This is an application for renewal of a grant that was previously entitled """"""""PCP, sigma opiates and glutamatergic transmission"""""""". During the past grant cycle, the applicant discovered that when adult rats or mice are treated subcutaneously with phencyclidine (PCP), or related PCP receptor ligands (PRL), all of which are non-competitive antagonists of NMDA glutamate receptors, it causes acute pathomorphological changes in pyramidal neurons in the posterior cingulate and retrosplenial cerebral cortices. These changes are reversible over a 24 hour period following a low dose of PRL, but cerebrocortical neurons are killed at higher doses. In recent studies, we have gained significant insight into the mechanisms that mediate the reversible neurotoxic reaction, but the cell killing actions of PRL have not been studies. The focus of the present application is on the irreversible neuron-necrotizing action of PRL.
Aim #1 is devoted to the fundamental task of developing accurate and more complete characterization of the neuron-necrotizing action of PRL and identifying variables that are critical for its expression. Within this aim, we will study: a) The acutely evolving neuron-necrotizing process by light and electron microscopy; b) The distribution of neurons affected by the process; c) The relationship between the cell killing effect and concomitant induction of heat shock protein in affected neurons; d) Age dependency of the neuron-necrotizing process; e) Sex differences in susceptibility; f) Ability of competitive NMDA receptor antagonists to mimic the neuron-necrotizing action of PRL.
In Aim #2, we will study ways of preventing PRL from killing cerebrocortical neurons; in essence, the strategy will be to determine whether methods already developed for preventing the reversible neurotoxic action of PRL also prevent the cell killing activity.
In Aim #3, we will study the opposite, i.e., we will study ways of maximizing the cell killing activity, so that PrL can serve as tools for selectively deleting cingulate/retrosplenial neurons from the brain and thereby providing a means of studying the functional roles of these neurons.
In Aim #4, we will follow-up our preliminary finding that high dose PRL treatment causes a profound chronic impairment in memory. Animals treated with a high dose of PRL will be studied behaviorally for disturbances in learning/memory or other behavioral parameters such as nociception and emotional reactivity. Since PRL are agents that are abused by pregnant women with unknown consequences for their fetuses, abused by adolescents and young adults with psychotic consequences, used in human anesthesia (ketamine) with transient psychotic side effects and are being developed by the pharmaceutical industry as drugs for protecting neurons against ischemic injury, it is important to have a detailed and accurate understanding of the neurotoxic potential of these agents. All of the proposed research will be conducted in mice. Methods employed will include light and electron microscopic histopathology, immunocytochemistry, selective brain lesioning and behavioral analysis.
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