Neurotoxicity of NMDA Receptor Antagonists

Project: Research project

Description

DESCRIPTION The non-competitive NMDA
receptor antagonists, including phencyclidine (PCP, angel dust), ketamine
(Special K), and dizocilpine (MK-801), have been used as anesthetics, protect
against experimental stroke, are increasing as drugs of abuse, and continue to
be developed for treatment of various neurological diseases. However, these
drugs produce psychosis in normal people and exacerbate psychosis in patients
with schizophrenia. The drugs also injure rodent limbic cortex, killing some
neurons and injuring others that have cytoplasmic vacuoles and express HSP7O
and HO-i heat shock proteins. Since anti-psychotic drugs prevent the injury,
the circuits mediating the injury in rodents may be similar to the circuits
that mediate psychosis in humans. Our preliminary data demonstrate that NMDA
antagonists injure limbic, retrosplenial cortex of rats by blocking NMDA
receptors on GABA neurons in anterior thalamus, leading to thalamic excitotoxic
injury of retrosplenial cortical pyramidal neurons via AMPA and other non-NMDA
receptors. This proposal will continue to define the mechanisms of this
neurotoxic injury. The first aim will determine whether injections of Dl, D2
and D4 dopamine receptor antagonists into retrosplenial cortex and anterior
thalamus prevent the induction of HSP7O and other markers of injury produced by
systemic PCP and MK-801. The second aim will determine whether blockade of NMDA
receptors in substantia nigra (SN) and the adjacent ventral tegmental area
(VTA) by PCP and ketamine produce and/or aggravate injury to retrosplenial
cortex. The third aim will determine whether specific AMPA receptor
antagonists, specific kainate receptor antagonists, and specific metabotropic
glutamate receptor agents prevent injury to limbic cortex produced by systemic
PCP and ketamine. The fourth aim will determine whether activation of
substantia nigral ventral tegmental area and limbic cortex GABA receptors with
GABA agonists prevent the injury produced by systemic PCP and MK-801. The fifth
aim will determine whether visual sensory input contributes to the non-NMDA
glutamate-mediated limbic cortical injury produced by NMDA antagonists. The
last aim will determine whether NMDA receptor antagonists produce limbic
cortical injury in cats and whether typical and atypical antipsychotic drugs,
like haloperidol and clozapine, block injury. These studies will define the
circuits and receptors that mediate the cortical injury produced by NMDA
receptor antagonists in experimental animals. These studies will also
contribute to understanding the circuits and transmitters that mediate
psychosis due to psychomimetic drugs like PCP and Special K in people, and they
will also contribute to understanding the circuits and receptors that mediate
acute psychosis in patients with schizophrenia and other psychotic disorders.
StatusFinished
Effective start/end date9/12/027/31/06

Funding

  • National Institutes of Health: $383,750.00
  • National Institutes of Health: $303,000.00
  • National Institutes of Health: $383,750.00
  • National Institutes of Health: $334,738.00

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N-Methyl-D-Aspartate Receptors
Wounds and Injuries
Dizocilpine Maleate
Psychotic Disorders
Ketamine
Phencyclidine
Ventral Tegmental Area
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Substantia Nigra
Rodentia
Schizophrenia
Pharmaceutical Preparations
Anterior Thalamic Nuclei
GABA Agonists
Kainic Acid Receptors
GABAergic Neurons
Dopamine Antagonists
Pyramidal Cells
Clozapine
Street Drugs

ASJC

  • Medicine(all)