The 5-HT1A receptor antagonist (S)-UH-301 blocks the (R)-8-OH-DPAT-induced inhibition of serotonergic dorsal raphe cell firing in the rat

Abstract

(S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin, 0.5-4.0 mg/kg i.v.] did not significantly alter the firing rate of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN) as a group, although some individual cells were activated whereas others were depressed. However, (S)-UH-301 (2.0 mg/kg i.v.) consistently reversed the inhibition of DRN-5-HT cells produced by the selective 5-HT1A receptor agonist (R)-8-OH-DPAT (0.5 microgram/kg i.v.) and the dose-response curve for this effect of (R)-8-OH-DPAT was markedly shifted to the right by pretreatment with (S)-UH-301 (1.0 mg/kg i.v.). These results support the notion that (S)-UH-301 acts as an antagonist at central 5-HT1A receptors.

The Pharmacology of the Neurochemical Transmission in the Midbrain Raphe Nuclei of the Rat

“…This finding is in line of previous suggestions that 5-HT 2 receptor antagonists may augment 5-HT uptake inhibitory properties of certain compounds [36]. The somatodendritic 5-HT 1 receptors have multifunctional roles since they are involved in the regulation of 5-HT release and synthesis as well as in the regulation of neuronal impulse generation and firing activity [7,9,49,83]. Raphe nuclei possess at least two autoreceptor mechanisms that control 5-HT release: one directly mediated by 5-HT 1B and/or 5-HT 1D receptors and the other one indirectly mediated by 5-HT 1A autoreceptors that also modulate neural firing rate [15].…”

“…3 H]5-HT release indirectly in raphe nuclei serving as heteroreceptors rather than autoreceptors in release inhibition and in fact, observations that exclude the autoreceptor function of 5-HT 7 receptors have also been reported [132].…”

“…Although no selective agonist for 5-HT 7 receptors is yet available, 5-carboxamidotryptamine (5-CT) and 5-methoxytryptamine express high affinity and 8-OH-DPAT binds with moderate affinity to 5-HT 7 receptors [14,86,135]. SB-258719, SB-258741, and SB-269970 were the first selective 5-HT 7 receptor antagonists [61,69,102], which were recently introduced as research tools.…”

“…These are the spontaneous, slow firing activity of 5-HT neurons, the 5-HT release-mediated autoinhibition of the neurons and the excitatory and inhibitory afferent inputs mediated by non-5-HT receptors [126]. The autoinhibitory properties of serotonergic neurons, which include regulation of transmitter release and synthesis and neural firing, are determined by various metabotropic (5-HT 1A/1B/1D , 5-HT 2A/2C , 5-HT 7 ) and ionotropic (5-HT 3 ) 5-HT receptors [11,15,180]. Different 5-HT 1 receptor subtypes are present on 5-HT-containing neurons in the raphe nuclei and they inhibit 5-HT release [49,125,149,153] albeit their regulatory function in this process is different.…”

Comparison of the Novel Antipsychotic Ziprasidone with Clozapine and Olanzapine Inhibition of Dorsal Raphe Cell Firing and the Role of 5-HT1A Receptor Activation

“…Early work noted the ability of LSD and 5-HT itself to slow neuronal firing (Aghajanian et al 1972); later more selective 5-HT 1A receptor agents, led in large part by 8-OH-DPAT, were employed to establish the receptor subtype of the somatodendritic autoreceptors known to modulate firing rate (deMontigny et al 1984;VanderMaelen et al 1986;Sprouse and Aghajanian 1987). Clearly, however, the most compelling evidence for 5-HT 1A receptor-mediated inhibition lay in the blockade or reversal of the agonist-induced response by first non-selective 5-HT 1 antagonists (Sprouse and Aghajanian 1986;Lum and Piercey 1988) and later by low efficacy compounds selective for the 5-HT 1A subtype among the family of 5-HT receptors (Arborelius et al 1994;Fletcher et al 1994;Fornal et al 1996). As a result, new agents, outside of the prototypical class, can be regarded as 5-HT 1A receptor agonists by virtue of their ability to mimic the inhibitory actions of 8-OH-DPAT on serotonin neuronal firing and the sensitivity of such inhibition to 5-HT 1A receptor antagonists.…”