dizocilpine-maleate and neramexane

Effects of acamprosate and ionotropic uncompetitive N-methyl-D-aspartate receptor antagonists and group I metabotropic glutamatergic receptor antagonists on the expression of ethanol-induced sensitization were investigated in mice. The results indicated that acamprosate (200 and 400 mg/kg) and N-methyl-D-aspartate receptor antagonists, neramexane (10 and 20 mg/kg) and MK-801 (0.1 and 0.2 mg/kg), inhibited the expression of ethanol-induced sensitization. Acamprosate, but not the other compounds tested, also blocked the stimulant effect of acute injections of ethanol. Among the group I metabotropic glutamatergic receptor antagonists, only the metabotropic glutamatergic receptor 5 antagonist, MTEP (5, 10, and 20 mg/kg) showed an effect similar to the N-methyl-D-aspartate receptor antagonists. The metabotropic glutamatergic receptor 1 antagonist, EMQMCM (5, 10, and 20 mg/kg), however, potentiated the inhibitory effect of MK-801 on the expression of ethanol-induced sensitization. The findings indicate that glutamatergic neurotransmission is important in the ethanol-induced sensitization process, and suggest that co-administration of metabotropic glutamatergic receptor 1 antagonists and N-methyl-D-aspartate receptor antagonists may be useful in therapy for alcoholism.

Topics: Acamprosate; Alcoholism; Animals; Brain; Cyclopentanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Ethanol; Glutamic Acid; Male; Mice; Motor Activity; N-Methylaspartate; Pyridines; Quinolines; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior; Synaptic Transmission; Taurine; Thiazoles

Mice were subjected to two successive treatment protocols: first with NMDA receptor channel blockers (14 days, once a day) and second with morphine (5 mg/kg, 8 days, once a day). Treatment with the higher doses of dizocilpine (1 mg/kg), memantine (30 mg/kg), and MRZ 2/576 (30 mg/kg) upon discontinuation revealed only minor behavioral abnormalities attributable to the state of withdrawal. Following repeated administration of low-dose morphine, tolerance to morphine analgesia developed in mice preexposed to dizocilpine (1 mg/kg but not 0.3 mg/kg) but not memantine (10 and 30 mg/kg), MRZ 2/579 (10 and 30 mg/kg), or saline. There were no signs of morphine dependence in any treatment group. Overall, the present study found only minor effects of the subchronic administration of high doses of NMDA receptor channel blockers, suggesting that clinical use of NMDA receptor channel blockers such as memantine will not be accompanied by increased propensity to induction of morphine tolerance and dependence.

Topics: Analgesics, Opioid; Animals; Cyclopentanes; Dizocilpine Maleate; Drug Tolerance; Excitatory Amino Acid Antagonists; Interpersonal Relations; Male; Memantine; Mice; Morphine; Morphine Dependence; Reaction Time; Receptors, N-Methyl-D-Aspartate

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.

Topics: Analysis of Variance; Animals; Cyclopentanes; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Injections, Intravenous; Male; Memantine; Mice; Mice, Inbred DBA; Morphine; Narcotics; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Self Administration