NMDA and sigma receptors in psychiatry

Hypoactive N-methyl-d-aspartate (NMDA) receptors lead to mesolimbic dopamine (DA) hyperactivity associated with positive symptoms of psychosis. If NMDA receptors are hypoactive then mesocortical DA pathways also become hypoactive explaining cognitive, negative and affective symptoms of schizophrenia. NMDA receptor hypofunction in glutamatergic corticostriatal and corticoaccumbens projections reduces the excitatory drive on gamma aminobutyric acid (GABA) neurons that create the thalamic filter, which can lead to excess sensory information escaping to the cortex. Drugs antagonising NMDA receptor have antidepressant effect. D-cycloserine facilitates glutamate release, thus GABA inhibition is strengthened which is the predominant fear extinction pathway. Acamprosate acts as anticraving by binding with NMDA receptor. NMDA receptors play a role in the development of kindled state. Memantine is NMDA antagonist, blocks NMDA receptor and prevents neurodegenaration. Initially reported as opioid receptor but when it could not be blocked by naltrexone and naloxone, later termed as sigma receptor. Functions of sigma receptors include modulation of calcium release, modulation of cardiac myocyte contractility and inhibition of voltage gated potassium channel. Association between sigma receptor 1 gene (SIGMAR1) with susceptibility to schizophrenia has been found. Interaction of sigma 1 receptor with NMDA receptor modulates spatial memory in rats. Most conventional neuroleptics showed a significant affinity to sigma receptors.