Serotonin autoreceptor function and antidepressant drug action

Abstract

This article briefly summarizes, within the context of a brief review of the relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)1A versus 5-HT1B autoreceptors in the mechanism of action of 5-HT reuptake blocking agents, including putative regional differences in this regard, and (2) autoreceptor responsiveness following chronic SSRI administration. First, our data are consistent with the primacy of 5-HT1A autoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1B autoreceptors appear to have an accessory role in this regard. Second, there is an important interplay between cell body and nerve terminal 5-HT autoreceptors, and recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particular, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and nerve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively. Third, 5-HT autoreceptors evidently retain the capability to limit the 5-HT transmission-promoting effect of SSRIs after chronic treatment. Thus, although the responsiveness of these sites is probably somewhat reduced, residual autoreceptor capacity still remains an effective restraint on large increases in extracellular 5-HT, even after prolonged treatment. If a further increase in extracellular 5-HT is crucial to the remission of depression in patients responding only partially to prolonged administration of antidepressants, then sustained adjunctive treatment with autoreceptor-blocking drugs may consequently prove useful in the long term.

Effects of Acute and Long-Term Administration of Escitalopram and Citalopram on Serotonin Neurotransmission: an In Vivo Electrophysiological Study in Rat Brain

“…However, the increase of 5-HT level was similar in rats treated for 13 days with escitalopram (10 mg/kg/day) and citalopram (20 mg/kg/day) (Ceglia et al, 2004). Although no microdialysis studies were undertaken in hippocampus following long-term administration of these two SSRIs, several other studies have shown that the net impact of different SSRIs on extracellular 5-HT could vary with brain regions, such as between the frontal cortex and hippocampus (Malagié et al, 1996;Hervas and Artigas, 1998; see for a review Hjorth et al, 2000) depending on their innervation by DRN vs median raphe nucleus, respectively. The greater efficacy of escitalopram compared to citalopram in increasing extracellular 5-HT in hippocampus, if any, does not appear to result in differential increase in tonic activation of postsynaptic 5-HT 1A receptors, as was shown with other antidepressant, thus suggesting that other mechanisms are involved.…”

“…Although complex, the combination of several adaptive changes such as desensitization of the 5-HT 1A receptors in the raphe nucleus, amygdala and hypothalamus, normosensitive 5-HT 1A receptors in hippocampus and cortex, and the interplay between 5-HT soma and nerve terminal might contribute, at least in part, to the antidepressant responses of SSRIs (for a review see Hjorth et al, 2000;Hensler, 2003). Nevertheless, the results obtained from raphe dorsalis suggest that the gradual recovery of normal firing activity of DRN neurons, which was reported to underlie the delayed effect of SSRI on 5-HT neurotransmission , is in accordance with the earlier onset of action of escitalopram vs citalopram in animal models of depression and anxiety (Sánchez et al, 2003a, b;Fish et al, 2004).…”

Augmentation of SSRI Effects on Serotonin by 5-HT2C Antagonists: Mechanistic Studies

“…Most augmentation strategies are derived from the hypothesis that chronic selective serotonin reuptake inhibitor (SSRI) treatment results in a desensitization of presynaptic serotonergic (5-HT) autoreceptors. This blunted autoreceptor control leads to increased effects of SSRIs on central serotonin levels in time, which is postulated to parallel the antidepressant effect (Hjorth et al, 2000;Blier, 2001;Blier et al, 1987).…”

“…Over the last few decades, several such augmentation strategies have been developed. These add-on strategies range from antagonism of serotonergic autoreceptors like 5-HT 1A and 5-HT 1B (Hjorth et al, 2000;Blier et al, 1998;Artigas et al, 1994Artigas et al, , 1996Bosker et al, 2001;Celada et al, 2001;Cremers et al, 2000a, b), but also comprise heteroceptors such as adrenoceptors (Bengtsson et al, 1998;Szabo and Blier, 2001;Besson et al, 2000;Hopwood and Stamford, 2001;Bortolozzi and Artigas, 2003;Pudovkina et al, 2003;Rouquier et al, 1994;Amargos-Bosch et al, 2003;Weikop et al, 2004;Gobert et al, 1997;Gobert and Millan, 1999;De Boer et al, 1996), 5-HT 2A receptors (Szabo and Blier, 2002), GABA B receptors (Abellan et al, 2000;Slattery et al, 2005;Mombereau et al, 2004;Nakagawa et al, 1996), and substance P receptors (Guiard et al, 2004), to mention but a few.…”

A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

“…Repeated activation of this receptor has been shown to induce a desensitization phenomenon, a mechanism that has been associated to the delayed therapeutic action of selective 5-HT reuptake inhibitors. 17,19 Previous anecdotal reports on the absence of 5-HT1A expression in serotonergic neurons can be found in the literature, but most studies lack convincing proof and/or thorough quantification. To address this question, we used a combination of histochemistry techniques, and molecular detection with single-cell resolution.…”