New potential antipsychotic drug BMY 20661: A profile of its effects on midbrain dopamine neurons

Abstract

AbstractThe new potential antipsychotic drug BMY 20661 was subjected to a series of electrophysiological tests to determine its effects on midbrain dopamine (DA) neurons in the rat substantia nigra pars compacta (A9) and ventral tegmental area (A10). Acute intravenous (i.v.) administration of BMY 20661 exerted little effect on the basal spontaneous firing rates of either A9 or A10 DA neurons. Following suppression of DA unit activity by the DA agonist apomorphine (APO), BMY 20661 consistently increased the firing of A10, but not A9, DA cells. However, the rates of A10 DA cells seldom recovered to pre‐APO basal levels following BMY 20661 administration. The ability of BMY 20661 to partially reverse the APO‐induced rate suppression was apparently not due to blockade of DA receptors since pretreatment with BMY 20661 (6.3 mg/kg, i.v.) only slightly (nonsignificantly) reduced the ability of APO to inhibit the firing of A10 cells. Surprisingly, BMY 20661 significantly attenuated the effects of APO on A9 DA cells. These findings suggest that BMY 20661 influences A10 DA neurons by a non‐DA mechanism. Because BMY 20661 has been reported to bind to 5‐HT1A receptors, the acute effects of this compound were compared to those of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), a known 5HT1A agonist. These compounds demonstrated similar profiles in their ability to reverse APO‐induced suppression of A10 DA cells but, unlike BMY 20661, 8‐OH‐DPAT was also active on A9 DA cells. Repeated administration of BMY 20661 for 28 days (either 5 or 10 mg/kg/day) failed to alter significantly the number of spontaneously active A10 DA cells but caused a small, but statistically significant, increase in the number of A9 DA cells/track. Because the ability to decrease the number of spontaneously active A10 DA cells has been proposed as a predictive model for antipsychotic drug action, the results obtained following repeated administration of BMY 20661 fail to support a potential antipsychotic profile for this new compound.