Enhanced Cerebrovascular Responsiveness to Hypercapnia following Depletion of Central Serotonergic Terminals

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Abstract
Serotonin-containing nerve fibres innervate cerebral blood vessels, but the source of this innervation and the physiological effects of perivascular serotonin release remain controversial. The purpose of the present study was to examine the effects of central serotonergic depletion upon the relationship between CBF and glucose utilization under both normo- and hypercapnic conditions. To induce the loss of serotonergic terminals, rats were injected twice daily for 4 consecutive days with 20 mg/kg of the specific serotonergic neurotoxin methylenedioxyamphetamine (MDA). Between 4 and 6 weeks later, local CBF and glucose utilization were measured using the fully quantitative [14C]iodoantipyrine and [14C]2-deoxyglucose autoradiographic techniques, respectively, and the efficacy of the lesioning protocol was assessed using [3H]paroxetine radioligand binding analysis. In all animals treated with MDA, there was a significant decrease in serotonin uptake sites throughout the brain, falling from 223 ± 20 to 40 ± 16 fmol/mg tissue in parietal cortex, for example, although the raphe nuclei themselves were unaffected (300 ± 20 fmol/mg tissue in controls and 291 ± 18 in MDA-treated rats). In normocapnic rats, the effects of MDA pretreatment upon blood flow and glucose use were slight and focally concentrated. However, when the animals were rendered hypercapnic, CBF was significantly higher in MDA-treated rats than in normal controls, for example, increasing from 356 ± 22 ml 100 g−1 min−1 in frontal cortex of hypercapnic controls to 700 ± 81 ml 100 g−1 min−1 in MDA-pretreated rats with similar levels of hypercapnia. In some brain areas of hypercapnic MDA-pretreated rats, blood flows were too high (>800 ml 100 g−1 min−1) to be accurately quantified. The results of this study are consistent with a constrictor role for perivascular serotonergic innervation that becomes manifest when, as in hypercapnia, cerebrovascular tone is low.