Classic antipsychotics treat schizophrenics's hallucinations, but not their social withdrawal and flattened affect. These drugs also produce extremely unpleasant motor side effects, because these compounds were originally selected based on their ability to produce motor disturbances in rats. Clozapine is an atypical antipsychotic which treats both types of symptoms with very few motor side effects, but it can also produce a potentially lethal side effect, agranulocytosis. Thus, a tremendous demand exists to develop safer and more effective atypical antipsychotics. In order for a compound to show promise as an antipsychotic in preclinical trials, it must have appropriate behavioral and biological actions. The goal of this research is to develop a better method for detecting atypical compounds by testing the hypotheses that atypical antipsychotics will differ from classic antipsychotics in terms of their effects on PCP-induced social withdrawal with repeated administration. In particular, atypical antipsychotics are predicted to be more efficacious at alleviating PCP- induced social withdrawal with repeated administration. In particular, atypical antipsychotics are predicted to be more efficacious at alleviating PCP-induced social withdrawal. Atypical antipsychotics are also predicted to produce greater tolerance to the initial increases in extracellular dopamine in mesocorticolimbic structures, while having a limited effect on striatal dopamine, compared to typical antipsychotics. This hypothesis will be examined using simultaneous sampling from pairs of structures using in vivo dialysis coupled to HPLC. The results will provide scientists with: 1) a profile of social behaviors in a rodent model for candidate atypical compounds to restore in order to be effective at treating both types of symptoms in schizophrenia; and 2) a neurochemical model with limited effects on striatal dopamine and only transient elevations in mesocorticolimbic structures. These studies would improve the manner in which compounds are selected for human clinical trials and enhance our understanding of biological mechanism involved in the atypical antipsychotic effect.
