| Effects of NRA0045, a novel potent antagonist at dopamine D4, 5-HT2A, and alpha1 adrenaline receptors, and NRA0160, a selective D4 receptor antagonist, on phencyclidine-induced behavior and glutamate release in rats. | |
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MedLine Citation:
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PMID: 12898123 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Administration of phencyclidine (PCP) to animals produces abnormal behavior such as hyperlocomotion, stereotyped behavior, and ataxia; this abnormal behavior is only weakly blocked by dopamine D(2) receptor antagonists. This study examined the effects of a novel thiazole derivative, NRA0045 which potently antagonizes not only dopamine D(4) receptors but also 5-HT(2A) and alpha(1) adrenaline receptors, and NRA0160, a selective dopamine D(4) receptor antagonist, on PCP-induced abnormal behavior, and accompanying increases in extracellular levels of glutamate in the medial prefrontal cortex. Furthermore, this study compared the effects of these drugs with those of clozapine and haloperidol. METHODS: To study the effects of NRA-drugs, atypical and typical antipsychotics, we measured locomotor activity with an infra-red sensor, and stereotypy and ataxia on a rating scale. Extracellular glutamate levels were measured by in vivo microdialysis. RESULTS: NRA0045 (1 or 3 mg/kg) or clozapine (1 mg/kg) attenuated hyperlocomotion, stereotypy, and ataxia induced by PCP (7.5 mg/kg) without affecting behavior after saline injection. Although haloperidol (0.1 or 1 mg/kg) attenuated or inhibited PCP-induced behavior, this drug also affected behavior after saline injection. NRA0160 (0.1, 1, or 3 mg/kg) had no effect on behavior induced by PCP or saline. NRA0045 (3 mg/kg), but not NRA0160, inhibited PCP-induced increases in glutamate levels in the medial prefrontal cortex. PCP-induced hyperlocomotion correlated with the PCP-induced increases in glutamate levels in this brain region. CONCLUSIONS: These results suggest that the effects of NRA0045 on PCP-induced abnormal behavior are similar to those of the atypical antipsychotic clozapine. NRA0045 probably attenuates PCP-induced abnormal behavior by inhibiting the PCP-induced increase in glutamate levels in the medial prefrontal cortex; this inhibition may be mediated via the blockade of 5-HT(2A) receptors. |
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Authors:
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T Abekawa; M Honda; K Ito; T Koyama |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2003-07-31 |
Journal Detail:
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Title: Psychopharmacology Volume: 169 ISSN: 0033-3158 ISO Abbreviation: Psychopharmacology (Berl.) Publication Date: 2003 Sep |
Date Detail:
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Created Date: 2003-10-07 Completed Date: 2004-02-23 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7608025 Medline TA: Psychopharmacology (Berl) Country: Germany |
Other Details:
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Languages: eng Pagination: 247-56 Citation Subset: IM |
Affiliation:
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Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, 060-8638, Sapporo, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chromatography, High Pressure Liquid Clozapine / pharmacology Dose-Response Relationship, Drug Drug Interactions Glutamic Acid / metabolism* Haloperidol / pharmacology Male Microdialysis / methods Motor Activity / drug effects Phencyclidine / pharmacology* Piperidines / pharmacology* Pyrrolidines / pharmacology* Rats Rats, Sprague-Dawley Receptor, Serotonin, 5-HT2A / antagonists & inhibitors Receptors, Adrenergic, alpha-1 / antagonists & inhibitors Receptors, Dopamine D2 / antagonists & inhibitors* Receptors, Dopamine D4 Serotonin Antagonists / pharmacology Stereotyped Behavior / drug effects*, physiology Thiazoles / pharmacology* Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Drd4 protein, rat; 0/NRA 0045; 0/NRA 0160; 0/Piperidines; 0/Pyrrolidines; 0/Receptor, Serotonin, 5-HT2A; 0/Receptors, Adrenergic, alpha-1; 0/Receptors, Dopamine D2; 0/Serotonin Antagonists; 0/Thiazoles; 137750-34-6/Receptors, Dopamine D4; 52-86-8/Haloperidol; 56-86-0/Glutamic Acid; 5786-21-0/Clozapine; 77-10-1/Phencyclidine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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