MKC-242, a novel 5-HT1A receptor agonist, facilitates cortical acetylcholine release by a mechanism different from that of 8-OH-DPAT in awake rats

• Published in: Neuropharmacology Vol. 36; no. 11-12; pp. 1733 - 1739
• Main Authors: SOMBOONTHUM, P, MATSUDA, T, ASANO, S, SAKAUE, M, BABA, A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01-11-1997
• Subjects: 5,7-Dihydroxytryptamine - pharmacology; 8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology; Acetylcholine - metabolism; Adrenergic beta-Antagonists - pharmacology; Animals; Biological and medical sciences; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cholinergic system; Dioxanes - pharmacology; Dioxoles - pharmacology; Extracellular Space - drug effects; Extracellular Space - metabolism; Injections, Subcutaneous; Male; Medical sciences; Microdialysis; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - pharmacology; Propranolol - pharmacology; Rats; Rats, Wistar; Serotonin Agents - pharmacology; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology; Wakefulness - physiology; Cholinergic neuron; Agonist; Cerebral cortex; Rat; Psychotropic; Rodentia; Central nervous system; Autoreceptor; Vertebrata; Mammalia; 5-HT1A Serotonine receptor; Tranquillizer; Animal; Acetylcholine; Brain (vertebrata); Cholinergic transmission
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(97)00174-3

We have previously reported that 5-¿3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy¿-1,3-be nzodioxole (MKC-242), a potent and selective serotonin (5-HT)1A receptor agonist, exerts anxiolytic- and antidepressant-like effects in animal models and that the antidepressant-like effect may be mediated by postsynaptic 5-HT1A receptors. The present study, using a microdialysis technique, was undertaken to characterize in vivo the effect of MKC-242 on cholinergic neurons. Subcutaneous injection of MKC-242 (0.5-1.0 mg/kg), like the typical 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), increased extracellular acetylcholine (ACh) levels in the rat cerebral cortex. The increase in ACh release by MKC-242 was also observed in the hippocampus. The effect of MKC-242 on cortical ACh release was attenuated by pretreatment with the 5-HT1A receptor antagonists (10 mg/kg, s.c.) propranolol and N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropana mide. The increase in cortical ACh release by MKC-242 was blocked by lesion of serotonergic neurons with 5,7-dihydroxytryptamine, whereas that by 8-OH-DPAT was not. Lesion of noradrenergic neurons with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not affect the MKC-242-induced increase in ACh release. These results suggest that systemic injection of MKC-242 facilitates in vivo ACh release via an activation of somadendritic 5-HT1A autoreceptors, and that MKC-242 and 8-OH-DPAT affect cholinergic neurons in the rat cerebral cortex via different mechanisms.