INHIBITION OF A9 AND A10 DOPAMINE CELLS BY THE CHOLECYSTOKININ-B ANTAGONIST LY262691 - MEDIATION THROUGH FEEDBACK PATHWAYS FROM FOREBRAIN SITES

The diphenylpyrazolidinone cholecystokinin-B (CCK-B) antagonist LY2626 91 has been shown to decrease the number of spontaneously active dopam ine (DA) cells in the ventral tegmental area (A10) and substantia nigr a (A9) of the anesthetized rat. In the present study, we examined the localization of the receptors mediating these effects of LY262691 on A 9 and A10 DA cells. In one group of anesthetized rats, the effects of systemic administration of LY262691 on the number of spontaneously act ive A9 or A10 DA cells was determined using extracellular, single-unit recordings after radio frequency lesions were placed in the nucleus a ccumbens, caudate-putamen, or medial prefrontal cortex. Lesions of the caudate-putamen blocked the effects of systemically administered LY26 2691 on the number of spontaneously active A9, but not A10, DA cells. Conversely, lesions of the n. accumbens blocked the effects of systemi cally administered LY262691 on A10, but not A9, DA cells. Lesions of t he medial prefrontal cortex blocked the effects of systemically admini stered LY262691 on both A9 and A10 DA cells. In a separate group of an esthetized rats, the number of spontaneously active A9 or A10 DA cells was determined after LY262691 was microinjected into the n. accumbens , caudate-putamen, or medial prefrontal cortex. Microinjection of LY26 2691 into the caudate-putamen led to a significant decrease in the num ber of spontaneously active A9, but not A10, DA cells. Conversely, mic roinjection of LY262691 into the n. accumbens or medial prefrontal cor tex led to a significant decrease in the number of spontaneously activ e A10, but not A9, DA cells. Microinjection of a structurally related CCK-A antagonist (LY219057) into the n. accumbens or medial prefrontal cortex did not affect the number of spontaneously active A10 DA cells , and microinjection of LY219057 into the caudate-putamen did not affe ct the number of spontaneously active A9 DA cells. These results indic ate that, consistent with known feedback pathways between forebrain st ructures and midbrain DA neurons, the effects of LY262691 on A9 cells are mediated, at least in part, by antagonism of CCK-B receptors in th e caudate-putamen, whereas the effects of LY262691 on A10 cells are me diated, at least in part, by antagonism of CCK-B receptors in the n. a ccumbens and medial prefrontal cortex. (C) 1993 Wiley-Liss, Inc.