Dizocilpine is a Selective and non-Competitive NMDA Receptor Antagonist

N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. NMDA receptor antagonists exhibit a neuroprotective effect in models of ischemic, hypoglycemic, and seizure-mediated brain damage. The noncompetitive NMDA antagonist Dizocilpine (MK-801) protects against neuronal damage following forebrain ischemia and that it possesses anti-convulsive properties. Additionally, Dizocilpine (MK-801) exhibits sympathomimetic and anxiolytic effects. It has the potential as a treatment for stroke and epilepsy in several centers.

Dizocilpine has a low molecular weight, and blockade of glutamatergic transmission by MK-801 induces robust and dose-dependent increases in locomotor activity. MK-801 (i.p.) causes schizophrenia-like behavioral and metabolic changes in the animal’s brain. Therefore, MK-801 has produced an animal model of schizophrenia. However, none of the previous studies have investigated whether inhaled MK-801 reaches the brain and exerts its effects.

Dizocilpine progressively suppresses current induced by NMDA. Mg2+ (10 mM) prevents Dizocilpine from blocking the N-Me-D-Asp-induced current, even when Dizocilpine is applied for a long time in the presence of NMDA. It blocks NMDA-activated single-channel activity in outside-out patches. Dizocilpine (1 mg/kg) treatment before each METH injection reduces the extent of DA depletion by 55% in striatal of mice. Dizocilpine (1 mg/kg) also attenuates the effects of METH on microglial activation in striatal mice. In addition, Dizocilpine disrupts reconsolidation of a cocaine-associated memory for conditioned place preference but not for self-administration in rats. In addition, Dizocilpine acts by binding to a site located within the NMDA-associated ion channel and thus prevents Ca2+ flux.

Dizocilpine is a potent anticonvulsant.  It is also a selective and non-competitive NMDA receptor antagonist.


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