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.