Assessment of neuroleptic-like properties of progesterone

There is considerable evidence from epidemiological studies that the onset of psychiatric disorders may be related to changes in the secretion of gonadal hormones. For example, the postpartum period appears to be a vulnerable phase for the occurrence of psychiatric disturbances such as dysphoric mood and even severe psychotic disturbances. It has been suggested that a sudden drop in progesterone concentrations may contribute to the development of such disorders. Because the administration of this steroid might be of therapeutic value in psychiatric disturbances, we investigated the behavioral properties of progesterone in the rat to assess putative neuroleptic-like properties of this steroid. Progesterone administration dose-dependently increased the EEG activity during wakefulness in the 10- to 30-Hz frequency bands and decreased locomotor activity. While no anxiolytic activity could be detected in the plus maze, the highest dose of progesterone (90 mg/kg) exerted an inhibitory effect on the conditioned avoidance response. In contrast to haloperidol (0.5 mg/kg), progesterone neither produced catalepsy nor antagonized amphetamine-induced stereotypy. However, both progesterone (10, 30 and 90 mg/kg) and haloperidol (0.1 mg/kg) effectively restored the disruption of the prepulse inhibition (PPI) of the acoustic startle response (ASR) that was evoked by apomorphine (2 mg/kg). In contrast, allopregnanolone (10 mg/kg), one of the main metabolites of progesterone, did not significantly antagonize the effect of apomorphine on the PPI. This behavioral profile of progesterone is compatible with the sedative properties of its metabolite allopregnanolone via the GABAA receptor, but also with the possibility that progesterone itself shares some properties with atypical antipsychotics, which may be relevant for the development and treatment of psychotic disturbances.