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

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 25; no. 4; pp. 489 - 497
• Main Authors: Barbaccia, Maria Luisa, Affricano, Daniela, Purdy, Robert H, Maciocco, Elisabetta, Spiga, Francesca, Biggio, Giovanni
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2001; Nature Publishing; Nature Publishing Group
• Subjects: Adrenalectomy; Allopregnanolone; Allotetrahydrodeoxycorticosterone; Animals; Antipsychotic; Antipsychotic Agents - pharmacology; Antipsychotics; Biological and medical sciences; Brain; Brain Chemistry - drug effects; Clozapine - pharmacology; Desoxycorticosterone - analogs & derivatives; Desoxycorticosterone - metabolism; Drug dosages; GABA; Haloperidol - pharmacology; Male; Medical sciences; Neuropharmacology; Neurosciences; Neurotransmitter Agents - metabolism; Orchiectomy; Pharmacology. Drug treatments; Progesterone; Progesterone - metabolism; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Psychotropic drugs; Rats; Rats, Sprague-Dawley; Steroids; Steroids - metabolism; Rome Italy; Italy; GABA; Antipsychotic; Progesterone; Allotetrahydrodeoxycorticosterone; Allopregnanolone; Cerebral cortex; Intraperitoneal administration; Rat; Neuroleptic; Psychotropic; Central nervous system; Chlorine ion; Ionic current; Haloperidol; Glucocorticoid; Blood; Blood plasma; Mechanism of action; Steroid hormone; Rodentia; Single dose; Butyrophenone derivatives; Clozapine; Long term; Pregnanolone; Ovarian hormone; Vertebrata; Mammalia; Animal; Sex steroid hormone; Gabaergic receptor A; Comparative study; Brain (vertebrata)
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1016/S0893-133X(01)00254-8

The extrapyramidal side effects of typical antipsychotics, which are induced to a markedly reduced extent by clozapine, have been linked to a dysfunction of central γ-aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, AP) and 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), two potent and endogenous positive allosteric modulators of GABA-mediated chloride current intensities at GABAA receptors, were compared with those of the typical antipsychotic haloperidol. A single administration of clozapine (1.25–20 mg/kg, IP), but not of haloperidol (0.1 or 0.5 mg/kg, IP), induced dose- and time-dependent increases in the concentrations of progesterone, AP, and THDOC in the cerebral cortex and striatum of rats. Clozapine (at 10 mg/kg, but 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 increase the cortical concentrations of AP and THDOC in adrenalectomized-orchidectomized rats. An acute challenge with clozapine (10 mg/kg), administered 48 h after the termination of daily treatment with the same dose for 19 days, still increased the cortical concentrations of progesterone, AP, and THDOC. These results suggest that the clozapine-induced increases in neuroactive steroid concentrations in the brain may contribute to the atypical pharmacological profile of this antipsychotic drug.