetron alone or in combination with haloperidol on midbrain...

In this study, we examined the effects of acute and chronic administration of the 5-HT3 receptor antagonist granisetron (0.1, 1.0 or 10 mg/kg i.p.) alone or in combination with haloperidol (0.5 mg/kg i.p.) on the number of spontaneously active dopamine neurons in the substantia nigra pars compacta (SNC or A9) and the ventral tegmental area (VTA or A10). This was accomplished using the technique of extracellular single unit recording. Acute granisetron at 0.1 mg/kg, but not at higher doses, selectively decreased the number of spontaneously active A10 DA cells. Chronic administration of 0.1 or 1 mg/kg granisetron selectively decreased the number of spontaneously active A10 dopamine cells compared to controls, mimicking the effect produced by chronic treatment with the atypical neuroleptic drug clozapine. However, unlike the effect produced by neuroleptics, this granisetron-induced effect was not reversed by the systemic administration of apomorphine (50 micrograms/kg). These results suggest that the chronic granisetron-induced reduction of the number of spontaneous active dopamine cells is not the result of depolarization inactivation. Chronic coadministration of granisetron with haloperidol negates the effects produced by either compound alone. Acute coadministration of granisetron with haloperidol also attenuated or abolished haloperidol's action, particularly that on the A9 dopamine cells. Overall, it appears that at 0.1 and 1.0 mg/kg, chronic granisetron may possess atypical neuroleptic drug potential. However, the combination of haloperidol and granisetron nullifies changes in midbrain dopamine neurons observed with either agent alone.