Contrasting effects of increased and decreased dopamine transmission on latent inhibition in ovariectomized rats and their modulation by 17beta-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 psychosis-inducing 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. 17beta-Estradiol (50, 150 microg/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; 17beta-estradiol and clozapine were effective only at high doses (150 microg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17beta-estradiol (50 microg/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 17beta-estradiol exerts antipsychotic activity.

Figure 1

LI in OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) OVX rats in three pre-exposure/conditioning combinations (number of pre-exposures+number of conditioning trials): 40 pre-exposures and 1 conditioning trial (40+1); 40 pre-exposures and 2 conditioning trials (40+2); and 50 pre-exposures and 2 conditioning trials (50+2). Asterisks (^**) indicate significant difference between the PE and NPE groups, namely, presence of LI (p<0.01).

Figure 2

Effects of amphetamine (1 mg/kg) on LI in sham and OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) sham and OVX rats injected with saline or 1 mg/kg amphetamine. Asterisks (^**) indicate significant difference between the PE and NPE groups, namely, presence of LI (p<0.01).

Figure 3

Effects of 17β-estradiol (10, 50, or 150 μg/kg) on amphetamine-induced LI disruption in sham and OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) saline- or amphetamine (amph)-injected sham (sh) and OVX (ovx) females, administered with 0, 10, 50, or 150 μg/kg of 17β-estradiol (oil, E 10 μg/kg, E 50 μg/kg, or E 150 μg/kg, respectively). Asterisks indicate a significant difference between the PE and NPE groups, namely, presence of LI (^*p<0.05; ^**p<0.01).

Figure 4

Effects of haloperidol (0.1, 0.3 mg/kg) on amphetamine-induced LI disruption in sham and OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) saline- or amphetamine (amph)-injected sham and OVX rats that received haloperidol (0.1 or 0.3 mg/kg to half of the group), amphetamine+0.1 mg/kg haloperidol, or amphetamine+0.3 mg/kg haloperidol. Asterisks (^**) indicate significant difference between the PE and NPE groups, namely, presence of LI (p<0.01).

Figure 5

Effects of clozapine (5, 10 mg/kg) on amphetamine-induced LI disruption in sham and OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) saline- or amphetamine (amph)-injected sham and OVX rats that received clozapine (5 or 10 mg/kg to half of the group), amphetamine+5 mg/kg clozapine, or amphetamine+10 mg/kg clozapine. Asterisks (^**) indicate significant difference between the PE and NPE groups, namely, presence of LI (p<0.01).

Figure 6

Effects of coadministration of haloperidol (0.1 mg/kg) and 17β-estradiol (50 μg/kg) on amphetamine-induced LI disruption in OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) saline- or amphetamine (amph)-injected OVX rats administered with vehicle (vehicle), 50 μg/kg 17β-estradiol (17β-estradiol), 0.1 mg/kg haloperidol (haloperidol), or 17β-estradiol+haloperidol. Asterisks (^**) indicate significant difference between the PE and NPE groups, namely, presence of LI (p<0.01).

Figure 7

Effects of coadministration of clozapine (5 mg/kg) and 17β-estradiol (50 μg/kg) on amphetamine-induced LI disruption in OVX rats. Mean (±SEM) log times to complete licks 76–100 (after tone onset) of the pre-exposed (PE) and the non-pre-exposed (NPE) saline- or amphetamine (amph)-injected OVX rats administered with vehicle (vehicle), 50 μg/kg (17β-estradiol), 5 mg/kg (clozapine), or 17β-estradiol+clozapine. Asterisks (^**) indicate significant difference between the PE and NPE groups, namely, presence of LI p<0.01).