Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH041440-06
Application #
3380014
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1985-07-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

Ninan, Ipe; Jardemark, Kent E; Liang, Xiaofu et al. (2003) Calcium/calmodulin-dependent kinase II is involved in the facilitating effect of clozapine on NMDA- and electrically evoked responses in the medial prefrontal cortical pyramidal cells. Synapse 47:285-94
Jardemark, K E; Ninan, I; Liang, X et al. (2003) Protein kinase C is involved in clozapine's facilitation of N-methyl-D-aspartate- and electrically evoked responses in pyramidal cells of the medial prefrontal cortex. Neuroscience 118:501-12
Ninan, Ipe; Wang, Rex Y (2003) Modulation of the ability of clozapine to facilitate NMDA- and electrically evoked responses in pyramidal cells of the rat medial prefrontal cortex by dopamine: pharmacological evidence. Eur J Neurosci 17:1306-12
Jardemark, K E; Liang, X; Arvanov, V et al. (2000) Subchronic treatment with either clozapine, olanzapine or haloperidol produces a hyposensitive response of the rat cortical cells to N-methyl-D-aspartate. Neuroscience 100:9-Jan
Arvanov, V L; Wang, R Y (1999) Clozapine, but not haloperidol, prevents the functional hyperactivity of N-methyl-D-aspartate receptors in rat cortical neurons induced by subchronic administration of phencyclidine. J Pharmacol Exp Ther 289:1000-6
Arvanov, V L; Liang, X; Magro, P et al. (1999) A pre- and postsynaptic modulatory action of 5-HT and the 5-HT2A, 2C receptor agonist DOB on NMDA-evoked responses in the rat medial prefrontal cortex. Eur J Neurosci 11:2917-34
Arvanov, V L; Liang, X; Russo, A et al. (1999) LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex. Eur J Neurosci 11:3064-72
Liang, X; Arvanov, V L; Wang, R Y (1998) Inhibition of NMDA-receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5-HT3 receptor agonist SR 57227A and 5-HT: intracellular studies. Synapse 29:257-68
Wang, R Y; Liang, X (1998) M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortical slice. Neuropsychopharmacology 19:74-85
Liang, X; Wang, R Y (1998) Biphasic modulatory action of the selective sigma receptor ligand SR 31742A on N-methyl-D-aspartate-induced neuronal responses in the frontal cortex. Brain Res 807:208-13

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