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 17β-estradiol and the atypical APD clozapine, whereas the typical APD haloperidol was ineffective unless co-administered with 17β-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 17β-estradiol (150 μg/kg) and clozapine (2.5 mg/kg), but not by haloperidol (0.1 mg/kg) or lower doses of 17β-estradiol (10 and 50 μg/kg). However, co-administration of haloperidol with 17β-estradiol (50 μg/kg) was effective. In sham rats low 17β-estradiol (10 μg/kg) produced rapid reversal, while high 17β-estradiol (150 μg/kg), haloperidol alone, or haloperidol-17β-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.