Abnormally rapid reversal learning and reduced response to antipsychotic drugs following ovariectomy in female rats

Epidemiological and clinical life cycle studies indicate that favorable illness course and better response to antipsychotic drugs (APDs) in women with schizophrenia are positively correlated with estrogen levels. Accordingly, the estrogen hypothesis of schizophrenia proposes a neuroprotective role of estrogen in women vulnerable to schizophrenia. Previously we demonstrated in the rat that low levels of estrogen induced by ovariectomy led to disruption of latent inhibition (LI) reflecting impairment of selective attention, a core deficit of schizophrenia. LI disruption was reversed by 17 beta-estradiol and the atypical APD clozapine, whereas the typical APD haloperidol was ineffective unless co-administered with 17 beta-estradiol. Here we aimed to extend these findings by testing ovariectomized rats in another selective attention task, discrimination reversal. Ovariectomy led to a loss of selective attention as manifested in abnormally rapid reversal. The latter was normalized by high dose of 17 beta-estradiol (150 mu g/kg) and clozapine (2.5 mg/kg), but not by haloperidol (0.1 mg/kg) or lower doses of 17 beta-estradiol (10 and 50 mu g/kg). However, co-administration of haloperidol with 17 beta-estradiol (50 mu g/kg) was effective. In sham rats low 17 beta-estradiol (10 mu g/kg) produced rapid reversal, while high 17 beta-estradiol (150 mu g/kg), haloperidol alone, or haloperidol-17 beta-estradiol combination reduced reversal speed. Clozapine did not affect reversal speed in sham rats. These results strengthen our previous results in suggesting that schizophrenia-like attentional abnormalities as well as reduced response to APDs in female rats are associated with low level of gonadal hormones. In addition, they support the possibility that estrogen may have an antipsychotic-like action in animal models. (C) 2011 Elsevier Ltd. All rights reserved.