PCP and ketamine inhibit non-NMDA glutamate receptor mediated hsp70 induction.
J W Sharp
Brain Research July 29, 1996 DOI: 10.1016/0006-8993(96)00411-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mammalian brain tissue (rats, implied by in vivo dosing) |
| Interventions | Quisqualate AMPA Kainate Ketamine |
| Dose | Quisqualate 5 microliters of 2 mg/ml i.c.v.; AMPA 4 microliters of 1 mg/ml i.c.v.; kainate 15 mg/kg i.p.; PCP 20 mg/kg i.p.; ketamine 60 mg/kg i.p. |
| Measures | hsp70 induction |
| Topics | Esketamine Ketamine |
| Key findings | The authors report that PCP and ketamine both reduced quisqualate- and AMPA-induced hsp70 expression in hippocampal CA1, CA2, CA3, the dentate gyrus polymorph area, and parietal neocortex. PCP significantly (P < 0.05) reduced kainate-induced hsp70 only in CA1 and neocortex, and ketamine did not reduce it. They conclude AMPA receptors act via glutamate release opening NMDA channels, while kainate receptors probably act mainly via direct calcium conductance. |
Abstract
The physiological model for glutamate receptor mediated excitotoxicity entails elevation of intraneuronal calcium levels. Excessive activation of the NMDA receptor leads to excitotoxicity by prolonged calcium influx via its calcium channel. The purpose of this research was to examine the mechanism of non-NMDA glutamate receptor mediated excitotoxicity. Mammalian AMPA receptors do not show significant calcium conductance. However, some kainate receptors show significant calcium conductance. The hypothesis of this research states that non-NMDA glutamate agonists (quisqualate (5 microliters of 2 mg/ml i.c.v.), AMPA (4 microliters of 1 mg/ml i.c.v.), and kainate (15 mg/kg i.p.)) produce significant heat shock gene, hsp70, induction via glutamate release with subsequent opening of the NMDA receptor calcium channel. PCP (phencyclidine) and ketamine are noncompetitive blockers of the NMDA calcium channel. They act to prevent significant NMDA receptor excitotoxicity. PCP (20 mg/kg i.p.) and ketamine (60 mg/kg i.p.) both diminished quisqualate and AMPA hsp70 induction in the CA1, CA2, CA3 areas of the hippocampus, in the polymorph area of the dentate gyrus, and in the parietal neocortex. PCP significantly (P < 0.05) diminished kainate hsp70 induction only in the CA1 area and the neocortex. Ketamine failed to reduce kainate hsp70 induction. AMPA receptors appear to result in excitotoxic damage via glutamate release. Glutamate opens NMDA receptor calcium channels which increases intraneuronal calcium levels. Kainate receptors probably mediate excitotoxicity via direct calcium conductance with glutamate release being important in the CA1 area and neocortex.
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 |