Evidence for a differential cholecystokinin-B and -A receptor regulation of GABA release in the rat nucleus accumbens mediated via dopaminergic and cholinergic mechanisms

Abstract In the present study we characterized the cholecystokinin receptor regulation of (i) the dopamine D 2 agonist binding sites in striatal sections including the nucleus accumbens and (ii) GABA and dopamine release in the central part of the rat nucleus accumbens, by combining the in vitro filter wipe-off and the in vivo microdialysis techniques. In the binding study we demonstrate that sulphated cholecystokinin octapeptide (1 μ M) increased (219 ± 30%) the K D value of the D 2 agonist [ 3 H] N -propy-lnorapomorphine binding sites in sections from the striatum including the accumbens. This effect was counteracted by the cholecystokinin-B antagonist PD 134308 (50 nM). In a parallel study using microdialysis in the central nucleus accumbens, we found that local perfusion with sulphated cholecystokinin octapeptide (1 ± M) induced an increase in GABA (135 ±7%) and dopamine (146 ± 8%) release which was unaffected by the cholecystokinin-A antagonist L-364, 718 (10 μ M). In contrast, when the cholecystokinin-B antagonist PD134308 (10 μ M) was co-perfused with the peptide it prevented the increase in dopamine and decreased GABA release (-24 ± 2%). This reduction was counteracted by the addition to the perfusate medium of the cholecystokinin-A antagonist or the cholinergic muscarinic M 2 receptor antagonist AF-DX 116 (0.1 μM). Taken together, these data demonstrate that the facilitation by sulphated cholecystokinin octapeptide of GABA and dopamine release in the central accumbens probably reflects an inhibitory effect of the peptide on both pre- and postsynaptic D 2 receptors, mediated via cholecystokinin-B receptor activation. In addition, for the first time we provide evidence for a differential cholecystokinin-A and -B receptor-mediated regulation of GABA transmission in the central accumbens, where the cholecystokinin-B receptor exerts a dominant excitatory influence while the cholecystokinin-A receptor mediates an inhibition of GABA release via a local muscarinic M 2 receptor.