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.
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.
Somboonthum
P
P
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Matsuda
T
T
Asano
S
S
Sakaue
M
M
Baba
A
A
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000109:Acetylcholine / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014851:Wakefulness / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D004146:Dioxanes; D004149:Dioxoles; D010879:Piperazines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081293:WAY 100135; D015116:5,7-Dihydroxytryptamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011433:Propranolol; C096294:osemozotan; D000109:Acetylcholine