Cholecystokinin combined with serotonin in the hypothalamus limits accumbens dopamine release while increasing acetylcholine: a possible satiation mechanism.

Serotonin (5-HT) or cholecystokinin (CCK) injected in the hypothalamic paraventricular nucleus (PVN) inhibits feeding, but the mechanism is unknown. Prior research suggests that dopamine (DA) input to the nucleus accumbens (NAc) motivates behavior, and a component of that motivation circuit includes hypothalamic feeding systems. Acetylcholine (ACh) in the NAc, on the other hand, may act in part to inhibit feeding and generate satiety. If so, 5-HT and/or CCK in the PVN should lower extracellular DA or release ACh in the NAc. Rats were prepared with microdialysis probes in the NAc and injectors in the PVN. Serotonin (7.75 microg) or CCK-8 (0.12 microg) injected in the PVN significantly decreased ipsilateral accumbens DA (63 and 73% of baseline, respectively, without effect on ACh). However, 5-HT plus CCK injected in combination decreased DA to 72% (P<0.001) and simultaneously increased extracellular ACh to 128% of baseline (P<0.001). In later tests with the same doses and the same animals, unilateral PVN injections of 5-HT, CCK, or both combined, significantly inhibited food intake in the early dark period. The results suggest that 5-HT in the PVN acts as a neural modulator that primes a hypothalamic satiation system to respond to CCK when the gastrointestinal tract contains food to be digested. The synergistic action of 5-HT plus phasic CCK may then activate a circuit that simultaneously limits DA and releases ACh in the accumbens as part of the satiation process.