Glutamate pharmacology and the treatment of schizophrenia: current status and future directions.
Carol A. Tamminga, Henry H. Holcomb, X M Gao, Adrienne C. Lahti
International Clinical Psychopharmacology September 1, 1995 DOI: 10.1097/00004850-199509000-00005 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Schizophrenic patients and normal human volunteers, plus rats in immediate early gene experiments |
| Interventions | Ketamine Phencyclidine (PCP) Haloperidol |
| Topics | Ketamine |
| Keywords | Hippocampus Humans Glutamic acid Rna, messenger Neurotransmitter agents Blood flow velocity Autoradiography Schizophrenia Cerebrovascular circulation |
| Key findings | Argues that glutamate-mediated neurotransmission strongly influences schizophrenia, though the specifics remain to be articulated. Ketamine intensified each schizophrenic patient's underlying psychosis, an effect not blocked by haloperidol, and selectively increased cerebral blood flow in the anterior cingulate cortex while reducing it in the hippocampus and lingual gyrus. |
Abstract
Glutamate-containing neuronal terminals are ubiquitous in the central nervous system and their functional importance in mental activity is considerable. Therefore, the involvement of this neurotransmitter in the pathology of schizophrenia is being studied. Biochemical evidence has suggested that glutamatergic transmission may be regionally reduced in schizophrenia, although this evidence has never been completely consistent nor fully replicable. More striking has been the behavioral effects in humans of the antiglutamatergic drugs phencyclidine (PCP) and its congener ketamine. By historical report, PCP produces a 'schizophrenia-like' psychosis in normal humans and aggravates the psychosis in schizophrenics. More recently, ketamine has been shown to produce a mild psychotomimetic effect in normal volunteers, which has some schizophrenia-like features. We have studied the effects of ketamine in schizophrenic patients. Here, ketamine intensified each patient's specific underlying psychosis, an effect not blocked by haloperidol. Moreover, ketamine selectively increased cerebral blood flow (CBF) in the anterior cingulate cortex and reduced CBF in hippocampus and lingual gyrus. These data may be pertinent to the subject's psychosis exacerbation, especially because both cingulate and hippocampus have been previously implicated in schizophrenic psychosis. In addition, ketamine produced a distinctive dynamic time-course of regional CBF changes in different anatomic regions, with immediate (5-10 min) changes in cingulate, but somewhat more delayed changes (20-40 min) in the thalamus and cerebellum. Our immediate early gene (IEG) time-course data with c-fos and zif268 in rats following PCP suggest that a single dose of this antiglutamatergic compound can have an effect in some brain areas which lasts beyond 48 h, an effect which is distinct by IEG and by region. Together, these data suggest that glutamate-mediated neurotransmission has a strong influence in schizophrenia, although the specifics of this involvement have yet to be articulated.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 8
- Ketamine Disrupts Frontal and Hippocampal Contribution to Encoding and Retrieval of Episodic Memory: An fMRI Study Cerebral Cortex November 10, 2004
- Ketamine impairs the performance of male mice in novel recognition object test and reduces the immunoreactivity of GAD67 in the hippocampus: Role of pioglitazone. Pharmacology, Biochemistry, and Behavior February 1, 2025
- Phencyclidine/schizophrenia: one view toward the past, the other to the future. Schizophrenia Bulletin September 1, 2012
- Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. International review of neurobiology 2007
- Dopamine agonist action of phencyclidine. Synapse December 15, 2005
and 3 more in the library