Agmatine interaction with imidazoline receptor inhibits manifestation of depression-like behavior in 3-Nitropropionic acid-induced Huntington's disease-like phenotype in rats.

Huntington's disease (HD)-associated depression is a prevalent psychiatric symptom affecting between one-third and over two-thirds of patients, significantly impacting their quality of life. Agmatine, a biogenic amine produced by the decarboxylation of L-arginine, has recently garnered attention for its antidepressant-like effects by modulating imidazoline receptors in neurodegenerative and mood disorders. This study aimed to investigate the effect of agmatine in attenuating depression-like behavior through its interaction with imidazoline receptors in a 3-Nitropropionic acid (3-NP) rat model of HD. 3-NP is a selective mitochondrial toxin known to induce bilateral striatal lesions by inhibiting succinate dehydrogenase enzyme, thereby contributing to psychiatric symptoms observed in HD. Rats received 3-NP (10 mg/kg, i.p.) on days 1, 3, 5, 7, and 9, followed by agmatine treatment on days 18-20. Systemic administration of 3-NP produced significant depressive-like behaviors, neurochemical imbalance, and neuroinflammation. However, treatment with imidazoline I1/I2 receptor agonist agmatine (10-20 mg/kg; i.p.), imidazoline I1 receptor agonist moxonidine (0.25 mg/kg; i.p.), and imidazoline I2 receptor agonist 2-(2-Benzofuranyl)-2-imidazoline hydrochloride (3 mg/kg; i.p.) with agmatine (5 mg/kg, i.p.) resulted in marked improvement in behavioral abnormalities exhibited by reduced immobility time in forced swim test, normalization of GABA/glutamate levels, decreased proinflammatory cytokines, and restored BDNF expression. Conversely, anti-depressant effects of agmatine were blocked by I1 receptor antagonist efaroxan (1 mg/kg; i.p.) and I2 receptor antagonist idazoxan (1 mg/kg; i.p.), signifying the involvement of imidazoline receptors in the beneficial effects of agmatine. In conclusion, these findings highlight the therapeutic potential of agmatine in mitigating psychiatric complications associated with HD through receptor-mediated mechanisms.