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.
Venator
D K
DK
Department of Neuroscience, University of Pittsburgh, PA 15260, USA.
Lewis
D A
DA
Finlay
J M
JM
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D005110:Extracellular Space / Q000201:enzymology / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D017551:Microdialysis; D016627:Oxidopamine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000201:enzymology / Q000378:metabolism*; D013565:Sympatholytics / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D013565:Sympatholytics; D015102:3,4-Dihydroxyphenylacetic Acid; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine; D006719:Homovanillic Acid