Neonatal depletion of cortical dopamine: effects on dopamine turnover and motor behavior in juvenile and adult rats.

Abnormal development of mesoprefrontal dopamine (DA) neurons may contribute to the pathophysiology of schizophrenia. Consistent with this hypothesis, DA nerve terminal density is decreased in the cortex of schizophrenic subjects [M. Akil, J.N. Pierri, R.E. Whitehead, C.L. Edgar, C. Mohila, A.R. Sampson, and D.A. Lewis, Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects, Am. J. Psychiatry, 156 (1999) 1580-1589]. This abnormality may be present early in development, giving rise to dysfunction as an individual matures. The present studies examined the effects of early partial loss of medial prefrontal cortex (mPFC) DA on DA turnover and locomotor behavior in juvenile, pubertal, and adult rats (30, 45, and 60 days of age, respectively). Local infusions of 6-hydroxydopamine on postnatal day (PN) 12-14 produced persistent decreases in basal tissue DA concentrations and increases in 3,4-dihydroxyphenylacetic acid (DOPAC):DA ratios in the mPFC. In the nucleus accumbens of lesioned rats, basal DA concentrations were decreased and DOPAC:DA ratios were increased on PN30, but not PN45 or 60. Footshock (30 min at 0.6 mA) increased DOPAC and DOPAC:DA ratios in the mPFC of PN30 and 60 control rats. These effects were attenuated in age-matched rats previously sustaining approximately 50% loss of mPFC DA on PN12-14. Footshock did not affect DOPAC:DA ratios in the nucleus accumbens of control or lesioned rats. The lesion also failed to alter basal or stress-evoked motor activity. The present data suggest that a decreased density of mPFC DA nerve terminals occurring early in development results in persistent alterations in basal and stress-evoked activity of mesoprefrontal DA neurons, but not mesoaccumbens DA neurons.