| Evidence suggests that glutamate dysfunction, specifically at the N-methyl-D-aspartate (NMDA) receptor site, is involved in the pathophysiology of schizophrenia. NMDA antagonists, such as PCP and ketamine, induce schizophrenia-like features in healthy humans better than other pharmacological agents. According to the NMDA receptor hypofunction hypothesis, NMDA blockade results in inhibition of GABAergic neurons, which then causes disinhibition of glutamatergic neurons that converge onto pyramidal neurons in vast cortical regions resulting in schizophrenia-like features. Supporting this hypothesis, synaptic glutamate concentrations in the prefrontal cortex were found to increase in awake rats when administered ketamine. Providing some indirect evidence, PET studies in humans have shown elevations of blood flow and glucose metabolism in the anterior cingulate (AC) with ketamine administration. However, studies directly assessing the effects of ketamine on glutamatergic activity and the relation to schizophrenia-like features in humans have not been conducted. The present study investigated the effects of ketamine on AC glutamatergic activity and the relation to ketamine-induced schizophrenia-like features in healthy humans with high field proton magnetic resonance spectroscopy (1H-MRS). Consistent with hypotheses, results revealed a significant increase in AC glutamine, a putative marker of glutamate neurotransmitter release, with ketamine administration. However, glutamine increases were not significantly related to schizophrenia-like symptoms. Therefore, increased cortical glutamatergic activity may not be related to psychotic symptoms, but may be an adverse downstream effect, and could be an important catalyst in the deteriorating course (cognitive and social functioning) of schizophrenia. Also consistent with hypotheses, results revealed ketamine to impair acquisition but not retrieval of verbal information. This is the first study in humans to suggest that NMDA antagonism results in increased glutamate release in the AC. This provides important evidence for a missing component of the NMDA hypofunction model of schizophrenia. |
