Agmatine Enhances Dorsal Raphe Serotonergic Neuron Activity via Dual Regulation of 5-HT_2A and 5-HT_1B Receptors

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.