In the latent inhibition model
In the latent inhibition model, a conditioned stimulus (CS) is pre-exposed alone without any consequences (i.e., unconditioned stimulus [US]) in the pre-exposure phase. The CS is then associated with a US to form a CS-US association. The strength of the CS-induced response in the pre-exposure group is less than that in the non-pre-exposure group, referred to as latent inhibition (Escobar et al., 2002, Weiner and Feldon, 1997). Schizophrenia patients do not obtain latent inhibition (Lubow and Gewirtz, 1995) and cannot learn the CS-nothing association, which consequently interferes with subsequent CS-US conditioning (Escobar et al., 2002). One important issue is the involvement of glutamate neurotransmission in latent inhibition associated with schizophrenia. Numerous studies on this subject have reported discrepant results. For example, some studies suggested that glutamate antagonism in the brain disrupts the formation of latent inhibition (Davis and Gould, 2005, Razoux et al., 2007, Schauz and Koch, 2000, Traverso et al., 2010, Traverso et al., 2003). N-methyl-D-aspartate (NMDA) receptor antagonist ketamine injections impaired latent inhibition when it was administered in the pre-exposure phase (Aguado et al., 1994, Razoux et al., 2007). Rats that receive injections of the noncompetitive NMDA receptor antagonist MK-801 after the pre-exposure phase exhibit a disruption of latent inhibition in the conditioned taste aversion paradigm (Traverso et al., 2003) and the cued fear conditioning paradigm (Davis and Gould, 2005). Infused D,L-2-amino-5-phosphonopentanoic Azacyclonol (AP5; an NMDA receptor antagonist) in the basolateral nucleus of the amygdala prior to CS pre-exposure could abolish latent inhibition in the footshock-induced fear conditioning (Schauz and Koch, 2000) and conditioned taste aversion (Traverso et al., 2010) paradigms. A high (but not low) dose of phencyclidine (PCP), which is an NMDA receptor antagonist, appeared to disrupt latent inhibition when PCP was administered in the pre-exposure and conditioning phases (Turgeon et al., 2000, Turgeon et al., 1998). However, another research indicates that glutamate antagonism may potentiate latent inhibition (Gaisler-Salomon et al., 2009), and glutamate agonism may disrupt latent inhibition (Gaisler-Salomon et al., 2009, Gaisler-Salomon and Weiner, 2003). For example, a recent study on latent inhibition showed that glutaminase-deficient mice, which reduced glutamate transmission, potentiated latent inhibition (Gaisler-Salomon et al., 2009). A systematic administration of MK-801 appeared to be a persistent effect of latent inhibition, suggesting that glutamate antagonists might play a role in the facilitation or persistence of latent inhibition (Gaisler-Salomon and Weiner, 2003). In addition, the third hypothesis suggests that NMDA receptors do not govern latent inhibition and that NMDA antagonists do not affect latent inhibition (Palsson et al., 2005, Tenn et al., 2005, Weiner and Feldon, 1992). For example, a behavioral sensitization study showed that rats that were repeatedly exposed to amphetamine-induced sensitization exhibited an attenuation of latent inhibition, but PCP-sensitized rats did not present impairment in latent inhibition (Tenn et al., 2005). A similar study indicated that PCP did not affect latent inhibition when it was injected in the pre-exposure phase, although it was shown to potentiate latent inhibition when it was administered prior to the conditioning phase (Palsson et al., 2005). Furthermore, a behavioral pharmacology study found that low and high doses of PCP did not affect latent inhibition when PCP was injected during the pre-exposure, conditioning, and test phases, respectively (Weiner and Feldon, 1992). Therefore, the present study used glutamate antagonist MK-801 and glutamate agonist NMDA to examine whether the glutamate system influences latent inhibition in the animal model of schizophrenia. On the other hand, sexual dimorphism has been investigated in latent inhibition (Bethus et al., 2005, Wang et al., 2012, Weiner et al., 1985). For example, a previous study showed that female rats exhibited latent inhibition regardless of the handling/non-handling conditions. Meanwhile, male rats exhibited latent inhibition in the handling condition but not in the non-handling condition (Weiner et al., 1985). Male rats that were not exposed to stress exhibited less latent inhibition than did female rats that were not exposed to stress. However, prenatal stress was shown to increase the magnitude of latent inhibition only in male rats and not in female rats (Bethus et al., 2005). Sex differentially affects the involvement of the brain's dopamine system in latent inhibition (Wang et al., 2012). Therefore, whether sex difference exhibits sexual dimorphism in the glutamate's latent inhibition model needed to be scrutinized in the present study.