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

Br J Pharmacol. 1993 Apr;108(4):1156-63. doi: 10.1111/j.1476-5381.1993.tb13520.x.


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.

MeSH terms

  • Animals
  • Brain Chemistry / drug effects
  • Dialysis
  • Dizocilpine Maleate / antagonists & inhibitors*
  • Dizocilpine Maleate / pharmacology
  • Dopamine / metabolism
  • Dopamine / physiology*
  • Limbic System / drug effects*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Motor Activity / drug effects
  • Phencyclidine / antagonists & inhibitors*
  • Phencyclidine / pharmacology
  • Postural Balance / drug effects
  • Pyrrolidinones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*


  • Pyrrolidinones
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • 1-hydroxy-3-amino-2-pyrrolidone
  • Phencyclidine
  • Dopamine