Synergistic antidepressant-like action of gaboxadol and escitalopram

Abstract

According to current theories on the etiopathogenesis and pathophysiology of depression, both GABAergic and monoaminergic transmitter systems are perturbed. Consequently, the present study addressed the putative antidepressant action of the sedative-hypnotic GABAA receptor agonist, gaboxadol, separately and in combination with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The rat chronic mild stress model was used to test the chronic antidepressant properties of gaboxadol in this depression model. Sucrose intake used as a read-out on anhedonic-like behavior indicated that the drug response rate for gaboxadol (5 mg/kg/day, i.p.) was similar to that measured for escitalopram (5 mg/kg/day, i.p.), however, the rate increased when the two drugs were co-administered, suggesting a synergistic action. Using in vivo electrophysiological recordings in dorsal raphe nucleus (DRN) of anesthetised rats, the present results showed that one week treatment with gaboxadol (5 mg/kg/day, i.p.) or with escitalopram (5 mg/kg/day, i.p.), followed by a 24 h washout period, did not affect DRN 5-HT neuronal firing per se, but in rats treated with both drugs for one week, the firing rate of DRN 5-HT neurons was significantly increased. Immunohistochemical estimations of cell proliferation in the hippocampal dentate gyrus did not reveal any effect of gaboxadol on chronic mild stressed rats, indicating that neurogenesis per se is not systematically associated with recovery from anhedonic-like behavior. Taken together, our data reveal for the first time an antidepressant action of gaboxadol and indicate a synergistic mechanism, regarding rapid onset of action and efficacy, when co-administered with escitalopram.