Psychopharmacology

, Volume 169, Issue 3–4, pp 247–256 | Cite as

Effects of NRA0045, a novel potent antagonist at dopamine D4, 5-HT2A, and α1 adrenaline receptors, and NRA0160, a selective D4 receptor antagonist, on phencyclidine-induced behavior and glutamate release in rats

  • T. Abekawa
  • M. Honda
  • K. Ito
  • T. Koyama
Original Investigation
First Online:
Received:
Accepted:

Abstract

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 D2 receptor antagonists. This study examined the effects of a novel thiazole derivative, NRA0045 which potently antagonizes not only dopamine D4 receptors but also 5-HT2A and α1 adrenaline receptors, and NRA0160, a selective dopamine D4 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-HT2A receptors.

Keywords

Phencyclidine NRA0045 Dopamine D4 receptor 5-HT2A receptor α1-adrenaline receptor 
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Notes

Acknowledgements

This work was supported in part by Grant-in-Aid No 09670968 and No 11670925 for Scientific Research from the Ministry of Education, Science and Culture, Japan.

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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • T. Abekawa
    • 1
  • M. Honda
    • 1
  • K. Ito
    • 1
  • T. Koyama
    • 1
  1. 1.Department of Psychiatry, Graduate School of MedicineHokkaido UniversitySapporoJapan

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