uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the postsynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, there is no evidence as yet that the ability of memantine to protect against extrasynaptic NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models. Memantine's antagonism on NMDA receptors has aroused interest in repurposing it for mental illnesses such as bipolar disorder, considering the involvement of the glutamatergic system in the pathophysiology of mood disorders. Serotonin Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor. Many 5-HT3 antagonists function as antiemetics, however the clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown. Cholinergic Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments. It can be noted that memantine is an antagonist at Alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment. It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs. Dopamine Memantine was shown in a study to act as an agonist at the dopamine D2HIGH receptor with equal or slightly higher affinity than to the NMDA receptors; however, the relevance of this may be negligible, as studies have shown very low affinity for binding to D2 receptors in general. Sigmaergic Memantine acts as an agonist at