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.
Women with schizophrenia have a more favorable course of illness than men during the reproductive years, characterized by later onset of symptoms, lower symptom severity and better response to antipsychotic treatment (Hafner, 2003, Hafner et al., 1989, Kulkarni, 2009, Kulkarni et al., 1996, Kulkarni et al., 2008b, Riecher-Rossler and Hafner, 1993 and Seeman and Lang, 1990). However, elevated symptom severity and reduced response to treatment are seen postmenopausally, and there is a second onset peak unique to postmenopausal women (Horacek et al., 2006, Kulkarni et al., 1996, Kulkarni et al., 2008b, Lane et al., 1999, Riecher-Rossler et al., 1994, Salokangas, 1995, Saugstad, 1989 and Seeman and Lang, 1990). These observations have led to the suggestion that estrogen may be protective in women vulnerable to schizophrenia, and by extension, that exogenous estrogen may have therapeutic potential in schizophrenia given on its own or as an adjuvant to antipsychotic drugs (APDs), but clinical data have been inconsistent (Akhondzadeh et al., 2003, Cyr et al., 2002, Korhonen et al., 1995, Kulkarni et al., 1996, Kulkarni et al., 2008a, Kulkarni et al., 2008b, Kulkarni et al., 2001, Mortimer, 2007 and Riecher-Rossler, 2002). Lately the estrogen hypothesis of schizophrenia received further support from genetic studies suggesting a mutation in estrogen receptor alpha is correlated with increased risk for schizophrenia (Mellios et al., 2010, Perlman et al., 2004, Perlman et al., 2005, Weickert et al., 2008, Wong and Weickert, 2009 and Wong et al., 2011). Another support comes from a study showing a therapeutic effect of estradiol in schizophrenic men (Kulkarni et al., 2011).
