The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents.

1. The effects of the glycine/N-methyl-D-aspartate (NMDA) receptor antagonist, R-(+)-HA-966 on the neurochemical and behavioural responses to phencyclidine (PCP) and dizocilpine (MK-801) have been determined in rodents. 2. In rats, pretreatment with PCP (5 and 10 mg kg-1) or MK-801 (0.25 and 0.5 mg kg-1) dose-dependently stimulated dopamine turnover in nucleus accumbens, amygdala and medial prefrontal cortex, but had no effect in striatum. In contrast, pretreatment with (+)-HA-966 (10 and 30 mg kg-1) did not affect dopamine turnover in any brain region investigated. 3. Pretreatment with (+)-HA-966 (10 and 30 mg kg-1) significantly antagonized the stimulation of dopamine turnover induced by both PCP (10 mg kg-1) and MK-801 (0.5 mg kg-1) in rat nucleus accumbens, amygdala and medial prefrontal cortex. 4. Intracerebral dialysis studies in conscious rats demonstrated that systemic injection of PCP (10 mg kg-1) markedly stimulated dopamine release from the nucleus accumbens, an effect that was abolished by pretreatment with (+)-HA-966 (30 mg kg-1). 5. Pretreatment with PCP (3-30 mg kg-1) or MK-801 (0.1-1.6 mg kg-1) significantly increased locomotor activity in mice. In contrast, subcutaneous injection of (+)-HA-966 (10-100 mg kg-1) failed to stimulate activity. 6. Pretreatment with (+)-HA-966 (10 and 30 mg kg-1) dose-dependently antagonized both PCP (10 mg kg-1) and MK-801 (0.4 mg kg-1) induced hyperactivity in mice. 7. Blockade of PCP-induced hyperactivity by (+)-HA-966 is unlikely to be explained by the induction or potentiation of sedation/ataxia since PCP-induced rotarod deficits were not significantly different in mice pretreated with (+)-HA-966 (30 mg kg-1) or saline.8. The results demonstrate that (+ )-HA-966 antagonizes both the neurochemical and behavioural effects of PCP and MK-801, possibly through interactions at the glycine/NMDA receptor.
AuthorsL J Bristow, P H Hutson, L Thorn, M D Tricklebank
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 108 Issue 4 Pg. 1156-63 (Apr 1993) ISSN: 0007-1188 [Print] ENGLAND
PMID8485625 (Publication Type: Journal Article)
Chemical References
  • Pyrrolidinones
  • Receptors, N-Methyl-D-Aspartate
  • 1-hydroxy-3-amino-2-pyrrolidone
  • Dizocilpine Maleate
  • Phencyclidine
  • Dopamine
  • Animals
  • Brain Chemistry (drug effects)
  • Dialysis
  • Dizocilpine Maleate (antagonists & inhibitors, pharmacology)
  • Dopamine (metabolism, physiology)
  • Limbic System (drug effects)
  • Male
  • Mice
  • Mice, Inbred Strains
  • Motor Activity (drug effects)
  • Phencyclidine (antagonists & inhibitors, pharmacology)
  • Postural Balance (drug effects)
  • Pyrrolidinones (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)

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