Effects of partial dopamine loss in the medial prefrontal cortex on local baseline and stress-evoked extracellular dopamine concentrations

A reduction in the activity of mesoprefrontal dopamine neurons has been sug gested to play a role in the pathophysiology of schizophrenia. Indeed, a re cent study indicates that the density of tyrosine hydroxylase-immunoreactiv e axons is decreased in the deep layers of the prefrontal cortex of schizop hrenic subjects [Akil et al, (1999) Am. J. Psychiatry, in press]. To determ ine the impact of partial loss of prefrontal dopamine axons on the activity of the remaining dopamine axons, we examined the effects of 6-hydroxydopam ine lesions of the medial prefrontal cortex on local extracellular dopamine concentrations in the rat. In rats sustaining an average 63% loss of tyros ine hydroxylase-immunoreactive axons and no loss of dopamine-beta-hydroxyla se-immunoreactive axons in the medial prefrontal cortex (smaller lesion), t he baseline extracellular dopamine concentration was reduced by 63 +/- 9%. Thirty minutes of tail pressure increased extracellular dopamine in the med ial prefrontal cortex by a maximum of 1.28 +/- 0.28 pg in control rats, but only 0.74 +/- 0.18 pg in rats with smaller lesions. In rats sustaining an average 80% loss of tyrosine hydroxylase-immunoreactive axons and 25% loss of dopamine beta-hydroxylase-immunoreactive axons (larger lesion), the base line extracellular dopamine concentration in the medial prefrontal cortex d id not differ from control values. In addition, the maximum stress-evoked i ncrease in dopamine concentration was also similar to that observed in cont rol rats (+1.04 +/- 0.28 pg). The stress-induced increase in extracellular dopamine in the medial prefrontal cortex of rats sustaining smaller and lar ger lesions may occur in the absence of a corresponding increase in dopamin e synthesis in mesoprefrontal dopamine neurons. This proposal is supported by our observation that stress did not alter tissue or extracellular 3,4-di hydroxyphenylacetic acid concentrations in the medial prefrontal cortex of lesioned rats. These data suggest that moderate loss of tyrosine hydroxylase-immunoreactiv e axons in the prefrontal cortex is sufficient to reduce extracellular dopa mine concentrations in this brain region. In addition, a further reduction in tyrosine hydroxylase-immunoreactive axons in the medial prefrontal corte x, combined with the loss of dopamine-beta-hydroxylase-immunoreactive axons , results in normal extracellular dopamine concentrations in this area. We propose that the latter effect is due to increased neurochemical activity o f remaining mesoprefrontal dopamine axons and/or decreased clearance of ext racellular dopamine due to loss of both dopamine and norepinephrine transpo rters. (C) 1999 IBRO. Published by Elsevier Science Ltd.