Neonatal phencyclidine treatment selectively attenuates mesolimbic dopamine function in adult rats as revealed by methamphetamine-induced behavior and c-fos mRNA expression in the brain

One of the major hypotheses regarding the pathogenesis of schizophrenia is the implication of neurodevelopmental abnormality. However, the mechanism o f delayed onset of schizophrenic symptoms, in which increased dopaminergic activity in mesolimbic or mesocortical dopamine systems plays a pathologica l role, is not known. In this study, we investigated whether the chronic bl ockade of N-methyl-D-aspartate (NMDA) receptor by phencyclidine (PCP), an N MDA channel blocker, during development could disrupt the dopamine system d uring later life. Neonatal rats were injected with PCP subcutaneously daily from postnatal day (PD) 1 to PD 14 and their dopaminergic function was eva luated on PD 42 by rating the methamphetamine (MAP)-induced behavior. To il lustrate the activated brain regions, the expression of c-fos mRNA in respo nse to a MAP challenge was also studied utilizing in situ hybridization. Ch ronic neonatal PCP treatment attenuated MAP-induced oral stereotypy (lickin g and gnawing) and reduced MAP-induced expression of c-fos mRNA in the N. a ccumbens shell region and VTA but not in the N, accumbens core region, medi al striatum, or substantia nigra, These results suggest that neonatal block ade of NMDA receptor, which induces a number of effects in the developing n ervous system, may cause long-lasting functional changes of the mesolimbic dopamine system. (C) 2001 Wiley-Liss, Inc.