Cholecystokinin release mediated by 5‐HT 3 receptors in rat cerebral cortex and nucleus accumbens

1 The effects of 5‐hydroxytryptamine (5‐HT) on the release of cholecystokinin‐like immunoreactivity (CCK‐LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 m m KCl. 2 In both areas 5‐HT, tested between 0.1 and 100 n m , increased the calcium‐dependent, depolarization‐evoked CCK‐LI release in a concentration‐related manner. The concentration‐response curves did not differ significantly between the two brain areas (EC 50 : 0.4 + 0.045 n m and 0.48 ± 0.053 n m , respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 n m 5‐HT). 3 The 5‐HT 1 /5‐WT 2 receptor antagonist methiothepin (300 n m ) did not affect the CCK‐LI release elicited by 10 n m 5‐HT. However, the effects of 10 n m 5‐HT were antagonized in a concentration‐dependent manner by the 5‐HT 3 receptor antagonists (3α‐tropanyl)‐1H‐indole‐3‐carboxylic acid ester (ICS 205–930; 0.1–100 n m ; IC 50 : 3.56 ± 0.42 n m in the cortex and 3.90 ± 0.50 n m in the n. accumbens) and ondasetron (IC 50 : 8.15 + 0.73 n m in the cerebral cortex). 5‐HT (10 n m ) was also strongly antagonized by 100 n m 1αH, 3α5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate (MDL 72222) another blocker of the 5‐HT 3 receptor. Moreover, the 5‐HT3 receptor agonist 1‐phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 n m ) enhanced CCK‐LI release in a manner almost identical to that of 5‐HT (EC 50 = 0.64 + 0.071 n m ). 4 It is concluded that 5‐HT can act as a potent releaser of CCK‐LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5‐HT 3 type situated on the CCK‐releasing terminals. This interaction may provide a rationale for the clinical development of both 5‐HT 3 and CCK receptor antagonists as novel anxiolytic drugs.