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Dopamine-glutamate interaction in th...

City University of New York., Biology.

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Dopamine-glutamate interaction in the actions of typical antipsychotic drugs.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Dopamine-glutamate interaction in the actions of typical antipsychotic drugs./
Author:	Agovic, Mervan S.
Description:	112 p.
Notes:	Advisers: Theodore I. Lidsky; Shailesh P. Banerjee.
Contained By:	Dissertation Abstracts International70-02B.
Subject:	Biology, Neuroscience. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3344956
ISBN:	9781109051933

Dopamine-glutamate interaction in the actions of typical antipsychotic drugs.
Agovic, Mervan S.

Dopamine-glutamate interaction in the actions of typical antipsychotic drugs. - 112 p.

Advisers: Theodore I. Lidsky; Shailesh P. Banerjee.

Thesis (Ph.D.)--City University of New York, 2009.

Typical antipsychotic drugs (APD) are currently the most effective psychoactive agents for the treatment of schizophrenia. Studies suggest that besides their conventional action of blocking dopamine (DA) D2 receptors, these drugs also interact with glutamatergic N-methyl-D-aspartate (NMDA) receptors. In addition, blockade of DA D2 receptors is believed to result in DA cell depolarization block (DB) and movement disorders (catalepsy) in animals. Since it has been hypothesized that drug's antipsychotic potency may be predicted by its ability to produce DB and catalepsy, using CD rats in behavioral, microdialysis and receptor binding studies we investigated whether typical APD induce DB and catalepsy though action on the dopaminergic system, glutamatergic system, or through the interaction between the two systems. Focus of this project was on striatum (STR) and frontal cortex (FC), two brain regions implicated in the DA-glutamate interplay. Our behavioral results show that haloperidol, a potent APD and postsynaptic DA D2 receptor blocker is a strong catalepsy inducer. Receptor binding study showed that chronic administration of this drug caused a decrease in maximal binding at the NMDA receptors in STR and FC but no significant changes in the DA D 2 receptor densities were seen in the two brain areas. In contrast, metoclopramide, another DA D2 receptor blocker but not an APD, within the therapeutic doses (5 mg/kg-10 mg/kg) did not produce catalepsy in experimental animals. The maximal binding parameters for DA D2 and NMDA receptors in STR and FC after repeated administration of metoclopramide were significantly elevated as compared to haloperidol. However, when animals were pre-treated with metoclopramide (10 mg/kg) it sensitized the brain to haloperidol and enhanced catalepsy. Additionally, our receptor binding studies showed that psychotomimetic agents, PCP and ketamine that cause schizophrenia-like symptoms have several-fold higher binding affinity at NMDA receptors as compared to DA D2 receptors, indicating that pharmacological effect of these drugs may be mainly mediated by blockade of NMDA receptors. Finally, studying the neurochemical mechanism for DA cell DB we saw a decrease in striatal DA release after chronic cocaine treatment compared to controls. In a series of follow-up experiments we compared the effect of low dose (0.5 mg/kg) haloperidol and high dose (3.0 mg/kg) haloperidol by acute injection to the chronic cocaine treated rats and to the control animals. Low dose haloperidol significantly increased straital DA release compared to respective controls, while the high dose haloperidol significantly reduced it compared to the low dose. On the other hand, high dose haloperidol drastically increased striatal DA release in chronic cocaine-treated rats compared to controls. These results suggest that the mechanism for catalepsy is based on the concurrent DA D2 receptor antagonism and activation of glutamatergic NMDA transmission. Similarly, the mechanism for DA cell DB is mediated through blockade of dopaminergic D2 receptors and stimulation of NMDA receptors. Thus, catalepsy as well as antipsychotic activity appears to be mediated through modifications of dopaminergic and glutamatergic transmissions.

