The mechanism by which the selective 5-HT1A receptor antagonist S-(-) UH 301 produces head-twitches in mice.
Electrophysiological studies indicate that certain 5-HT1A receptor antagonists increase the basal firing rate of some but not all raphe neurons by antagonizing the inhibitory endogenous serotonin tone operating on the somatodendritic pulse-modulating presynaptic 5-HT1A autoreceptors. This effect should enhance the synaptic concentration of 5-HT (5-hydroxytryptamine) in serotonergic terminal fields, which may then activate postsynaptic 5-HT receptors. However, in vivo microdialysis studies show that generally such 5-HT1A antagonists by themselves do not increase the basal 5-HT release but potentiate the ability of serotonin reuptake blockers to increase the neuronal serotonin terminal output in the rat brain via the above mechanism. The purpose of the present study was to determine whether antagonism of the proposed endogenous serotonin tone on the 5-HT1A autoreceptors can potentiate the activity of other postsynaptic serotonin receptors. To this end, we utilized the head-twitch response (HTR) in mice as an in vivo model of postsynaptic 5-HT2A receptor function. The selective and silent 5-HT1A receptor antagonist, S-(-)UH 301, by itself, in a dose-dependent manner, produced the HTR in normal but not in reserpinized animals. The 5-HT2A antagonist, SR 46349B, completely prevented S-(-)UH 301-induced HTR. Pretreatment with S-(-)UH 301 also potentiated 5-hydroxytryptophan (5-HTP)-induced HTR both in normal and in the reserpinized mice. At low doses (0.06-0.25 mg/kg), the 5-HT2A selective agonist, 8-OH DPAT, significantly but partially inhibited 5-HTP-induced HTR. However, further attenuation was not observed following the administration of larger doses of 8-OH DPAT. Depending upon the dose used, S-(-)UH 301 pretreatment not only antagonized but also broke through the inhibitory effect of 8-OH DPAT on 5-HTP-induced HTR. The selective (sertraline) and nonselective (cocaine) serotonin reuptake blockers potentiated the ability of 5-HTP to induce the head-twitch behavior in mice. Pretreatment with S-(-)UH 301 enhanced the potentiating effect of serotonin reuptake blockers on the 5-HTP induced HTR. These results suggest that an endogenous 5-HT tone via the discussed mechanism controls the terminal field synapticactivity of serotonergic neurons in mice. In addition, disinhibition of pulse-modulating 5-HT1A autoreceptors by S-(-)UH 301 can potentiate the synaptic effects of serotonin reuptake blockers as well as the serotonin precursor 5-HTP. However, a more firm general conclusion regarding antagonism of presynaptic 5-HT1A receptors leading to indirect functional enhancement of other postsynaptic serotonergic receptors can only be made when the above hypothesis is further tested with other selective 5-HT1A receptor antagonists (such as WAY 100 635), which we were unable to obtain. The present study is the first report to show that a selective 5-HT1A antagonist by itself can produce a serotonin-mediated function via indirect stimulation of another serotonin receptor subtype in mice.
Darmani
N A
NA
Department of Pharmacology, Kirksville College of Osteopathic Medicine, MO 63501, USA.
Reeves
S L
SL
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology; D019416:Head Movements / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017729:Presynaptic Terminals / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000187:drug effects; D014364:Tryptophan / Q000494:pharmacology
D006916:5-Hydroxytryptophan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000319:Adrenergic beta-Antagonists; D018765:Dopamine Uptake Inhibitors; D005277:Fenfluramine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014364:Tryptophan; C064282:UH 301