Sex differences in the antidepressant-like response induced by the imidazoline-2 receptor compound 12d, a...

The synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates provided novel compounds with relevant affinities for imidazoline 2 (I2) receptors in human brain tissues. A selected compound, 12d, showed improved cognitive and analgesic properties at the preclinical level through the modulation of I2 receptors, but its potential innovative use as an antidepressant is still unknown.

Male and female adult Sprague-Dawley rats were treated with 3 ip injections of compound 12d (10 or 20 mg/kg), or vehicle (1 ml/kg DMSO), 24, 5, and 1 h prior to scoring its antidepressant-like efficacy under the stress of the forced-swim test. Hippocampal neuroplasticity markers (i.e., FADD, p-ERK/ERK, mBDNF) were evaluated 24 h post-treatment (and post-forced-swim test exposure).

The novel results proved a sex-dependent efficacy of 12d, with dose-dependent antidepressant-like effects in adult male rats, and an inefficacious response for females. Moreover, compound 12d did not alter any of the hippocampal markers evaluated.

These results presented 12d as a novel therapeutic antidepressant candidate at the tested conditions, although only for male rats, thus requiring further studies to better understand the observed sex disparities as well as its molecular underpinnings. Moreover, compound 12d joins the list of other I2 receptor ligands with known antidepressant-like efficacy, validating and strengthening this receptor as a target in this field for future drug development.