5-HT1A receptor ligands with putative antidepressant activity : pharmacological studies in the rat

<p>Several studies suggest that serotonin (5-hydroxytryptamine, 5-HT)IA receptor agonists possess antidepressant activity. Probably these agents exert their therapeutic effect through stimulation of postsynaptic 5-HT,A receptors. Recently, the addition of a 5-HT,A receptor antagonist has been proposed to increase the therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) by preferentially blocking inhibitory somatodendritic 5-HT,A autoreceptors, which regulate the neuronal activity of midbrain 5-HT cells. In the present study, the 5-HT,A receptor antagonistic actions of (S)-UH-301 were further characterized in vivo. The effects of (S)-UH-301 alone or in combination with acute or chronic treatment with the SSRI citalopram on the activity of 5-HT cells in the dorsal raphe nucleus (DRN) and neurotransmitter release from their nerve terminals were also studied.</p><p>Since central dopaminergic (DA) pathways, in particular the mesolimbocortical DA system, may also be involved in the therapeutic effects of antidepressant drugs the effects of (S)-UH-301 and the selective 5-HT,A receptor agonist (R)-8-OH- DPAT on the activity of DA neurons in the ventral tegmental area (VTA) and substantia nigra, zona compacta (SN-ZC), and their terminal release were also investigated.</p><p>The activity of midbrain 5-HT or DA neurons was extracellularly recorded in the anesthetized rat and extracellular concentrations of 5-HT, DA and its respective metabolites were assessed by microdialysis in freely moving rats. (S)-UH-301 antagonized the (R)-OH-DPAT-induced decreases in activity of DRN-5-HT cells and the release of 5-HT in the hippocampus. These findings contribute to the in vivo characterization of (S)-UH-301 as an antagonist at central 5-HTIA receptors. (S)-UH-301 alone increased the activity of some 5-HT neurons as well as the release of 5-HT in the frontal cortex, suggesting that at least some 5-HT neurons and the release from their terminals are subjected to a tonically active, negative feedback control by 5-HT through 5-HT,A receptors.</p><p>Concomitant administration of (S)-UH-301 antagonized the acute feedback inhibition of 5-HT neuronal activity produced by citalopram. Accordingly, pretreatment with (S)- UH-301 enhanced the acute facilitatory effect of citalopram on extracellular concentrations of 5-HT in the frontal cortex. (S)-UH-301 increased the activity of 5-HT neurons also in rats maintained on a chronic citalopram regimen, even when these neurons had regained normal activity. Moreover, (S)-UH-301 further increased the already elevated extracellular concentration of 5-HT in the frontal cortex of chronically citalopram treated rats.</p><p>Administration of (S)-UH-301 inhibited the activity of DA cells both in the VTA and in the SN-ZC, as well as the release of DA in the striatum and the nucleus accumbens, probably through direct stimulation of D2 autoreceptors. Systemically administered (R)-8-OH-DPAT increased the activity of DA neurons in the VTA, but not in SN-ZC, and selectively increased DA release in the prefrontal cortex, whereas that in other terminal regions was not affected. Recent clinical studies suggest that addition of a 5-HT,A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy resistant cases maintained on SSRI treatment, addition of a 5-HTIA receptor antagonist seem to improve clinical efficacy.</p><p>Since the therapeutic effect of SSRls in depression has been found to be critically linked to the availability of 5-HT in brain, our experimental results support, in principle, both of the above clinically based notions. Given the significance of the mesolimbocortical DA system for motivational processes, (S)-UH-301 may not necessarily display an optimal pharmacological profile for use in the treatment of depression. However, more selective 5-HTIA receptor antagonists may still, alone or in combination with e.g. SSRls, represent a new strategy in antidepressant treatment. The selective, stimulating action of (R)-8-OH-DPAT on the mesocortical DA system may contribute to the reported antidepressant effect of 5-HT,A receptor agonists.</p>