Studies will focus on a previously unappreciated ability of phencyclinoid exposure during brain development to promote permanent abnormalities of neuronal circuitry. The animal model to be studied involves audiogenic seizure (AGS) susceptibility which is easily assessed and which arises from known site, the inferior colliculus (IC). AGS susceptibility can be induced in rats by auditory trauma during neonatal development. Much evidence supports the notion that N-methyl-D-aspartate (NMDA)-mediated epileptiform events in the IC underlie AGS's. We report here that a single pretreatment with phencyclidine (PCP) or MK801 (NMDA receptor channel antagonists) prior to neonatal induction of susceptibility, resulted in profound increases in incidence of adult AGS's. Neither drug induced AGS susceptibility by itself. Moreover an effect of MK801 pretreatment was found in in vitro-studied IC brain slices. A transient enhancement of NMDA-mediated potentials occurred 2-4 days after administration. Thus acute exposure to phencyclinoids may render the brain transiently and inordinately susceptible to a type of secondary trauma which has an inherent potential to disrupt normal development. The in vitro results suggest the mechanism of this sensitization may relate to a transient """"""""up regulation"""""""" of NMDA receptors which reportedly occurs after acute MK801 administration. It is hypothesized that with acute exposure, blood or brain levels of phencyclinoids fall rapidly enough to """"""""unblock"""""""" up-regulated NMDA receptors. If this occurs while conditions of abnormal experience prevail, permanent errors in circuitry may be amplified. It is also hypothesized that if phencyclinoid exposure was chronic, those susceptibility-promoting effects would not occur. Since developmental events in the neonatal rat brain are equivalent to those occurring in the 22nd gestational week of human development, one must view with concern the fact that PCP is a street drug subject to abuse by pregnant women and MK801 is being considered for clinical usage in the treatment of hypoxic ischemia. Since experience-dependent, NMDA-mediated synaptogenesis is thought to be involved in learning and memory, visual discrimination, as well as epileptogenesis, the well-considered management of the maternity patient who has been exposed to phencyclinoids, is important. If the hypothesized difference in effect between chronic and acute exposure is supported, a slow withdrawal from these drugs is indicated. Proposed experiments include behavioral, electrophysiological, and pharmacological assessments.
