Involvement of the gabaergic, serotonergic and glucocorticoid mechanism in the anxiolytic-like effect of mastoparan-L

Abstract

Mastoparan-L (mast-L) is a cell-penetrating tetradecapeptide and stimulator of monoamine exocytosis. In the present study, we evaluated the anxiolytic-like effect of mast-L. Preliminary pharmacological tests were conducted to determine the most appropriate route of administration, extrapolate dose and detect potential toxic effects of this peptide. Oral and intracerebroventricular administration of mast-L (0.1, 0.3 or 0.9 mg.kg−1), diazepam (1 or 5 mg.kg−1), buspirone (10 mg.kg−1) or vehicle 10 mL.kg−1 was carried out prior to the exposure of mice to the anxiety models: open field, light-dark box and elevated plus-maze. To characterize the mechanism underlying the antianxiety-like effect of mast-L, pharmacological antagonism, blood plasma analysis, molecular docking, and receptor binding assays were performed. The absence of a neurotoxic sign, animal's death as well as lack of significant changes in the relative organ weight, hematological and biochemical parameters suggest that mast-L is relatively safe. The anxiolytic-like effect of mast-L was attenuated by flumazenil (antagonist of benzodiazepine binding site) and WAY100635 (selective antagonist of 5-HT1A receptors) pretreatments. Mast-L reduced plasma corticosterone and lowered the scoring function at GABAA −18.48 kcal/mol (Ki = 155 nM), 5-HT1A −22.39 kcal/mol (Ki = 130 nM), corticotropin-releasing factor receptor subtype 1 (CRF1) −11.95 kcal/mol (Ki = 299 nM) and glucocorticoid receptors (GR) −14.69 kcal/mol (Ki = 3552 nM). These data fit the binding affinity (Ki) and demonstrate the involvement of gabaergic, serotonergic and glucocorticoid mechanisms in the anxiolytic-like property of mast-L.