Background
Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by
producing disinhibtion in complex circuits, acutely produce psychosis and cognitive
disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor
Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into
the pathophysiology of psychotic disorders. Dopaminergic D2 and/or D3 agents can modify psychosis over days to weeks, suggesting involvement of these transmitter
system(s).
Methods
We studied the ability of D2/D3 agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute
exposure and after chronic daily exposure.
Results
Here we report that D2/D3 dopamine agonists, probably via D3 receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect
with D2/D3 agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol
does not affect NRHypo neurotoxicity when given acutely at D2/D3 doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does
prevent NRHypo neurotoxicity with longer durations producing greater protection.
Conclusions
Understanding the changes that occur in the NRHypo circuit after chronic exposure
to dopaminergic agents could provide important clues into the pathophysiology of psychotic
disorders.
Key Words
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References
- Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected.Arch Gen Psychiatry. 2003; 60: 1228-1235
- Phencyclidine, dizocilpine, and cerebrocortical neurons.Science. 1990; 247: 221
- Attenuation of the neuropsychiatric effects of ketamine with lamotrigine.Arch Gen Psychiatry. 2000; 57: 270-276
- A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194.J Pharmacol Exp Ther. 1998; 287: 187-197
- The experimental reproduction of amphetamine psychosis.Arch Gen Psychiatry. 1973; 29: 35-40
- Cocaine-induced psychosis.J Clin Psychiatry. 1991; 52: 509-512
- Differential effects of MK-801 on brain-derived neurotrophic factor mRNA levels in different regions of the rat brain.Exp Neurol. 1993; 122: 244-252
- Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina.J Neurosci. 2002; 22: 2165-2173
- The discovery of susceptibility genes for mental disorders.Proc Natl Acad Sci USA. 2002; 99: 13365-13367
- Multifocal brain damage induced by phencyclidine is augmented by pilocarpine.Brain Res. 1997; 752: 1-14
- A broad view of glutamate spillover.Nat Neurosci. 2002; 5: 291-292
- Abnormal mental states induced by phencyclidine as a model of schizophrenia.in: Domino E.F. PCP (Phencyclidine): Historical and current perspectives. NPP Books, Ann Arbor1981: 401-418
- MK-801 induces c-fos protein in thalamic and neocortical neurons of rat brain.Neurosci Lett. 1990; 111: 39-45
- Chronic administration of haloperidol and olanzapine attenuates ketamine-induced brain metabolic activation.J Pharmacol Exp Ther. 2003; 305: 999-1005
- Evolving behavior in the clinical and experimental amphetamine (model) psychosis.Am J Psychiatry. 1973; 130: 1088-1093
- Competitive and non-competitive NMDA antagonists induce similar limbic degeneration.Neuroreport. 1994; 5: 2688-2692
- Dissimilar patterns of degeneration in brain following four different addictive stimulants.Neuroreport. 1993; 5: 17-20
- The NMDA receptor hypofunction model of psychosis.Ann NY Acad Sci. 2003; 1003: 119-130
- α2 adrenergic agonists prevent MK-801 neurotoxicity.Neuropsychopharmacology. 1995; 12: 347-349
- Clozapine and related analogs block NMDA antagonist neurotoxicity: Implications for schizophrenia.Schizophr Res. 1995; 15: 57-58
- Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.Neuropsychopharmacology. 1998; 18: 57-62
- Muscimol prevents NMDA antagonist neurotoxicity by activating GABAA receptors in several brain regions.Brain Res. 2003; 993: 90-100
- Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity.Mol Psychiatry. 2002; 7: 726-733
- Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity.Mol Psychiatry. 2002; 7: 32-43
- Antipsychotic drugs block phencyclidine receptor-mediated neurotoxicity.Biol Psychiatry. 1993; 34: 119-121
- Age specific neurotoxicity in the rat associated with NMDA receptor blockade: potential relevance to schizophrenia?.Biol Psychiatry. 1995; 38: 788-796
- Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex.Exp Neurol. 1993; 123: 204-215
- Phencyclidine (PCP) and Dizocilpine (MK801) exert time-dependent effects on the expresion of immediate early genes in rat brain.Synapse. 1998; 29: 14-28
- Induction and suppression of immediate early genes in specific rat brain regions by the non-competitive N-methyl-D-aspartate antagonist, MK-801.Neuroscience. 1993; 53: 749-758
- NMDA receptor antagonists decrease GABA outflow from the septum and increase acetylcholine outflow from the hippocampus: a microdialysis study.J Neurosci. 1994; 14: 1358-1365
- Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study.J Clin Anesth. 2000; 12: 19-24
- MK-801-induced neuronal damage in rats.Brain Res. 1997; 753: 181-195
- MK801 induces immediate-early gene proteins and BDNF mRNA in rat cerebrocortical neurones.NeuroReport. 1993; 4: 183-186
