Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism.
G. Duncan, S. Miyamoto, Jeremy N Leipzig, Jeffrey A. Lieberman
Journal of Pharmacology and Experimental Therapeutics April 1, 2000 DOI: 10.1016/s0022-3565(24)39197-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine Risperidone Olanzapine |
| Dose | Ketamine 25 mg/kg; risperidone 0.3 mg/kg; olanzapine 10 mg/kg |
| Measures | regional [(14)C]2-deoxyglucose (2-DG) uptake |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine (25 mg/kg) increased 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, and basolateral amygdala in rats. Risperidone (0.3 mg/kg) did not block these effects, while olanzapine blocked them only at a higher dose (10 mg/kg) than expected from D2 and 5HT2 receptor blockade alone. The authors suggest the ketamine challenge 2-DG paradigm may help identify atypical antipsychotics and explore their mechanisms. |
Abstract
The ability of subanesthetic doses of N-methyl-D-aspartate (NMDA) antagonists to induce positive, negative, and cognitive schizophrenia-like symptoms suggests that reduced NMDA receptor function may contribute to the pathophysiology of schizophrenia. An increasing body of evidence indicates that antipsychotic drugs, especially those with "atypical" properties, can antagonize the effects of NMDA antagonists in a variety of experimental paradigms. We demonstrated previously that clozapine, the prototype of atypical antipsychotics, but not haloperidol, the typical antipsychotic, blocked ketamine-induced alterations in brain metabolism. In this study, effects of clozapine were compared with two of the newer atypical antipsychotic drugs, risperidone and olanzapine, on ketamine-induced alterations in regional [(14)C]2-deoxyglucose (2-DG) uptake. A subanesthetic dose of ketamine (25 mg/kg) induced robust increases in 2-DG uptake in limbic cortical regions, hippocampal formation, nucleus accumbens, and basolateral amygdala. Pretreatment of rats with risperidone (0.3 mg/kg) before ketamine administration did not alter the effects of ketamine. These data suggest that novel pharmacological properties may contribute to the effects of clozapine in this model, in addition to the well characterized actions at D(2) and 5HT(2A) receptors. In contrast to the results with risperidone, olanzapine blocked ketamine-induced increases in 2-DG uptake. However, a higher dose of olanzapine (10 mg/kg) was required to completely block the effects of ketamine than would be expected if D(2) and 5HT(2) receptor blocking properties of the drug were solely responsible for its action. The results suggest that the ketamine challenge 2-DG paradigm may be a useful model to identify antipsychotic drugs with atypical characteristics and to explore mechanisms of atypical antipsychotic action.
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 7
- Ketamine for Bipolar Depression: Biochemical, Psychotherapeutic, and Psychedelic Approaches Frontiers in Psychiatry May 23, 2022
- Sabinene's neuroprotective effect reverses ketamine-induced experimental schizophrenia in mice through enhancement of cholinergic, antioxidant, and anti-inflammatory mechanisms. Journal of Psychiatric Research March 5, 2026
- Dose-dependent effects of esketamine on brain activity in awake mice: A BOLD phMRI study. Pharmacology Research & Perspectives December 1, 2022
- "Addicted to Euphoria": The History, Clinical Presentation, and Management of Party Drug Misuse. International review of neurobiology 2015
- Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology February 1, 2003
and 2 more in the library
Cites 4
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