Reversal of helpless behavior by serotonin uptake blockers in rats

Serotonergic systems are thought to be involved in the mechanisms of action of antidepressants in humans. There is little evidence, however, to suggest that serotonin uptake blockers are efficacious in animal models of depression. To further explore the antidepressant activity of these drugs, four compounds from this class (citalopram, fluvoxamine, indalpine or zimelidine) were tested in rats subjected to helplessness training. Rats were first exposed to inescapable shocks and 48 h later, shuttle-box training was initiated to evaluate escape learning. Twice-daily IP injections of citalopram (1 mg/kg), fluvoxamine (4 mg/kg), indalpine (1 and 2 mg/kg) and zimelidine (1 and 2 mg/kg) reduced escape deficits in a manner similar to that produced by the tricyclic antidepressants desipramine and clomipramine. Reversal of escape deficit by serotonin uptake blockers was observed only when the drugs were administered after the shuttlebox sessions. At higher doses, the four serotonin uptake blockers were without effect. These data suggest that serotonin uptake blockers exert antidepressant-like effects in animals but only when they produce a moderate stimulation of serotonin neurotransmission.