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Subsequently Palvimaki et al corroborated
Subsequently, Palvimaki et al. (1999) corroborated Ni and Miledi's study by demonstrating that treatment with fluoxetine leads to 43% occupancy of the 5-HT2C receptors. Moreover, the affinity of fluoxetine for 5HT2C receptors (Ki 65 nM) is close to its affinity for 5-HT transporters (Ki 33 nM) (Ni and Miledi, 1997). Similarly, a study reported that chronic treatment with fluoxetine induced an increase in the 5-HT2C protein Ro 08-2750 mg levels within the amygdala (Baptista-de-Souza et al., 2014). This effect appears to be associated with the antinociceptive feature of fluoxetine, as well as the analgesic effects of SSRIs that occur because of the blockade of 5-HT2C receptors in the amygdala of rats exposed to an arthritis pain test (Grégoire and Neugebauer, 2013).
In our fifth experiment, in order to clarify the possible fluoxetine actions as an antagonist of 5-HT2C receptors, we proceeded with intra-amygdala injections of SB-242084 [a selective 5-HT2C receptor antagonist (0.1 nmol, a dose without intrinsic effects on nociceptive response; see results of Exp. 5)] combined with MK-212. We observed that similar to systemic fluoxetine, intra-amygdala SB-242084 prevented the increase in antinociception induced by MK-212. Altogether, these results seem to strengthen the hypothesis that fluoxetine acts on 5-HT2C receptors, blocking the OAA enhancement induced by activation of this serotonin receptor subtype.
In the same way, the influence of this SSRI on anxiety responses induced by MK-212 intra-amygdala was demonstrated by Vicente and Zangrossi (2014). Those authors demonstrated that chronic treatment with systemic fluoxetine successfully inhibited the anxiogenic effects of MK-212, suggesting that this effect is mediated by the 5-HT2C receptor.
Conclusion
The present study demonstrates that serotonin neurotransmission in the amygdaloid complex modulates the OAA. Specifically, we found that 5-HT1A receptors in the amygdala may be modulating antinociception through a direct action on nociceptive pathways. In this context, while intra-amygdala activation of 5-HT1A receptor attenuated the OAA (despite producing an intrinsic effect on nociceptive response in EA-confined animals), local injection of MK-212 (i.e. a drug that activates 5-HT2C receptor) selectively enhanced OAA. Interestingly, while prior systemic injection of fluoxetine did not change the effects of 8-OH-DPAT on nociceptive response, this SSRI prevented the OAA enhancement induced by intra-amygdala injection of MK-212, suggesting that fluoxetine may have acted as a 5-HT2C receptor antagonist. This hypothesis seems to be strengthened by the similar effect obtained with combined intra-amygdala injections of SB 242084, a selective 5-HT2C receptor antagonist, and MK-212.
Disclosure
Role of the funding source
The experiments described in this manuscript were funded by CAPES (Coordination for the Improvement of Higher Education Personnel) and CNPq (National Council for Scientific and Technical Development, 482356/2013-8), Brazil. L. R. R. Tavares received a scholarship from Capes, Brazil. D. Baptista-de-Souza received a scholarship from FAPESP (2009/17938-6), São Paulo, Brazil. A. Canto-de-Souza received a CNPQ, Brazil research fellowship CNPq (309201/2015-2).
Acknowledgments
Introduction
Glutamatergic system has recently gained much attention as a target for the development of novel antidepressants, as represented by the discovery of the robust antidepressant effects of ketamine, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist (Berman et al., 2000; Zarate et al., 2006). Among glutamatergic system, the metabotropic glutamate (mGlu) receptors are known to have modulatory roles in glutamatergic transmission, and their roles in depression have been actively investigated (Chaki et al., 2013; Pilc et al., 2008).
Eight receptor subtypes of the mGlu receptors, which are classified into three groups, have been identified (Nakanishi, 1994; Schoepp and Conn, 1993). Of these, the group II mGlu receptors, consisting of the mGlu2 and mGlu3 receptors, are mainly localized in the cortical and limbic areas of the brain (Schaffhauser et al., 1998), where they function as autoreceptors and heteroreceptors to negatively regulate release of neurotransmitters (Cartmell and Schoepp, 2000). We have previously demonstrated the antidepressant effects of mGlu2/3 receptor antagonists in various rodent models (Chaki et al., 2004, 2017; Yoshimizu et al., 2006). Importantly, mGlu2/3 receptor antagonists exert ketamine-like antidepressant effects in rodents; rapid-acting and long-lasting antidepressant effects (Dong et al., 2017; Dwyer et al., 2013) as well as efficacy in animal models refractory to conventional antidepressants (Ago et al., 2013; Koike et al., 2013b; Witkin et al., 2016). Consistent with the nature of their antidepressant actions, mGlu2/3 receptor antagonists also share some of the mechanisms underlying their antidepressant actions with ketamine. For example, both mGlu2/3 receptor antagonists and ketamine activate brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling (Autry et al., 2011; Koike et al., 2013a, 2013b) and mechanistic target of rapamycin complex-1 (mTORC1) signaling (Koike et al., 2011; Li et al., 2010), both of which are triggered by stimulation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor (Karasawa et al., 2005; Koike and Chaki, 2014; Maeng et al., 2008).