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

Abstract

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. 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. 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. 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). 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. 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. 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. 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. 1993 British Pharmacological Society