Glutamate Hypothesis of Schizophrenia

Some years after the development of the dopamine hypothesis there became increasing evidence that the hyperactivity of dopamine signalling in the brain could not be the only explanation about the underlying mechanisms of schizophrenia. The glutamate hypothesis, like the dopamine hypothesis, was made after observations on people's use of illegal drugs, this time phencyclidine (PCP or "Angel Dust"). Phencyclidine was originally developed in the 1950s as an anesthetic but human use was made illegal due to people experiencing severe side effects that mimicked both the positive and negative symptoms of schizophrenia. In the late 1970s the binding site for phencyclidine was found to be in the NMDA receptor for the excitatory neurotransmitter glutamate, and studies showed that its role is to inhibit the activation of the receptor by the binding of glutamate, thereby blocking the necessary diffusion of ions through the central pore.

As phencyclidine acts by antagonising the effect of glutamate on the receptor it was suggested that the symtoms of schizophrenia may be due to hypoactive glutamate signalling, and that therefore glutamate may have a mediatory role in the development of the disease. Research using animal models has found that symptoms of schizophrenia can be induced by administering PCP and also by genetically engineering mice to express lower numbers of the NMDA receptor. Both observations provide further support the glutamate hypothesis.