Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat

The extrapyramidal side effects of typical antipsychotics, which are induce d to a markedly reduced extent by clozapine, have been linked to a dysfunct ion of central gamma -aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3 alpha -hydroxy-5 alpha -pregnan-20-one (allopregnanolone, AP) and 3 alpha ,21-dihydroxy-5 al pha -pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), two potent and endogenous positive allosteric modulators of GABA-mediated chloride cur rent intensities at GABAA receptors, were compared with those of the typica l antipsychotic haloperidol, A single administration of clozapine (1.25-20 mg/kg, IP), but not of haloperidol (0.1 or 0.5 mg/kg, TP), induced dose- an d time-dependent increases in the concentrations of progesterone, AP, and T HDOC in the cerebral cortex and striatum of rats, Clozapine (at 10 mg/kg, b ut not at lower doses) also increased the concentrations of these steroids as well as that of corticosterone in plasma in intact rats, but failed to i ncrease the cortical concentrations of AP and THDOC in adrenalectomized-orc hidecomized rats. An acute challenge with clozapine (10 mg cg), administere d 48 h after the termination of daily treatment with the same dose for 19 d ays, still increased the cortical concentrations of progesterone, AP, and T HDOC. These results suggest that the clozapine-induced increases in neuroac tive steroid concentrations in the brain may contribute to the atypical pha rmacological profile of this antipsychotic drug.