Low-affinity NMDA receptor channel blockers inhibit acquisition of intravenous morphine self-administration in naive mice.

Experimental evidence suggests that NMDA receptor antagonists modulate behavioral effects of morphine in models assessing abuse potential of drugs. The present study sought to evaluate the ability of NMDA receptor channel blockers to affect the acquisition of morphine i.v. self-administration in drug- and experimentally naive mice. DBA/2 mice were allowed to self-administer morphine (0.125-4.0 mg/ml) or saline during the 30-min test. Each nose-poke of the active mouse resulted in a 1.6-microl infusion to both the active mouse and the passive (yoked control) mouse. In vehicle-treated mice, differences between operant activity of active and passive mice were most obvious when active mice were allowed to self-inject morphine at the concentration of 0.5 mg/ml (the optimum concentration). Pretreatment with MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride; 1, 3.2 and 10 mg/kg) shifted the optimum concentration to 0.75 mg/ml. Memantine (1-amino-3,5-dimethyladamantane hydrochloride; 0.3, 1, 3.2 and 10 mg/kg) suppressed both the morphine intake and the difference in nose-poke activity of active vs. passive mice across all tested concentrations of morphine. Dizocilpine ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate; 0.1 mg/kg) was ineffective. Taken together with earlier reports, the present results suggest that low-affinity NMDA receptor channel blockers--in contrast to dizocilpine--attenuate the rewarding potential of morphine.