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 ant agonists increase the basal firing rate of some but not all raphe neur ons by antagonizing the inhibitory endogenous serotonin tone operating on the somatodendritic pulse-modulating presynaptic 5-HT1A autorecept ors. This effect should enhance the synaptic concentration of 5-HT (5- hydroxytryptamine) in serotonergic terminal fields, which may then act ivate postsynaptic 5-HT receptors. However, in vivo microdialysis stud ies show that generally such 5-HT1A antagonists by themselves do not i ncrease 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 s tudy was to determine whether antagonism of the proposed endogenous se rotonin tone on the 5-HT1A autoreceptors can potentiate the activity o f other postsynaptic serotonin receptors. To this end, we utilized the head-twitch response (HTR) in mice as an in vivo model of postsynapti c 5-HT2A receptor function. The selective and silent 5-HT1A receptor a ntagonist, S-(-)UH 301, by itself, in a dose-dependent manner, produce d the HTR in normal but not in reserpinized animals. The 5-HT2A antago nist, SR 46349B, completely prevented S-(-)UH 301-induced HTR. Pretrea tment with S-(-)UH 301 also potentiated 5-hydroxytryptophan (5-HTP)-in duced HTR both in normal and in the reserpinized mice. At low doses (0 .06-0.25 mg/kg), the 5-HT1A selective agonist, X-OH DPAT, significantl y but partially inhibited 5-HTP-induced HTR. However, further attenuat ion was not observed following the administration of larger doses of 8 -OH DPAT. Depending upon the dose used, S-(-)UH 301 pretreatment not o nly antagonized but also broke through the inhibitory effect of S-OH D PAT 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 o n the 5-HTP-induced HTR. These results suggest that an endogenous 5-HT tone via the discussed mechanism controls the terminal field synaptic activity of serotonergic neurons in mice. In addition, disinhibition of pulse-modulating S-HT1A autoreceptors by S-(-)UH 301 can potentiate the synaptic effects of serotonin reuptake blockers as well as the se rotonin precursor 5-HTP. However, a more firm general conclusion regar ding antagonism of presynaptic 5-HT1A receptors leading to indirect fu nctional enhancement of other postsynaptic serotonergic receptors can only be made when the above hypothesis is further tested with other se lective 5-HT1A, receptor antagonists (such as WAY 100 635), which we w ere unable to obtain. The present study is the first report to show th at a selective 5-HT1A antagonist by itself can produce a serotonin-med iated function via indirect stimulation of another serotonin receptor subtype in mice.