A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

‘Can I be a kinky ace?’: How asexual people negotiate their experiences of kinks and fetishes

Prior research has found that asexual people may fantasise or participate in activities typically conceptualised as ‘sexual’. These behaviours may be considered paradoxical when an asexual person is conceptualised as someone who does not experience sexual attraction or desire. This research aimed to explore how kinks and fetishes are conceptualised, experienced, and negotiated by asexual individuals. Forty-eight participants were recruited to take part in an online qualitative survey. Thematic analysis resulted in three themes. In “Am I asexual?”: (How) can you be a kinky ace?, we discuss the sense of dissonance which some participants reported in negotiating what was seemingly the paradox between their self-identity as asexual and their exploration of kinks and fetishes. In the second theme, Between me and me’ and make believe: Kinks and fetishes as solo and imaginary, we report on how kinks, fetishes, and fantasies were often understood in a solitary context and as either undesirable – or impossible – to live out. In the final theme, Kink as a sensual enhancement in relationships, we highlight how participants positioned kinks and fetishes as an agent for intimacy. These findings expand our knowledge of how asexual people negotiate kinks and fetishes and capture the complexities of asexual identities

The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex

The basal fungus <i>Allomyces macrogynus</i> (<i>A. macrogynus</i>) produces motile male gametes displaying well-studied chemotaxis toward their female counterparts. This chemotaxis is driven by sirenin, a sexual pheromone released by the female gametes. The pheromone evokes a large calcium influx in the motile gametes, which could proceed through the cation channel of sperm (CatSper) complex. Herein, we report the total synthesis of sirenin in 10 steps and 8% overall yield and show that the synthetic pheromone activates the CatSper channel complex, indicated by a concentration-dependent increase in intracellular calcium in human sperm. Sirenin activation of the CatSper channel was confirmed using whole-cell patch clamp electrophysiology with human sperm. Based on this proficient synthetic route and confirmed activation of CatSper, analogues of sirenin can be designed as blockers of the CatSper channel that could provide male contraceptive agents