Electrophysiological effects of diphenylpyrazolidinone cholecystokinin-B and cholecystokinin-A antagonists on midbrain dopamine neurons

Abstract

The diphenylpyrazolidinone cholecystokinin (CCK)-B antagonist LY262691 has recently been demonstrated to decrease the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (A10) and substantia nigra (A9) of the anesthetized rat. In the present study, three structural analogs of LY262691 with high selectivity for CCK-B receptors, LY262684, LY191009 and LY242040, also decreased the number of spontaneously active A10 DA cells. Neither an inactive analog (LY206890) nor a CCK-A-selective analog (LY219057) affected the number of spontaneously active A10 DA cells. L-365,260, a benzodiazepine CCK-B antagonist, also decreased the number of spontaneously active A10 DA cells. In addition, the more active optical isomer of LY262691 (LY288513) caused twice as large a decrease in the number of spontaneously active A10 DA cells as the less active optical isomer (LY288512). The diphenylpyrazolidinone CCK-B antagonists, but neither the inactive nor the CCK-A selective analog, also decreased the number of spontaneously active A9 DA cells; however, none of these compounds produced catalepsy in awake animals. Single-unit recordings indicated that LY262691 administration inhibited the activity of individual A9 and A10 DA neurons. These results indicate that the firing of A9 and A10 DA neurons is suppressed specifically by antagonism of CCK-B, but not CCK-A receptors. CCK-B antagonists may therefore represent a novel class of antipsychotic drugs. Furthermore, because CCK-B antagonists have no cataleptogenic effects, they may also have a reduced propensity for producing extrapyramidal side effects. In addition, these actions on midbrain DA neurons may contribute to the known anxiolytic activity of CCK-B antagonists.