ISBN: 9781109051933Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Dopamine-glutamate interaction in the actions of typical antipsychotic drugs.
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100 1 $a Agovic, Mervan S. $3 1025351
245 1 0 $a Dopamine-glutamate interaction in the actions of typical antipsychotic drugs.
300 $a 112 p.
500 $a Advisers: Theodore I. Lidsky; Shailesh P. Banerjee.
500 $a Source: Dissertation Abstracts International, Volume: 70-02, Section: B, page: 0851.
502 $a Thesis (Ph.D.)--City University of New York, 2009.
520 $a Typical antipsychotic drugs (APD) are currently the most effective psychoactive agents for the treatment of schizophrenia. Studies suggest that besides their conventional action of blocking dopamine (DA) D2 receptors, these drugs also interact with glutamatergic N-methyl-D-aspartate (NMDA) receptors. In addition, blockade of DA D2 receptors is believed to result in DA cell depolarization block (DB) and movement disorders (catalepsy) in animals. Since it has been hypothesized that drug's antipsychotic potency may be predicted by its ability to produce DB and catalepsy, using CD rats in behavioral, microdialysis and receptor binding studies we investigated whether typical APD induce DB and catalepsy though action on the dopaminergic system, glutamatergic system, or through the interaction between the two systems. Focus of this project was on striatum (STR) and frontal cortex (FC), two brain regions implicated in the DA-glutamate interplay. Our behavioral results show that haloperidol, a potent APD and postsynaptic DA D2 receptor blocker is a strong catalepsy inducer. Receptor binding study showed that chronic administration of this drug caused a decrease in maximal binding at the NMDA receptors in STR and FC but no significant changes in the DA D 2 receptor densities were seen in the two brain areas. In contrast, metoclopramide, another DA D2 receptor blocker but not an APD, within the therapeutic doses (5 mg/kg-10 mg/kg) did not produce catalepsy in experimental animals. The maximal binding parameters for DA D2 and NMDA receptors in STR and FC after repeated administration of metoclopramide were significantly elevated as compared to haloperidol. However, when animals were pre-treated with metoclopramide (10 mg/kg) it sensitized the brain to haloperidol and enhanced catalepsy. Additionally, our receptor binding studies showed that psychotomimetic agents, PCP and ketamine that cause schizophrenia-like symptoms have several-fold higher binding affinity at NMDA receptors as compared to DA D2 receptors, indicating that pharmacological effect of these drugs may be mainly mediated by blockade of NMDA receptors. Finally, studying the neurochemical mechanism for DA cell DB we saw a decrease in striatal DA release after chronic cocaine treatment compared to controls. In a series of follow-up experiments we compared the effect of low dose (0.5 mg/kg) haloperidol and high dose (3.0 mg/kg) haloperidol by acute injection to the chronic cocaine treated rats and to the control animals. Low dose haloperidol significantly increased straital DA release compared to respective controls, while the high dose haloperidol significantly reduced it compared to the low dose. On the other hand, high dose haloperidol drastically increased striatal DA release in chronic cocaine-treated rats compared to controls. These results suggest that the mechanism for catalepsy is based on the concurrent DA D2 receptor antagonism and activation of glutamatergic NMDA transmission. Similarly, the mechanism for DA cell DB is mediated through blockade of dopaminergic D2 receptors and stimulation of NMDA receptors. Thus, catalepsy as well as antipsychotic activity appears to be mediated through modifications of dopaminergic and glutamatergic transmissions.
590 $a School code: 0046.
650 4 $a Biology, Neuroscience. $3 1017680
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0317
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710 2 $a City University of New York. $b Biology. $3 1025217
773 0 $t Dissertation Abstracts International $g 70-02B.
790 $a 0046
790 1 0 $a Banerjee, Shailesh P., $e advisor
790 1 0 $a Chan, Christopher Y. $e committee member
790 1 0 $a El Idrissi, Abdeslem $e committee member
790 1 0 $a Friedman, Eitan $e committee member
790 1 0 $a Gluck, Martin $e committee member
790 1 0 $a Lidsky, Theodore I., $e advisor
790 1 0 $a Trenkner, Ekkehart $e committee member
791 $a Ph.D.
792 $a 2009
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3344956