Hippocampal Serotonin 5‐HT_1A Receptor Enhances Acetylcholine Release in Conscious Rats

Abstract

We investigated changes in the extracellular levels of acetylcholine (ACh) following local application of serotonergic agents to the dorsal hippocampus of freely moving rats by means of perfusion using a microdialysis technique. Perfusion of serotonin (5‐HT; 10 μM, for 30 min at a rate of 3 μl/min), dissolved in Ringer's solution containing 10 μM eserine, showed no marked effect on the extracellular levels of ACh. 8‐Hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT; 20 μM), a 5‐HT1A agonist, increased ACh levels, whereas 7‐trifluoromethyl‐4‐(4‐methyl‐1 ‐piperazinyl)‐pymoto[1,2‐a]quinoxaline (CGS‐12066B; 100 μM), a 5‐HT1B agonist, decreased it. Clomipramine (2 μM), an uptake inhibitor of 5‐HT, had no effect on ACh levels. Following perfusion of 1‐(2‐methoxyphenyl)‐4‐[4‐ (2‐phthalimido)butyl]piperazine (NAN‐190; 10 μM), which is a selective 5‐HT1A antagonist, the effect of 8‐OH‐DPAT was totally abolished, whereas CGS‐12066B decreased extracellular ACh levels. 5‐HT, as well as Clomipramine, had a decreasing effect on ACh levels after pretreatment with NAN‐190. These results indicate that the 5‐HT1A receptor, which exists in the dorsal hippocampus, enhances the spontaneous ACh release, and that the mechanism of serotonergic modulation of ACh release partly depends on both the stimulatory control via the 5‐HT1A receptor and the suppressive one via the 5‐HT1B receptor in the dorsal hippocampus of rats.

5-HT Receptor Regulation of Neurotransmitter Release

“…However, the effects produced by each of the 372 few ligands applied in the investigations (Maura and Raiteri, 1986;Bolañ os-Jiménez et al, 1994;Izumi et al, 1994) in the rat hippocampus conform to the functional and pharmacological properties of the inhibitory presynaptic 5-HT 1B heteroreceptors, thus leading the authors to suggest that their study is dealing with this receptor type, a conclusion that appears to be justified.…”

“…Hence, non-G i/o protein coupling is a very improbable alternative to explain the facilitatory effect of 5-HT 1A receptor agonists on ACh release in vivo. Therefore, it is likely that the 5-HT 1A receptor is located on a noncholinergic neuron directly or indirectly innervating the ACh neuron (Izumi et al, 1994;Lü ttgen et al, 2005).…”

“…An alternative explanation of the facilitatory effect of systemically applied 5-HT 1A receptor agonists is founded on additional in vivo experiments in which 8-OH-DPAT and other 5-HT 1A receptor ligands were administered to the rat hippocampus via the dialysis probe (Izumi et al, 1994). This administration mimicked the effect of systemically injected 8-OH-DPAT, i.e., increased ACh release in a manner sensitive to blockade by the (partial) 5-HT 1A receptor antagonist These findings are compatible with the suggestion that the inhibitory 5-HT 1A receptor is located on inhibitory hippocampal interneurons, most probably GABAergic interneurons that are densely innervated by serotoninergic afferents (Freund et al, 1990;Halasy et al, 1992) and whose synaptic boutons are endowed with presynaptic heteroreceptors (Katsurabayashi et al, 2003) (section VI.…”

“…The results indicate that aging does not alter the function of presynaptic 5-HT heteroreceptors on cholinergic nerves. Obviously, the presynaptic 5-HT heteroreceptor mediating inhibition of ACh release in the rat hippocampus is also operative in vivo because in a microdialysis study (Izumi et al, 1994) such an effect was observed in response to CGS 12066B and, after blockade of 5-HT 1A receptors by , also to 5-HT and clomipramine (Table 2). There has been some controversy concerning the 5-HT receptor type that mediates the inhibitory effects of 5-HT in the rat hippocampus because this inhibition requires functional elimination of substance P interneurons endowed with 5-HT 2A receptors.…”

“…The inhibitory effect of 5-HT receptor agonists on [ 3 H]ACh release is mimicked in slices and in vivo by 5-HT uptake blockers such as 6-nitroquipazine (Maura et al, 1989), clomipramine (Izumi et al, 1994), and fluoxetine (Jackson et al, 1988) or by the 5-HT releasing drug d-fenfluramine (Maura et al, 1989). Both types of compounds, because of their specific effects on 5-HT inactivation in, and release from, serotoninergic neurons, respectively, increase the concentration of endogenous 5-HT in the biophase of the receptor.…”