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 suggested to play a role in the pathophysiology of schizophrenia. Indeed, a recent study indicates that the density of tyrosine hydroxylase-immunoreactive axons is decreased in the deep layers of the prefrontal cortex of schizophrenic subjects [Akil et al., (1999) Am. J. Psychiatry, in press]. To determine the impact of partial loss of prefrontal dopamine axons on the activity of the remaining dopamine axons, we examined the effects of 6-hydroxydopamine lesions of the medial prefrontal cortex on local extracellular dopamine concentrations in the rat. In rats sustaining an average 63% loss of tyrosine hydroxylase-immunoreactive axons and no loss of dopamine-beta-hydroxylase-immunoreactive axons in the medial prefrontal cortex (smaller lesion), the baseline extracellular dopamine concentration was reduced by 63+/-9%. Thirty minutes of tail pressure increased extracellular dopamine in the medial 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 baseline extracellular dopamine concentration in the medial prefrontal cortex did not differ from control values. In addition, the maximum stress-evoked increase in dopamine concentration was also similar to that observed in control rats (+1.04+/-0.28 pg). The stress-induced increase in extracellular dopamine in the medial prefrontal cortex of rats sustaining smaller and larger lesions may occur in the absence of a corresponding increase in dopamine synthesis in mesoprefrontal dopamine neurons. This proposal is supported by our observation that stress did not alter tissue or extracellular 3,4-dihydroxyphenylacetic acid concentrations in the medial prefrontal cortex of lesioned rats. These data suggest that moderate loss of tyrosine hydroxylase-immunoreactive axons in the prefrontal cortex is sufficient to reduce extracellular dopamine concentrations in this brain region. In addition, a further reduction in tyrosine hydroxylase-immunoreactive axons in the medial prefrontal cortex, 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 of remaining mesoprefrontal dopamine axons and/or decreased clearance of extracellular dopamine due to loss of both dopamine and norepinephrine transporters.