Cholecystokinin release mediated by 5‐HT3 receptors in rat cerebral cortex and nucleus accumbens

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Abstract
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 mm KCl. 2 In both areas 5-HT, tested between 0.1 and 100 nm, 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 (EC50: 0.4 + 0.045 nm and 0.48 ± 0.053 nm, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nm 5-HT). 3 The 5-HT1/5-WT2 receptor antagonist methiothepin (300 nm) did not affect the CCK-LI release elicited by 10 nm 5-HT. However, the effects of 10 nm 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3α-tropanyl)-1H-indole-3-carboxylic acid ester (ICS 205–930; 0.1–100 nm; IC50: 3.56 ± 0.42 nm in the cortex and 3.90 ± 0.50 nm in the n. accumbens) and ondasetron (IC50: 8.15 + 0.73 nm in the cerebral cortex). 5-HT (10 nm) was also strongly antagonized by 100 nm 1αH, 3α5αH-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100 nm) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC50 = 0.64 + 0.071 nm). 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-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs.