Assessment of neuroleptic-like properties of progesterone

Abstract

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.

Sensorimotor Gating and Dopamine Function in Postpartum Rats

“…Estrogen levels are consistently low throughout the postpartum period, while progesterone is low on PPD2 but then significantly increases by PPD14. Recent data in males suggests a 'neuroleptic-like' effect of progesterone (Rupprecht et al, 1999). Thus, it is possible that the decreased D2-receptor sensitivity observed on PPD14 may be related the increased progesterone levels in these females.…”

Clozapine, but not Haloperidol, Increases Brain Concentrations of Neuroactive Steroids in the Rat

“…Also, the marked increase in the brain concentration of progesterone induced by clozapine may be important in the pharmacological profile of this drug. Progesterone not only is a precursor of AP but may also possess neuroleptic-like properties (Rupprecht et al 1999) and, by acting at its intracellular receptors, may regulate the expression of genes (i.e., GABA A receptor subunits, GABA synthesizing enzymes) that may be relevant for the delayed antipsychotic action of clozapine (Wilson 1996). The clozapineinduced increase in the brain and plasma concentrations of progesterone is consistent with the failure of clozapine to increase the plasma concentration of prolactin (Hansen et al 1997).…”

Antipsychotic-Like Properties of 5-α-Reductase Inhibitors

“…Previous evidence suggests that the ability of these compounds to affect the relative ratios of testosterone, progesterone, and their 5-a-reduced metabolites may be critical for their behavioral properties. Progesterone, but not AP, has been shown to reverse both PPI disruption (Rupprecht et al, 1999) and stereotyped behaviors (PalermoNeto and Dorce, 1990) mediated by APO in rats. Furthermore, some reports have suggested antipsychoticlike properties of progesterone in animals and humans (Bower and Altschule, 1956;Palermo-Neto and Dorce, 1990).…”

“…Notably, both progesterone and AP may play a role in the modulation of psychotic-like behaviors in rodents (Khisti et al, 2002;Rupprecht et al, 1999). This enzyme, however, is also responsible for the metabolism of several other steroid precursors into their 5-a-reduced metabolites.…”