Fluctuation of latent inhibition along the estrous cycle in the rat: Modeling the cyclicity of symptoms in schizophrenic women?

Abstract

Latent inhibition (LI) is a cross-species selective attention phenomenon manifested as poorer conditioning of stimuli that had been experienced as irrelevant prior to conditioning. Disruption of LI by pro-psychotic agents such as amphetamine and its restoration by antipsychotic drugs (APDs) is a well-established model of psychotic symptoms of schizophrenia. There is evidence that in schizophrenic women symptom severity and treatment response fluctuate along the menstrual cycle. Here we tested whether hormonal fluctuation along the estrous cycle in female rats (as determined indirectly via the cellular composition of the vaginal smears) would modulate the expression of LI and its response to APDs. The results showed that LI was seen if rats were in estrus during pre-exposure stage and in metestrus during the conditioning stage of the LI procedure (estrus-metestrus) but not along the remaining sequential phases of the cycle (metestrus-diestrus, diestrus-proestrus and proestrus-estrus). Additionally, the efficacy of typical and atypical APDs, haloperidol and clozapine, respectively, in restoring LI depended on estrous condition. Only LI disruption in proestrus-estrus exhibited sensitivity to both APDs, whereas LI disruption in the other two phases was alleviated by clozapine but not haloperidol. Our results show for the first time that both the expression of LI and its sensitivity to APDs are modulated along the estrous cycle, consistent with fluctuations in psychotic symptoms and response to APDs seen along women's menstrual cycle. Importantly, the results indicate that although both low and high levels of hormones may give rise to psychotic-like behavior as manifested in LI loss, the pro-psychotic state associated with low hormonal level is more severe due to reduced sensitivity to typical APDs. The latter constellation may mimic states of increased vulnerability to psychosis coupled with reduced treatment response documented in schizophrenic women during periods associated with low levels of hormones.