5‐HT_1A agonists increase and 5‐HT₃ agonists decrease acetylcholine efflux from the cerebral cortex of freely‐moving guinea‐pigs

Abstract

1 The influence of 5-hydroxytryptaminelA (5-HT1A), 5-HT2 and 5-HT3 agonists and antagonists on acetylcholine (ACh) release from the cerebral cortex was studied in freely moving guinea-pigs. 2 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-lmgkg-1, s.c.) caused the 5-HT syndrome and dose-dependently increased ACh release. Ru 24969 (1-lOmgkg-', s.c.) shared the same effects, but it was less potent. (--Propranolol (5mgkg-1) and metitepine (2mgkg-1) prevented these behavioural and neurochemical responses.3 (±)-1(4-Iodo-2,5-dimethoxyphenyl)2-aminopropane (DOI) up to 2mgkg-1 did not modify ACh release and ketanserin (0.5 mg kg-1) was ineffective on 5-HT-induced changes of ACh outflow.

5-HT Receptor Regulation of Neurotransmitter Release

“…Classification. The 5-HT receptors modulating ACh release in response to 5-HT 3 receptor ligands in the rat, guinea pig, and human cerebral cortex and in the rat hippocampus can unequivocally be classified as 5-HT 3 (Barnes et al, 1989;Bianchi et al, 1990;Siniscalchi et al, 1991;Maura et al, 1992;Consolo et al, 1994b). This statement is proven by the findings that inhibition or increase of release is induced by 5-HT 3 receptor agonists such as 2-methyl-5-HT or 1-phenylbiguanide (or by exogenous or endogenous 5-HT) and that the effect of the agonists is blocked by 5-HT 3 receptor antagonists such as GR 38032F, zacopride, ondansetron, tropisetron, DAU 6215, or MDL 72222 (Table 4).…”

Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system

“…For example, interactions between 5-HT3-receptor mediated mechanisms and ACh may differ in cortex and hippocampus, and either or both of these may involve interactions with other neuronal systems. In the case of the cortex, increased release or turnover of ACh has been demonstrated following depletion of 5-HT by lesion or synthesis inhibition (Vizi et al 1981, Robinson 1983, an effect linked to 5-HT3 receptors by findings that antagonists increase, and agonists reduce release of ACh from human cortical synaptosomes, and guinea pig cortex (Bianchi et al 1990;Maura et al 1992). Bianchi et al's findings further suggest that the inhibitory effects of 5-HT on release of ACh are mediated indirectly through interneurons.…”

“…Depletion of 5-HT by lesion or synthesis inhibition increases release of cortical acetylcholine (ACh) (Vizi et al 1981) and increases 5-HT turnover in cortex and hippocampus (Robinson 1983), suggesting that 5-HT exerts tonic inhibitory control over both cortical and hippocampal branches of the FCPS. Evidence for bidirectional effects of 5-HT3 receptor agonists and antagonists in respectively counteracting or promoting ACh release in human cortical synaptosomes (Maura et al 1992) and in cortex of freely moving guinea pigs (Bianchi et al 1990), suggests that 5-HT3 receptors play a key role in cortical serotonergic control of ACh release. Effects of 5-HT3 receptors on release of ACh in hippocampus are not so clearcut.…”

Selective decline of 5-HT1A receptor binding sites in rat cortex, hippocampus and cholinergic basal forebrain nuclei during aging

“…The generalized decrease of 5-HT 1A receptor binding in the frontal and parietal neocortex and the selective decline in the dentate gyrus as found in the present study, might influence ACh release locally contributing to the learning and memory decline found in aged rats. In summary, cholinergic neurons are regulated by 5-HT 1A receptor sites twofold: directly through somatodendritic synapses at the level of the cholinergic nuclei (Sprouse and Aghajanian, 1987;Khateb et al, 1993), and probably indirectly at the level of cortical target areas (Bianchi et al, 1990;Izumi et al, 1994). What the characteristic decline of 5-HT 1A receptor binding at these two levels mean for the functional properties of cholinergic neurons during aging is only partly understood and will certainly require further study.…”