Abstract
A key problem with animal models of psychosis lies with the animal’s inability to self-report its own internal state. In the present study, we used the drug discrimination paradigm, an assay that can provide an objective measure of an animal’s subjective internal state, to assess whether the subjective internal state experienced by rats that model a specific etiological schizophrenia risk factor (maternal immune activation; MIA) is analogous to that experienced in a model of human psychosis. After initial PPI testing, MIA (rats born from dams exposed to Poly I.C., a viral mimetic that produces activation of the immune system) and control rats, were trained to discriminate 7.5 mg/kg ketamine from saline in a two-lever operant chamber. Once discriminative control was established, dose-effect determinations were made. Controls procedures were conducted to rule out potential confounds resulting from MIA treatment, including, a pre-feeding challenge evaluating satiety as a non-drug internal cue and morphine discrimination to evaluate the rat’s performance with a drug cue unrelated to psychosis. Finally, an open field assay was conducted to investigate alterations in the sensitivity to ketamine-evoked hyperlocomotion. The results showed a deficit in PPI and impaired drug discrimination of ketamine in MIA rats, with the difference in discrimination between MIA and control particular to the psychotomimetic dose range (3-10 mg/kg). These results were not due to a deficit in the rat’s ability to learn or perform in the drug discrimination task, as MIA animals readily acquired morphine discrimination, a decreased sensitivity to ketamine, as MIA rats were actually more sensitive at psychotomimetic doses to ketamine-evoked hyperlocomotion, or a general decrease in sensitivity to internal states, as these animals were as sensitive to the satiety cue as their control counterparts. Overall these data provide support for the assertion that the subjective state of MIA rats is similar to that experienced in a ketamine model of psychosis and therefore may be analogous to that experienced in human psychosis. This indicates that the drug-discrimination paradigm may be a useful tool for understanding the neurophysiological underpinnings of human psychosis in animal models.