Competitive NMDA receptor antagonists do not produce locomotor hyperactivity by a dopamine-dependent mechanism

Abstract

The involvement of dopaminergic activity in the mediation of the behavioural effects produced by blockade of NMDA receptors in the nucleus accumbens was investigated. Intra-accumbens infusion of the competitive NMDA receptor antagonist, dl-2-amino-5-phosphonovaleric acid (AP-5) (2, 4 and 10 μg/0.5 μl) induced a dose-dependent increase in locomotor activity in rats. Pharmacological blockade of dopamine receptors locally in the nucleus accumbens with haloperidol (5 μg/μl) failed to reduce the locomotor effects of AP-5 (10 μg), but antagonized the effects induced by the non-competitive NMDA receptor antagonist, MK-801 ((+)-5-methyl-10,11-dihydro( a,d)-cyclohepten-5,10-imine hydrogen maleate salt) (10 μg). The effects of dopamine co-administered with AP-5 at various doses in the nucleus accumbens were also examined. When the level of locomotor activity induced by AP-5 (10 μg) was similar to that produced by dopamine (10 μg), the simultaneous infusion of both compounds at this dose did not increase or decrease the locomotor response. When the level of locomotor activity induced by AP-5 (10 or 4 μg) was lower than that produced by a higher dose of dopamine (20 μg), the combined infusion of both compounds resulted in a locomotor response similar to that induced by AP-5 alone, indicating a reduction of dopamine locomotor effects. These results show that the locomotor hyperactivity induced by AP-5 was not modified when the dopaminergic activity in the nucleus accumbens was either reduced or enhanced, suggesting that the behavioural effects resulting from the blockade of NMDA receptors with the competitive NMDA receptor antagonist, AP-5, is not mediated by endogenous dopamine in this brain area.