Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT₃ and 5-HT_1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT₃ and 5-HT_1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT_1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT₃ and 5-HT_1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.

Agmatine is a naturally occurring biogenic amine that acts primarily as an inhibitor of neuronal nitric oxide synthase (nNOS). Previous studies have shown that both acute and chronic agmatine administration induced anxiolytic and antidepressant-like effects in rodents. In the dorsal raphe nucleus (DRN), nitric oxide (NO) donors inhibit serotonergic (5-HT) neuronal activity, with the nNOS-expressing 5-HT neurons showing lower baseline firing rates than the non-nNOS expressing neurons. Our study aimed to test the hypothesis that the psychoactive effects of agmatine are mediated, at least in part, via a mechanism involving the stimulation of the DRN 5-HT neurons, as well as to assess the molecular pathway allowing agmatine to modulate the excitability of 5-HT neurons. Using extracellular in vivo electrophysiology, we demonstrated that both acute (1–3 mg/kg, i.v.) and chronic (40 mg/kg/day, i.p., 14 days) agmatine administration significantly increased the firing rate of DRN 5-HT neurons. Quantitative PCR (qPCR) analysis revealed that chronic agmatine treatment selectively upregulated the expression of serotonin-1B (5-HT_1B) and serotonin-2A (5-HT_2A) receptor mRNA in the DRN. Previous studies have shown that DRN 5-HT_2A receptor activation stimulates 5-HT neurons and produces antidepressant-like effects; our findings suggest that agmatine’s excitatory effect on DRN 5-HT neurons may be partially 5-HT_2A receptor-dependent. Given that modulation of the 5-HT neuronal firing activity is critical for the proper antidepressant efficacy, nNOS inhibitors can be potential antidepressants by their own and/or effective adjuncts to other antidepressant drugs.

Agmatine is a naturally occurring biogenic amine, acts primarily as an inhibitor of neuronal nitric oxide synthase (nNOS). Previous studies have shown that both acute and chronic agmatine administration induced anxiolytic and antidepressant-like effects in rodents. In the dorsal raphe nucleus (DRN), nitric oxide (NO) donors inhibit serotonergic (5-HT) neuronal activity, with nNOS expressing 5-HT neurons showing lower baseline firing rates than non-nNOS expressing neurons. Our study aimed to test the hypothesis that the psychoactive effects of agmatine are mediated, at least in part, via a mechanism involving the stimulation of the DRN 5-HT neurons, and to assess the molecular pathway allowing agmatine to modulate the excitability of 5-HT neurons. Using extracellular in vivo electrophysiology, we demonstrated that both acute (1-3 mg/kg, i.v.) and chronic (40 mg/kg/day, i.p., 14 days) agmatine administration significantly increased the firing rate of DRN 5-HT neurons. Quantitative PCR (qPCR) analysis revealed that chronic agmatine treatment selectively upregulated the expression of serotonin-1B (5-HT1B) and serotonin-2A (5-HT2A) receptor mRNA in the DRN. Since previous studies have shown that DRN 5-HT2A receptor activation stimulates 5-HT neurons and produces antidepressant-like effects, out findings suggest that agmatine’s excitatory effect on DRN 5-HT neurons may be partially 5-HT2A receptor-dependent. . Given that modulation of the 5-HT neuronal firing activity is critical for the proper antidepressant efficacy, nNOS inhibitors can be potential antidepressants by their own and/or effective adjuncts to other antidepressant drugs.

Background: Royal jelly is a protein-rich honeybee secretion that is used in the nutrition of larvae and adult queens. Previous studies have reported that royal jelly had induced pro-cognitive, anxiolytic, and antidepressant-like effects in laboratory rats. Since serotonin (5-HT), noradrenaline, and dopamine play an important role in the control of several mental functions, changes in the excitability of monoaminergic neurons may be involved in the mechanisms of the behavioral and neurochemical effects of royal jelly. The present study aimed to test this hypothesis. Methods: Adult male Wistar rats were treated with royal jelly for two weeks. Thereafter, their cognitive performance was evaluated using the novel object recognition (NOR) test. The excitability of monoaminergic neurons was assessed using in vivo single-unit extracellular electrophysiology. Results: We found that rats treated with royal jelly had a higher recognition index in the NOR test and a higher burst activity of dopaminergic neurons of the ventral tegmental area (VTA) compared to the vehicle-treated controls. The firing activities of 5-HT neurons of the dorsal raphe nucleus (DRN) and the noradrenergic neurons of the locus coeruleus (LC) were not altered. Conclusions: We conclude that the pro-cognitive effect of royal jelly is mediated, at least in part, by mechanisms involving the excitability of mesolimbic dopaminergic neurons. The present findings encourage further research towards the improvement of the safety and efficacy of currently available therapies for cognitive dysfunction.