The recent development of specific serotonin 3(5-HT3) receptor antagonists opens the door for detailed characterization of this 5-HT receptor subtype and for determination of its functional role in the brain. Recent radioligand binding studies have shown that rat brain membrane contains binding sites specific for 5-HT3 antagonists. A moderate to high concentration of 5-HT3 binding sites are present in the amygdala, nucleus accumbens (naC) and entorhinal and frontal cortices. Behavioral testing in animal models have implicated that 5-HT3 antagonists modulates dopamine (DA) hyperactivity and may represent a new class of antipsychotic drugs (APDs). Since numerous studies have shown that 5-HT exerts a modulatory action upon DA systems, which play an important role in the pathophysiology of schizophrenia and actions of APDs, it is likely some of 5-HT's action might be mediated by 5-HT3 receptors. We have decided to identify and characterize physiological and pharmacological properties of 5-HT3 receptors on midbrain DA-containing neurons and neurons in the DA target structures such as the medial prefrontal cortex (mPFc), NAc and caudate-putamen (CPu) using the technique of single unit recording and microiontophoresis. The possible interactions between 5-HT3 receptors and DA receptor subtypes will be investigated. Moreover, the differential actions of typical and atypical APDs on 5-HT3 receptors and on the interactions between 5-HT3 and DA receptors will be characterized and compared on A9 and A10 DA neurons and neurons in the A9 and A10 DA target structures. In parallel to electrophysiological studies, biochemical and pharmacological approaches will be used to study the action of typical and atypical APDs on 5-HT3 binding sites and 5-HT3 receptor coupled phosphoinositide hydrolysis. The results of the present proposal should help us to understand the role of 5-HT3 receptors in the mode of action of APDs. Ultimately, such knowledge will help us to understand how and where the APDs act in the brain and develop new types of APDs with maximum therapeutic efficacy and minimum side effects.

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National Institute of Mental Health (NIMH)
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State University New York Stony Brook
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