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In this study, we evaluated the ability of the selective sigma1 agonist SA 4503 to produce changes in brain function, similar to those elicited by classical antidepressants. We focused more specifically on the influence of SA 4503 on central serotonergic (5-HT) transmission, and on hippocampal cell proliferation. A 2-d continuous treatment with SA 4503 (1-40 mg/kg.d) increased 5-HT neuron firing rate in a dose-dependent, bell-shaped manner, with a culminating effect of +90% at 10 mg/kg.d. The same dose induced the appearance of a 5-HT1A receptor-mediated inhibitory tonus on hippocampal pyramidal neurons, as revealed by intravenous injections of the selective 5-HT1A antagonist WAY 100635. Moreover, continuous administration of SA 4503 (3 and 10 mg/kg.d, 3 d) dose-dependently enhanced the number of bromodeoxyuridine-positive cells in the subgranular zone of the hippocampus (+48% and +94%, respectively), thus indicating an increased cell proliferation. Finally, a single administration of SA 4503 (3 and 10 mg/kg i.p.) increased the time spent swimming in the forced swimming test. Together, these results provide both functional and behavioural evidence that this compound has an important antidepressant potential. Further, the fact that the functional changes occurred within a short time-frame (2-3 d) suggest that this antidepressant potential might have a rapid onset of action.

Further evidence for an antidepressant potential of the selective σ1 agonist SA 4503: electrophysiological, morphological and behavioural studies