Antidepressant-like effects of ascorbic acid and ketamine involve modulation of GABAA and GABAB receptors

Background: It has been suggested that dysregulation of gamma-aminobutyric acid (GABA)-mediated neurotransmission is involved in the etiology of major depressive disorder and in the action of the fast acting antidepressant ketamine. Considering that recent evidence has suggested that ascorbic acid may exert an antidepressant-like effect through mechanisms similar to ketamine, this study evaluated the involvement of GABA(A) and GABA(B) receptors in the antidepressant-like effect of ascorbic acid, comparing the results with those obtained with ketamine. Methods: To investigate the involvement of GABAA in the antidepressant-like effect of ascorbic acid and ketamine in the tail suspension test (TST), mice were treated with a sub-effective dose of ascorbic acid (0.1 mg/kg, po), ketamine (0.1 mg/kg, ip) or vehicle and 30 minutes later, a sub-effective dose of muscimol (0.1 mg/kg, ip, GABAA receptor agonist) or vehicle was administered. In another set of experiments, mice were treated with ascorbic acid (1 mg/kg, po, active dose in the TST) or vehicle and 30 minutes later, baclofen (1 mg/kg, ip, GABAB receptor agonist) was administered. A similar experimental protocol was performed with ketamine (1 mg/kg, ip). Results: The administration of muscimol combined with ascorbic acid or ketamine produced a synergistic antidepressant-like effect in the TST. Moreover, the antidepressant-like effects of ascorbic acid and ketamine were abolished by baclofen. There was no alteration in spontaneous locomotion in any experimental group. Conclusions: Results indicate that the anti-immobility effect of ascorbic acid and ketamine in TST may involve an activation of GABAA receptors and a possible inhibition of GABAB receptors. (C) 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.