Region- and phase-dependent effects of 5-HT1A and 5-HT2C receptor activation on adult neurogenesis
Introduction
The best illustration of the key role of serotonin (5-HT) in the pathophysiology of major depression is the therapeutic action of selective 5-HT reuptake inhibitors (SSRIs) in depressed patients (Millan, 2006). Activation of one or more 5-HT receptors plays a role in mediating the antidepressant action of SSRIs (Middlemiss et al., 2002). Abnormalities in binding and expression of several 5-HT receptor subtypes are observed in depressed subjects (Parsey et al., 2006, Drevets et al., 2007). Conversely, SSRIs activate postsynaptic 5-HT1A receptors in the hippocampus, a region largely involved in emotion and response to stress (Campbell and Macqueen, 2004), and desensitize 5-HT1A autoreceptors in the raphe nuclei thereby inducing a more generalized increase in 5-HT level (Blier and Ward, 2003, Hensler, 2003). The 5-HT2C receptors are also involved in depression, anxiety, and in the effects of SSRIs, although a number of data suggest a complex regulation of their function in mood disorders (Millan, 2005, Holmes, 2008), since both 5-HT2C receptor agonists and antagonists have antidepressant activity (Millan, 2005, Heisler et al., 2007, Rosenzweig-Lipson et al., 2007). Furthermore, increased 5-HT2C receptor editing has been observed in the prefrontal cortex of depressed subjects (Gurevich et al., 2002), and in animals after stress exposure that can be normalized by antidepressant treatment (Englander et al., 2005).
Beyond the monoamine hypothesis and because of the delay of action of antidepressants, it has been suggested that neural adaptive mechanisms may underlie antidepressant efficacy. Recently, a neurotrophic–neurogenic theory of depression and antidepressant action has been proposed, in which adult neurogenesis takes a part (Jacobs, 2002, Duman and Monteggia, 2006, Czeh and Lucassen, 2007, Sahay and Hen, 2007). Indeed, a number of studies have demonstrated that SSRIs such as fluoxetine or citalopram increase cell proliferation and neurogenesis in the dentate gyrus (DG) of the hippocampus (Malberg et al., 2000, Santarelli et al., 2003, Sairanen et al., 2005, Jaako-Movits et al., 2006, Marcussen et al., 2008), and gliogenesis in the prefrontal cortex (Kodama et al., 2004). In the same regions, SSRIs reverse or prevent the negative effects of stress in various animal models of depression (Malberg and Duman, 2003, Jayatissa et al., 2006, Czeh et al., 2007, Hitoshi et al., 2007, Banasr et al., 2007). Changes in cell proliferation have also been observed following olfactory bulbectomy, another animal model of depression, both in the hippocampus and the subventricular zone (SVZ), showing that various components of the limbic circuitry may exhibit alterations in neuroplasticity that can be reversed by monoaminergic antidepressants (Keilhoff et al., 2006).
The effects of SSRIs on adult neurogenesis mentioned above are consistent with our previous studies showing that 5-HT is a potent stimulator of this process in the DG, and in the SVZ-olfactory bulb (OB) system (Brezun and Daszuta, 1999, Brezun and Daszuta, 2000a, Brezun and Daszuta, 2000b). Not only 5-HT1A (Radley and Jacobs, 2002, Santarelli et al., 2003, Banasr et al., 2004, Huang and Herbert, 2005), but also 5-HT1B, 5-HT2A, 5-HT2C and 5-HT4 receptor subtypes are involved in this regulation (Banasr et al., 2004, Lucas et al., 2007, Jha et al., 2008). We previously demonstrated that acute or chronic activation of 5-HT1A receptors increases the proliferation of newly formed cells leading to a net increase of neurogenesis in the DG and OB (Banasr et al., 2004). By contrast, activation of 5-HT2C receptors has no effect in the DG and increases neurogenesis in the OB (Banasr et al., 2004). In the present study, we focused on another critical phase of neurogenesis, the survival of newly formed cells in rats chronically treated with selective 5-HT1A (8-OH-DPAT) or 5-HT2C (RO600,175) receptor agonists. We extended our investigation from the canonical neurogenic zones, the DG and OB, to potential neurogenic zones: the prefrontal cortex (PFC) and the striatum (ST), that have also been associated to certain aspects of depression (Esposito, 2006, Banasr and Duman, 2007, Stein, 2008).
We compared the effects of these treatments by giving bromodeoxyuridine (BrdU), a marker of mitotic cell that remains in place and passed down to daughter cells, not only after but also before 8-OH-DPAT or RO600,175 treatments and for different time windows corresponding to different developmental stages. Indeed, about half of the newly formed cells die within the first two weeks of life (Dayer et al., 2003), and increasing their survival may have profound functional consequences. Furthermore, regional analyses were carried out due to functional dissociations between dorsal and ventral DG (Banasr et al., 2006), or medial and lateral ST (Voorn et al., 2004). The other reasons for this regional analysis were a possible migration of neural progenitors from the SVZ and rostral migratory stream towards the CPF or ST (Picard-Riera et al., 2004, Dayer et al., 2005), and the selective distribution of 5-HT1A and 5-HT2C receptors in these regions (Wright et al., 1995, Eberle-Wang et al., 1997).
Section snippets
Animals and drug treatment
Adult 7-week-old male Wistar rats (200–225 g, Charles River, France) were group-housed under standard condition (12-hour light/dark cycle; 20 ± 2 °C), with water and food provided ad libitum. All procedures were conducted in accordance with the French Agriculture and Forestry Ministry (decree 87848, license 01498).
Experimental protocols
Animals received daily injections of either saline, selective 5-HT1A or 5-HT2C receptor agonist: 8-OH-DPAT (1 mg/kg, i.p.; Sigma-Aldrich, France) or RO600,175 (2.5 mg/kg, i.p.; La Roche,
Dentate gyrus
8-OH-DPAT but not RO600,175 increases the number and survival of new neurons.
Chronic administration of RO600,175 before BrdU administration had no effect on the number of BrdU-positive cells detected in the GCL after 4 weeks of development (Cytogenesis; Fig. 2A), when compared to vehicle administrated animals. By contrast, significant increases in the number of BrdU-positive cells were observed following the 8-OH-DPAT treatment (F2,12 = 18.06, p = 0.0002, treatment main effect); independently of the
Discussion
These results show that 8-OH-DPAT, a selective agonist of 5-HT1A receptor subtype, produces significant increases in neurogenesis in the DG and OB and gliogenesis in the CPF and ST. However, the regulation of cell survival appears to differ from one region to another, showing increase, decrease and no change. The results also suggest a possible control of cell migration in the SVZ with a long-term treatment. By contrast, RO 600,175 does not affect the cell survival whereas it selectively
Role of the funding source
Funding for this study was provided by CNRS. CNRS had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
A.S., M.B. and A.D. designed the research. A.S., M.B. and A.D. performed the research. A.S. and M.B. performed the quantification and statistical analyses. A.S., M.B. and A.D wrote the manuscript. L.K. provided suggestions that improved the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare that they have no conflict of interest.
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Current address: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.