- Recent advances in the phencyclidine model of schizophrenia.Am J Psychiatry. 1991; 148: 1301-1308
- Isoflurane and propofol block neurotoxicity caused by MK-801 in the rat posterior cingulate/retrosplenial cortex.J Cereb Blood Flow Metab. 1997; 17: 168-174
- Dopamine regulation of extracellular glutamate in the nucleus accumbens.Brain Res. 1997; 761: 173-177
- Methods for Clinical Evaluation of Pharmacologic Treatments of Schizophrenia.in: Prien R.F. Robinson D.S. Clinical Evaluation of Psychotropic Drugs. Raven Press, LTD, New York1994: 345-380
- Evidence for onset of antipsychotic effects within the first 24 hours of treatment.Am J Psychiatry. 2005; 162: 939-946
- Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and α2-adrenergic agonists.Mol Psychiatry. 1999; 4: 344-352
- Presynaptic dopamine D2-like receptors inhibit excitatory transmission onto rat ventral tegmental dopaminergic neurones.J Physiol. 2000; 523 (Pt 1): 163-173
- Interactive effects of subanesthetic ketamine and haloperidol in healthy humans.Psychopharmacology. 1999; 145: 193-204
- Effects of MK-801 upon local cerebral glucose utilisation in conscious rats and in rats anaesthetised with halothane.J Cereb Blood Flow Metab. 1989; 9: 786-794
- Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.Neuropsychopharmacology. 1995; 13: 9-19
- Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended.Biol Psychiatry. 2005; 57: 1543-1549
- Dexmedetomidine premedication attenuates ketamine-induced cardiostimulatory effects and postanesthetic delirium.Anesthesiology. 1995; 82: 1117-1125
- The D3 dopamine receptor: neurobiology and potential clinical relevance.Pharmacol Rev. 1997; 49: 231-252
- Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine.Biol Psychiatry. 1997; 42: 664-668
- Localisation of phencyclidine-induced changes in brain energy metabolism.Nature. 1979; 282: 625-626
- 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.J Neurosci. 1997; 17: 2921-2927
- Halothane and diazepam inhibit ketamine-induced c-fos expression in the rat cingulate cortex.Anesthesiology. 1996; 85: 874-882
- Effects of phencyclidine on immediate early gene expression in the brain.J Neurosci Res. 1996; 45: 13-27
- Ketamine-induced changes in regional glucose utilization in the rat brain.Anesthesiology. 1980; 52: 330-334
- Guanabenz effects on NMDA antagonist-induced mental symptoms in humans.Abstr. Soc. Neurosci. 1998; 24: 525
- Age has a similar influence on the susceptibility to NMDA antagonist-induced neurodegeneration in most brain regions.Brain Res Dev Brain Res. 2005; 158: 82-91
- Protective effect of LY379268, a selective group II metabotropic glutamate receptor agonist, on dizocilpine-induced neuropathological changes in rat retrosplenial cortex.Brain Res. 2003; 992: 114-119
- Adenosine A1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist dizocilpine.Neuropsychopharmacology. 2004; 29: 544-550
- Glutamate receptor dysfunction and schizophrenia.Arch Gen Psychiatry. 1995; 52: 998-1007
- Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs.Science. 1989; 244: 1360-1362
- NMDA antagonist neurotoxicity: mechanism and prevention.Science. 1991; 254: 1515-1518
- The rat brain in stereotaxic coordinates. 4th ed. Academic Press, New York1998
- Rapid onset of therapeutic effect of risperidone versus haloperidol in a double-blind randomized trial.J Clin Psychiatry. 2001; 62: 343-346
- Ketamine: an update on the first twenty-five years of clinical experience.Can J Anaesth. 1989; 36: 186-197
- D3 dopamine receptor, behavioral sensitization, and psychosis.Neurosci Biobehav Rev. 2001; 25: 427-443
- Clinical features of cocaine-induced paranoia.Am J Psychiatry. 1991; 148: 495-498
- Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis.Biol Psychiatry. 1983; 18: 429-440
- A functional test identifies dopamine agonists selective for D3 versus D2 receptors.Neuroreport. 1995; 6: 329-332
- Behavioral sensitization in humans.J Addict Dis. 2001; 20: 55-65
- Antipsychotic drug doses and neuroleptic/dopamine receptors.Nature. 1976; 261: 717-719
- MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex.Ann Neurol. 1991; 30: 801-809
- Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects.Pharmacol Rev. 2001; 53: 119-133
- Pharmacology and behavioral pharmacology of the mesocortical dopamine system.Prog Neurobiol. 2001; 63: 241-320
- The dopamine D3-receptor: a postsynaptic receptor inhibitory on rat locomotor activity.J Neural Transm Gen Sect. 1993; 94: 11-19
- Ketamine—its pharmacology and therapeutic uses.Anesthesiology. 1982; 56: 119-136
- Disseminated corticolimbic neuronal degeneration induced in rat brain by MK-801: relevance to Alzheimer’s disease.Neurobiology Dis. 1998; 5: 305-322
- Dopaminergic modulation of glutamate release in striatum as measured by microdialysis.J Neurochem. 1992; 58: 1736-1742
Article info
Publication history
Published online: April 17, 2006
Accepted:
February 8,
2006
Received in revised form:
January 3,
2006
Received:
August 23,
2005
Identification
Copyright
© 2006 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
