Effects of clozapine and alprazolam on cognitive deficits and anxiety-like behaviors in a ketamine-induced rat model of schizophrenia.

摘要

Schizophrenia is a debilitating mental illness that affects approximately 2.2 million Americans (1% of the population) each year. Despite the large number of people affected by schizophrenia, there is no known cure for this disorder but antispychotics help to manage the symptoms of schizophrenia. Unfortunately, antipsychotic medications are frequently accompanied by debilitating side effects (e.g., extrapyramidal side effects, tardive dyskinesia) and low compliance. Alternative pharmacological treatment options are needed to improve the treatment and quality of life for individuals suffering from schizophrenia.; This doctoral research project examined the hypothesis that the cognitive deficits associated with schizophrenia can be medicated indirectly using anxiolytics, drugs that decrease anxiety, based upon a proposed relationship between anxiety and cognitive disruptions in schizophrenia. The current research also evaluated the validity and potential usefulness of ketamine administration to create a novel animal model that includes symptoms of schizophrenia and anxiety.; Two experiments were conducted to address these goals. Experiment #1 examined the effects of clozapine (an antipsychotic), alprazolam (an anxiolytic), and a combination treatment on ketamine-induced cognitive disruptions in prepulse inhibition (PPI) of the acoustic startle reflex and passive avoidance. Experiment #2 examined the effects of clozapine, alprazolam, and a combination treatment on ketamine-induced anxiety-like behaviors on the elevated plus maze, open field test, and social interaction test.; The major findings of the study were: (1) ketamine administration caused cognitive disruptions in PPI as well as passive avoidance; (2) only clozapine attenuated the cognitive disruptions caused by ketamine, and only in the PPI measure; (3) ketamine administration caused an increase in anxiety-like behaviors on the EPM, open field locomotor activity, and social interaction; (4) only alprazolam decreased the ketamine-induced increases in anxiety-like behaviors, and only in the measure of social interaction. The findings failed to support the hypothesis that ketamine-induced cognitive deficits could be attenuated with anxiolytic medications. In addition, these findings suggest that ketamine administration may provide a useful, but limited, model of concurrent symptoms of schizophrenia and anxiety.