The Glutamate Hypofunction Hypothesis

Glutamate is the major excitatory neurotransmitter in the CNS, and antagonists of the NMDA (N-methyl-D-aspartate) subtype of glutamate receptor, the psychotomimetics, phencyclidine 2 (PCP) and ketamine 3, mimic the positive, negative, and cognitive symptoms of schizophrenia.13 In the clinic, NMDA receptor antagonists faithfully mimic the symptoms of schizophrenia to the extent that it is difficult to differentiate the two. Controlled human studies of psychosis induced by the NMDA receptor modulators, PCP or ketamine, as well as observations in recreational PCP abusers, have resulted in a convincing list of similarities between the psychosis induced by NMDA receptor antagonism and schizophrenia. In addition, NMDA receptor antagonists can exacerbate the symptoms in schizophrenics, and can trigger the re-emergence of symptoms in stable patients. Finally, the finding that NMDA receptor coagonists such as glycine 4, D-cycloserine 5, D-serine 6, and milacemide 7, produce modest benefits in schizophrenic patients implicates

NMDA receptor hypofunction in this disorder.14 While these findings suggest a decrease in activation of NMDA receptors in schizophrenia, a simple model of decreased NMDA function in the forebrain is insufficient. In fact, acute systemic treatment with an NMDA antagonist in freely behaving rats induces a dramatic increase in cortical glutamate levels, leading to an increase in non-NMDA-mediated glutamatergic transmission and a subsequent increase in DA efflux.15 The importance of this increase in cortical glutamate release is further supported by the finding that activation of group II metabotropic glutamate receptors by LY 354740 8, which decreases presynaptic glutamate release, blocks both the PCP-induced increase in glutamate release and the behavioral effects of the psychostimulant. This, combined with studies demonstrating a dissociation between cortical DA levels and the behavioral effects of PCP, suggests that NMDA antagonist-induced increases in cortical glutamate represent a key event underlying the psychotomimetic effects of PCP and ketamine.

Glutamate Hypofunction

One of the more attractive features of the glutamate/NMDA hypofunction hypothesis is that it does not contradict either the DA or 5HT hypotheses. Rather, glutamate, and in particular NMDA-mediated glutamatergic transmission, may provide a unifying link between the two systems. For example, the observation that cortical DA efflux increases after NMDA antagonist treatment15 suggests that NMDA hypofunction could be a causative factor in inducing a hyperdopaminergic state and may, in part, explain the efficacy of typical and atypical antipsychotics in reversing the psychotomimetic actions of NMDA antagonists in both animal models and the clinic. Furthermore, studies on the interaction between glutamate and 5HT in the prefrontal cortex have led to a better understanding of the hallucinogenic actions of 5HT2A agonists indicating that the 5HT hypothesis of schizophrenia may be compatible with the NMDA hypofunction model. Activation of 5HT2A receptors increases the frequency of excitatory postsynaptic potentials at thalamocortical synapses in neocortical layer V pyramidal neurons. 5HT2 agonists also induce an asynchronous release of glutamate producing a slow, late excitatory postsynaptic potential in layer V neurons.16 Therefore, both NMDA antagonists and 5HT2A agonists may share a common path of psychotomimetic action through the induction of increased glutamate release in the cortex.

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