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

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Abstract
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.

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