?s abstract): 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.
| Sharp, Frank R; Hendren, Robert L (2007) Psychosis: atypical limbic epilepsy versus limbic hyperexcitability with onset at puberty? Epilepsy Behav 10:515-20 |
| Dickerson, Jon; Sharp, Frank R (2006) Atypical antipsychotics and a Src kinase inhibitor (PP1) prevent cortical injury produced by the psychomimetic, noncompetitive NMDA receptor antagonist MK-801. Neuropsychopharmacology 31:1420-30 |
| Carter, Kevin; Dickerson, Jon; Schoepp, Darryle D et al. (2004) The mGlu2/3 receptor agonist LY379268 injected into cortex or thalamus decreases neuronal injury in retrosplenial cortex produced by NMDA receptor antagonist MK-801: possible implications for psychosis. Neuropharmacology 47:1135-45 |
