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

Abstract

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 ␥ -aminobutyric acid (GABA)-mediated neurotransmission. The effects of clozapine on the brain concentrations of 3 ␣ -hydroxy-5 ␣ AP) and 3 ␣ , THDOC)Clozapine, the prototype of atypical antipsychotic drugs, exhibits the clinical efficacy of classical antipsychotics but lacks or induces to a greatly reduced extent most of the motor side effects of these latter drugs. The molecular mechanisms that underlie the pharmacological profile of clozapine remain unclear. Emphasis has been placed on the purported "selective" action of clozapine on mesocortical and mesolimbic dopaminergic pathways thought to result from its higher affinity for D 4 dopamine receptors than for D 2 receptors (Seeman 1992), as well as on its mixed antagonistic/agonistic action at D 2 and D 1 receptors (Coward et al. 1989;Brunello et al., 1995;Gerlach et al. 1996) and its high affinity for different subtypes of serotonin receptors (Brunello et al. 1995). More recently, the ratios of the affinities of clozapine for D 2 and 5HT 1a , D 2 and 5HT 1b or 5HT 1d , and D 2 and ␣ 2 -adrenergic receptors have been suggested to play a role in the anticata-

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

“…It is therefore possible that olanzapine-and clozapine-induced elevations in the anxiolytic neuroactive steroid allopregnanolone contribute to the anxiolytic-like effects of these compounds. The absence of haloperidol-induced effects on this neuroactive steroid is consistent with recent efforts by Barbaccia et al (2001). To our knowledge, this is the first report demonstrating that acute risperidone administration does not affect central allopregnanolone levels.…”

“…Allopregnanolone levels in the cerebral cortex following clozapine administration in these experiments are comparable to levels reported recently by Barbaccia et al (2001), utilizing 10.0 and 20.0 mg/kg dosing strategies. In contrast to olanzapine and clozapine, the antipsychotics risperidone and haloperidol had no significant effects on allopregnanolone levels in the cerebral cortex, confirming our initial hypothesis.…”

“…Other recent efforts have also demonstrated that adrenalectomy prevents clozapine-induced cerebral cortical allopregnanolone formation (Barbaccia et al, 2001). We report for the first time that adrenalectomy also prevents olanzapine-induced elevations in this neuroactive steroid.…”

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

“…Several preclinical studies have shown that haloperidol failed to alter the brain concentrations of neurosteroids (Barbaccia et al, 2001;Nechmad et al, 2003), whereas clozapine administered for 8 days reduced the brain concentrations of DHEA and DHEAS (Nechmad et al, 2003).…”

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

“…It has recently been demonstrated that both olanzapine and clozapine, but not risperidone and haloperidol, elevate brain cortical levels of the GABA A -positive neuroactive steroid allopregnanolone (ALLO), leading to a putative increase in GABAergic tone (Barbaccia et al, 2001;Marx et al, 2000Marx et al, , 2003. Neuroactive steroids including ALLO are synthesized de novo in the brain from cholesterol or from peripheral steroids in adrenal or gonads (Purdy et al, 1991 and are present in the CNS at concentrations that may modulate GABA A receptor function Robel and Baulieu, 1995;Bixo et al, 1997;Rupprecht and Holsboer, 1999).…”