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.
BACKGROUND
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.
Abekawa
T
T
Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, 060-8638, Sapporo, Japan.
Honda
M
M
Ito
K
K
Koyama
T
T
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors
D058668:Adrenergic alpha-1 Receptor Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; C106996:NRA 0045; C121249:NRA 0160; D010880:Piperidines; D011759:Pyrrolidines; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D013844:Thiazoles; D050638:Receptors, Dopamine D4; D018698:Glutamic Acid; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol