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Kisspeptins are reported to be the most potent activators of the hypothalamus-pituitary-gonadal (HPG) axis known to date. Kisspeptin potently elicits gonadotropin-releasing hormone (GnRH) release and luteinizing hormone (LH) secretion, even in the pre-pubertal period. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network primarily implicated in emotional behaviors alongside sexual functions. Therefore, an increasing body of studies has implicated kisspeptin as having many influences on emotional behaviors. The study was set out to explore if the kisspeptin/GPR54 signaling system is required for the anti-depressant-like effect of kisspeptin-10 (KP-10), besides the regulation of the HPG axis. To test this concept, peptide 234 (P234), a kisspeptin antagonist, was given to the male rats, and its modulatory effect on the anti-depressant-like effects of kisspeptin was investigated by using a forced swimming test (FST). The study has also sought to know whether kisspeptin can exert its effects through adrenergic and serotonergic receptors. To investigate this, the agents yohimbine (Yoh), an alpha-2 adrenergic receptor antagonist, and cyproheptadine (Cry), a non-selective 5-HT2 serotonergic receptor antagonist, were administered in the experiments. Our results indicate that, in rats, the anti-depressant-like effects of KP-10 in a modified rat FST are mediated by GPR54 receptors, since the kisspeptin antagonist peptide 234 reversed kisspeptin-induced anti-depressant-like effects. Our data also demonstrate that the anti-depressant-like effects of kisspeptin, at least in part, are mediated by an interaction of the alpha-2 adrenergic and 5-HT2 serotonergic receptors.

Excessive high fructose corn syrup (HFCS) consumption is known to cause oxidative stress, which induces transient receptor potential melastatin type 2 (TRPM2) channel gating. Oxidative stress-induced TRPM2 gating is suggested to play an important role in neurons, indicating a role for the TRPM2 channel in a variety of neuropsychiatric disorders including depression and anxiety. We investigated the effects of HFCS and chronic immobilization stress (CIS) on TRPM2 channel immunoreactivity, anxiety, and depressive-like behaviors in adult male rats. The male rats (n=8/group) were divided into 4 groups: Control, 20% HFCS (F20), 40% HFCS (F40), and stress. The control group received tap water, and F20 and F40 groups were exposed to HFCS 20% and 40% respectively for 14 consecutive days. Rats in the stress group were subjected to immobilization stress for 3 or 6 hours daily in the first and second weeks to induce CIS. Then, light/dark tests, open field tests (OFT), and tail suspension tests (TST) were performed, respectively. In the light/dark test, the time spent in the dark chamber significantly increased in all groups vs the control group (P<0.01). In support of this result, time spent in the light chamber significantly decreased in all groups vs the control group (P<0.01). Besides, CIS significantly increased depressive-like behavior in the stress group vs the control group (P<0.05). In serum hormone levels, corticosterone (CORT) levels significantly increased in the F40 and stress groups vs the control group (P<0.01). TRPM2 immunoreactivity significantly increased in the hippocampus, prefrontal cortex (PFC), nucleus accumbens (NaC), and amygdala regions by HFCS and CIS treatments. For the first time in the present study,  showed that f increased immunoreactivity of the TRPM2 cation channels may be linked to the anxiety-like behavior induced by HFCS.