Babies born to mothers abusing the psychotomimetic drug phencyclidine (PCP), often show profound deficits in CNS function. It is now reported that PCP can cause progressive degeneration and death in human fetal cerebral cortical neurons in culture and sublethal levels of PCP can inhibit axon outgrowth. In cerebral cortical cell cultures established from 14 week fetuses, exposure to 500 μM PCP resulted in a progressive degeneration of neurons over a 2-8 day period, characterized by early reversible vacuolation of the soma and later irreversible neurite fragmentation and cell death. A sublethal concentration of PCP (100 μM) suppressed axon outgrowth. The adverse effects of PCP on neurons were apparently not due to actions on N-methyl-d-aspartate (NMDA) receptors because: the neurons were not responsive to NMDA during the first 3 weeks in culture; concentrations of PCP that should block NMDA receptors maximally (1-50 μM) did not affect axon outgrowth or cell survival; and another NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) did not cause neurodegeneration or affect axon outgrowth. Exposure of cultures to the sigma receptor ligand, pentazocine (10 μM), did not significantly affect the survival of neurons and haloperidol did not reduce PCP-induced neurodegeneration, indicating that the effects of PCP were not mediated by sigma receptors. Degenerative effects, similar to those elicited by PCP, were observed in cortical neurons exposed to the K+ channel blockers, 4-aminopyridine and tetraethylammonium, a finding consistent with the possibility that the degenerative actions of PCP were mediated by its known inhibitory effects on K+ channels. In support of the latter possibility, it was found that PCP caused a progressive elevation in intracellular levels of calcium during several days of exposure. In addition to affecting neurons, PCP and K+ channel blockers caused vacuolation and degeneration of astrocytes. Taken together with previous data, indicating that PCP can be concentrated and retained in the fetal CNS, the present data suggest that high levels of PCP can disrupt the normal development of neural circuitry in the human fetus, which would be expected to result in profound functional impairments.
- human cerebral cortex
- N-methyl-d-aspartate receptor
- potassium channels
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Drug Discovery