EVIDENCE FOR A DIFFERENTIAL CHOLECYSTOKININ-B AND CHOLECYSTOKININ-A RECEPTOR REGULATION OF GABA RELEASE IN THE RAT NUCLEUS-ACCUMBENS MEDIATED VIA DOPAMINERGIC AND CHOLINERGIC MECHANISMS

In the present study we characterized the cholecystokinin receptor reg ulation of (i) the dopamine D-2 agonist binding sites in striatal sect ions including the nucleus accumbens and (ii) GABA and dopamine releas e in the central part of the rat nucleus accumbens, by combining the i n vitro filter wipe-off and the in vivo microdialysis techniques. In t he binding study we demonstrate that sulphated cholecystokinin octapep tide (1 nM) increased (219 +/- 30%) the K-D value of the D-2 agonist [ H-3]N-propylnorapomorphine binding sites in sections from the striatum including the accumbens. This effect was counteracted by the cholecys tokinin-B antagonist PD134308 (50 nM). In a parallel study using micro dialysis in the central nucleus accumbens, we found that local perfusi on with sulphated cholecystokinin octapeptide (1 mu M) induced an incr ease in GABA (135 +/- 7%) and dopamine (146 +/- 8%) release which was unaffected by the cholecystokinin-A antagonist L-364,718 (10 nM). In c ontrast, when the cholecystokinin-B antagonist PD134308 (10 nM) was co -perfused with the peptide it prevented the increase in dopamine and d ecreased GABA release (-24 +/- 2%). This reduction was counteracted by the addition to the perfusate medium of the cholecystokinin-A antagon ist or the cholinergic muscarinic M(2) receptor antagonist AF-DX 116 ( 0.1 mu M). Taken together, these data demonstrate that the facilitatio n by sulphated cholecystokinin octapeptide of GABA and dopamine releas e in the central accumbens probably reflects an inhibitory effect of t he peptide on both pre- and postsynaptic D-2 receptors, mediated via c holecystokinin-B receptor activation. In addition, for the first time we provide evidence for a differential cholecystokinin-A and -B recept or-mediated regulation of GABA transmission in the central accumbens, where the cholecystokinin-B receptor exerts a dominant excitatory infl uence while the cholecystokinin-A receptor mediates an inhibition of G ABA release via a local muscarinic M(2) receptor. Copyright (C) 1996 I BRO.