Contrasting Effects of Increased and Decreased Dopamine Transmission on Latent Inhibition in Ovariectomized Rats and Their Modulation by 17β-Estradiol: An Animal Model of Menopausal Psychosis?

Abstract

Women with schizophrenia have later onset and better response to antipsychotic drugs (APDs) than men during reproductive years, but the menopausal period is associated with increased symptom severity and reduced treatment response. Estrogen replacement therapy has been suggested as beneficial but clinical data are inconsistent. Latent inhibition (LI), the capacity to ignore irrelevant stimuli, is a measure of selective attention that is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosisinducing drug amphetamine and can be reversed by typical and atypical APDs. Here we used amphetamine (1 mg/kg)-induced disrupted LI in ovariectomized rats to model low levels of estrogen along with hyperfunction of the dopaminergic system that may be occurring in menopausal psychosis, and tested the efficacy of APDs and estrogen in reversing disrupted LI. 17b-Estradiol (50, 150 mg/kg), clozapine (atypical APD; 5, 10 mg/kg), and haloperidol (typical APD; 0.1, 0.3 mg/kg) effectively reversed amphetamine-induced LI disruption in sham rats, but were much less effective in ovariectomized rats; 17b-estradiol and clozapine were effective only at high doses (150 mg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17b-estradiol (50 mg/kg, an ineffective dose). Reduced sensitivity to dopamine (DA) blockade coupled with spared/potentiated sensitivity to DA stimulation after ovariectomy may provide a novel model recapitulating the combination of increased vulnerability to psychosis with reduced response to APD treatment in female patients during menopause. In addition, our data show that 17b-estradiol exerts antipsychotic activity.

Sex-Dependent Antipsychotic Capacity of 17β-Estradiol in the Latent Inhibition Model: A Typical Antipsychotic Drug in Both Sexes, Atypical Antipsychotic Drug in Males

“…17b-estradiol at 50 and 150 mg/kg doses, which potentiated LI under conditions that disrupted LI in untreated gonadally intact rats (strong conditioning), also reversed amphetamine-induced LI disruption, as typically found with APDs. The present results replicate our recent finding (Arad and Weiner, 2010) that 17b-estradiol prevents amphetamine from disrupting LI in gonadally intact female rats and extends this action of 17b-estradiol to gonadally intact male rats. Sex-dependent antipsychotic capacity of 17b-estradiol M Arad and I Weiner…”

“…We have previously obtained this same bimodal effect of 17b-estradiol on LI in OVX rats (Arad and Weiner, 2010) and Nofrey et al (2008) have also reported LI-disrupting effect of 10 mg/kg 17b-estradiol in OVX rats. The fact that 17b-estradiol produces contrasting effects on LI at low and high doses implies that estradiol acts dose-dependently on different neural substrates.…”

“…In summary, our previous (Arad and Weiner, 2010) and present data are clear in showing that estrogen can exert antipsychotic activity, reversing hyperdopaminergia-induced behavioral abnormality in gonadally intact rats of both sexes and in OVX rats, and reversing hypoglutamatergia-induced abnormality in male and OVX rats. By extension, these results suggest that estrogen can be viewed as an effective treatment not only for positive symptoms in women with schizophrenia, but also for a wide spectrum of symptoms in women and men with schizophrenia, including negative/cognitive symptoms.…”

“…Although gender differences in response to amphetamine and other psychostimulants have been widely reported (for review see Fattore et al, 2008), such differences are not evident in the pro-psychotic action of amphetamine in the LI model (Arad and Weiner, 2010). Disruption of LI reflects a selective attention deficit, whereby animals lose the capacity to ignore the irrelevant stimulus, and is also observed in amphetamine-treated humans and high-schizotypal humans, (BraunsteinBercovitz et al, 2002;Gray et al, 1992b;Salgado et al, 2000;Swerdlow et al, 2003;Thornton et al, 1996) as well as in acutely psychotic schizophrenia patients (Baruch et al, 1988;Gray et al, 1992a;Gray et al, 1995b;Rascle et al, 2001;Swerdlow et al, 2005).…”

“…at a dose of 50 mg/kg. These doses are routinely used in our LI studies (Arad and Weiner 2010;Barak et al, 2009;Black et al, 2008). 17b-estradiol (Sigma, Israel) was dissolved in corn oil and administered s.c. at doses of 10, 50, and 150 mg/kg.…”