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

Abstract

Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABA A receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 mg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 mg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3b-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3a-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABA A receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABA A receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO-mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

“…For example, both clozapine (Marx et al, 2003;Barbaccia et al, 2001) and olanzapine (Marx et al, 2000a(Marx et al, , 2003 dose dependently elevate the neuroactive steroid allopregnanolone in rodent brain, and we have hypothesized that neuroactive steroid induction may contribute the therapeutic efficacy of these compounds (Marx et al, 2003(Marx et al, , 2005. Furthermore, recent data support the possibility that allopregnanolone potentiates olanzapine actions on dopamine-mediated behaviors in rodents (Ugale et al, 2004). In addition to certain antipsychotics, fluoxetine also elevates allopregnanolone levels in animal models (Uzunov et al, 1996;Pinna et al, 2003Pinna et al, , 2004, and these increases have been linked to its antidepressant-like effects in rodent behavioral models (Khisti and Chopde, 2000a;Khisti et al, 2000b) and to the mitigation of aggression in socially isolated rats (Pinna et al, 2003).…”

Neuroactive Steroids in Schizophrenia

“…While some studies show that DHEA or DHEAS therapy improves some symptoms in schizophrenia (48)(49)(50), other studies reveal that low levels of these NASs may be beneficial for patients (44). Determining which symptoms improve and which get worse with DHEA and (or) DHEAS therapy and assessing each patient's symptom profile and primary pathological changes in the brain will determine which patients would benefit from DHEA therapy.…”

Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex

“…Kumar and co-workers (Kumar et al 2005;Ugale et al 2004) reported that muscimol-stimulated LORR was changed by PKC modulators and suggested that the mechanism involved modulation of PKC-mediated phosphorylation of GABA-A receptor. In our study, PKC phosphorylation was not altered by HALO-FLU, so this mechanism cannot explain the effect of this treatment on muscimol-induced LORR, and involvement of other receptors, such as serotonin and dopamine, is suggested.…”

“…The onset and the cessation of muscimol-induced sleep were assessed by presence of the righting reflex (LORR). Loss of LORR was defined as the inability to right three times in 1 min after placement in the supine position in a V-shaped support and its return as the ability of the animal to right itself three times in 1 min (Kumar et al 2005;Ugale et al 2004). …”