Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia

C Wang, J McInnis, M Ross-Sanchez, P Shinnick-Gallagher, J.L Wiley, K.M Johnson
2001 Neuroscience  
AbstractöBoth acute and chronic administration of N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and dizocilpine have been proposed to mimic some of the symptoms of schizophrenia. The purposes of the present study were ¢rst, to characterize the long-term behavioral and neurodegenerative e¡ects of subchronic administration of phencyclidine to perinatal rats and second, to determine whether pretreatment with olanzapine could attenuate these e¡ects. On postnatal days 7, 9
more » ... d 11 rat pups were pretreated with either vehicle or olanzapine prior to administration of either saline or phencyclidine (10 mg/kg). Some pups were killed on postnatal day 12 for biochemical determinations and others were tested on postnatal days 24^28 for prepulse inhibition of acoustic startle, on postnatal day 42 for phencyclidine-induced locomotor activity and between postnatal days 33 and 70 for acquisition of a delayed spatial learning task. Phencyclidine treatment resulted in a substantial increase in fragmented DNA in the frontal and olfactory cortices consistent with neurodegeneration by an apoptotic mechanism. An increase in the NMDA receptor NR1 subunit mRNA was also observed in the cortex. Gel shift assays showed that phencyclidine also increased the nuclear translocation of nuclear factor-UB proteins in the prefrontal cortex. In tissue from the frontal cortex, western blot analysis revealed that phencyclidine treatment increased Bax and decreased Bcl-X L proteins. Later in development, it was observed that perinatal phencyclidine treatment signi¢cantly retarded baseline prepulse inhibition of acoustic startle measured shortly after weaning. In 42-day-old rats, it was found that challenge with 2 mg/kg phencyclidine increased locomotor activity to a signi¢cantly greater extent in the rats that had been pretreated with phencyclidine. Similarly, perinatal phencyclidine treatment signi¢cantly delayed the acquisition of a delayed spatial alternation task. Each of the aforementioned changes (except for the spatial learning task, which was not tested) was signi¢cantly inhibited by olanzapine pretreatment, an antipsychotic drug known to be e¡ective against both positive and negative symptoms of schizophrenia. Further, olanzapine treatment for 12 days following the administration of phencyclidine was also able to reverse the phencyclidine-induced de¢cit in baseline prepulse inhibition. Together these data suggest that perinatal administration of phencyclidine results in long-term behavioral changes that may be mechanistically related to the apoptotic neurodegeneration observed in the frontal cortex. It is postulated that these de¢cits may model the hypofrontality observed in schizophrenia and that this model may be helpful in designing appropriate pharmacotherapy. ß
doi:10.1016/s0306-4522(01)00384-0 pmid:11720778 fatcat:h7osdjqrrzba3gshnqk7rzihxu