Possible mechanisms of N-methyl-D-aspartate antagonist induced neurotoxicity and psychosis.

摘要

In this dissertation, the ability of the N-Methyl-D-Aspartate (NMDA) antagonist phencyclidine (PCP) to produce seizures in several brain regions was examined. In EXPERIMENT 1, a 50 mg/kg dose of PCP was administered and seizures were recorded in areas which degenerate at this dose and those which do not. The results found a significant increase in the total average seizure time in the areas that degenerate during NMDA antagonist induced neurodegeneration (NAN) when compared to those which do not. In addition, the recordings revealed that status epilepticus (an extreme type of seizure able to produce neurodegeneration) was found in 20% of the rats tested. Based on the percentage rates in which the individual areas degenerate at this dose, the results suggest that PCP induced seizures are not the primary mechanism for retrosplenial damage seen during NAN but may be the cause of non-retrosplenial NAN damage. In EXPERMENT 2, a statistically significant positive linear relationship was established between the amount of PCP administered and total average seizure time. In addition, it was found that in order to produce consistent prolonged seizures one needs to administer 75 mg/kg PCP. In the final experiment, the effect of diazepam, riluzole, pilocarpine, or GYKI 52466 pretreatment on PCP induced seizures was tested in the retrosplenial cortex and dentate gyrus. Unfortunately, the pilocarpine pretreatment proved to be too lethal and had to be removed from the experiment. Examination of the rest of the data produced no statistically significant differences suggesting these drugs do not produce an overwhelming effect on these seizures. Alternatively, questions were raised regarding sufficient statistical power to measure many of the effects of these drugs.