A novel 5-HT2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants

Kisspeptin modulates the activity of the stress system and associated behaviours, the body temperature and nociception

“…These results suggest that KP-13's action is mediated by noradrenaline release and possibly α 2A -AR or α 2C -AR activation. This is in accord with previous findings that indicate that α 2A -AR agonists through the reduction in locus coeruleus firing activity compensate for the depletion of noradrenaline levels [164], which is characteristic in depressive disorders. Of the two subtypes of ARs, α 2A -AR seems to be more likely the culprit as studies using knockout models for the two subtypes suggest opposing roles for them in FST: α 2A -AR mediating anti depressive effect [165], whereas α 2C -AR activation leads to depressive phenotype [166].…”

“…Our results implicate 5 − HT 2 receptors to be involved in mediating kisspeptin's effect, which is in accord with literature data. There are multiple 5 − HT 2 receptors, of which both 5 − HT 2A and 5 − HT 2C could mediate the effect of KP-13 on depressive behaviour supported by, first, increased 5 − HT 2A expression in the cortex have been found in patients with depression or with depression-related personality traits [139,197] [166,164], third, co-administration with selective serotonin re-uptake inhibitors (SSRIs) 5 − HT 2A antagonists augment the effect of SSRIs [125]. On the other hand, 5 − HT 2C is expressed in distinct brain regions such as the amygdala, hippocampus and the substantial nigra among others [68] and both 5 − HT 2C agonists and antagonists were found to exhibit antidepressant actions in animal models of depression [35,40,45].…”

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: II. A Behavioral, Neurochemical, and Electrophysiological Characterization

“…Reversal by S32212 of the motor-depressant action (LRR) of S18616 mimics numerous antidepressants and has been putatively related to the relief of psychomotor retardation (Millan et al, 2001;Dekeyne et al, 2008). Selective 5-HT 2C antagonists are effective in all of the above procedures, whereas 5-HT 2A antagonists express variable and modest actions Millan, 2005Millan, , 2006Dekeyne et al, 2008;Landholt and Wehrle, 2009;Pandey et al, 2010;Carr and Lucki, 2011). Immobility in the forcedswim procedure is reduced by ␣ 2 -AR antagonists and genetic deletion of ␣ 2C -ARs (Sallinen et al, 2007;Millan, 2010).…”

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: I. A Mechanistic Characterization

“…S32212 abolished 5-HT 2A receptor-mediated G␣ q and PLC activation, which is a major transduction pathway at 5-HT 2A receptors . Although data from other cascades are awaited (Berg et al, 2008;Millan et al, 2008), confirming its antagonist properties at cerebral (frontal cortex) 5-HT 2A receptors, S32212 blocked induction of head twitches by the 5-HT precursor 5-HTP (Pandey et al, 2010). The prototypical agonist DOI elicits a well characterized discriminative stimulus mediated by 5-HT 2A sites (Schreiber et al, 1994), so its blockade by S32212 can also be attributed to the antagonism of 5-HT 2A receptors.…”