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

Abstract

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.

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.

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.

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.

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.

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.