Influence of mirtazapine on the sexual behavior of male rats

Rationale. Impairment of sexual activity is one of the most frequent side effects of antidepressant drugs. The increase in the synaptic concentrations of serotonin seems to be mainly responsible. Mirtazapine is a novel antidepressant that increases the synaptic concentrations of both noradrenaline and serotonin; moreover, it is an antagonist at 5-HT2C receptors, whose activation is considered to be responsible for some typical effects of serotonin on the ejaculation process (retardation of ejaculation, anorgasmia).<LF>Objectives. To study the influence of mirtazapine on copulatory performance and sexual motivation in male rats, in comparison-or in combination-with fluoxetine. <LF>Methods. Copulatory performance was studied either in sexually experienced or in sexually naive rats; sexual motivation was studied in sexually experienced rats. Mirtazapine (1, 5 or 10 mg/kg), fluoxetine (10 mg/kg), and the combination of mirtazapine + fluoxetine (10+10 mg/kg) were subcutaneously (s.c.) administered either acutely or daily for 13 days. Results. After acute administration, mirtazapine decreased mount latency (ML) and intromission latency (IL), and increased mount frequency (MF) and ejaculation latency (EL). Fluoxetine had no significant effect on any of the sexual behavior parameters. After a 13-day treatment, mirtazapine increased ML, IL and MF; fluoxetine increased ML, IL and the intercopulatory interval (ICI); the addition of mirtazapine to fluoxetine produced a reduction of ICI and an increase of MF. Moreover, mirtazapine significantly improved the performance of rats in the sexual motivation test. Conclusions. The present results show that, on the whole, the acute administration of mirtazapine improves several parameters of the copulatory performance of male rats and strongly stimulates sexual motivation, while the repeated administration produces minor, conflicting effects. This effect of mirtazapine on male rat sexual behavior is to be ascribed to the antagonism at brain alpha(2) adrenergic auto- and hetero-receptors, with consequent increased release of noradrenaline and serotonin, and antagonism at 5-HT2C receptors, which are involved in the negative influence of serotonin on male sexual behavior.