ENHANCED CEREBROVASCULAR RESPONSIVENESS TO HYPERCAPNIA FOLLOWING DEPLETION OF CENTRAL SEROTONERGIC TERMINALS

Serotonin-containing nerve fibres innervate cerebral blood vessels, bu t the source of this innervation and the physiological effects of peri vascular serotonin release remain controversial. The purpose of the pr esent study was to examine the effects of central serotonergic depleti on upon the relationship between CBF and glucose utilization under bot h normo- and hypercapnic conditions. To induce the loss of serotonergi c terminals, rats were injected twice daily for 4 consecutive days wit h 20 mg/kg of the specific serotonergic neurotoxin methylene-dioxyamph etamine (MDA). Between 4 and 6 weeks later, local CBF and glucose util ization were measured using the fully quantitative [C-14]iodoantipyrin e and [C-14]2-deoxyglucose autoradiographic techniques, respectively, and the efficacy of the lesioning protocol was assessed using [H-3]par oxetine 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 par ietal cortex, for example, although the raphe nuclei themselves were u naffected (300 +/- 20 fmol/mg tissue in controls and 291 +/- 18 in MDA -treated rats). In normocapnic rats, the effects of MDA pretreatment u pon blood flow and glucose use were slight and focally concentrated. H owever, when the animals were rendered hypercapnic, CBF was significan tly higher in MDA-treated rats than in normal controls, for example, i ncreasing from 356 +/- 22 ml 100 g(-1) min(-1) in frontal cortex of hy percapnic controls to 700 +/- 81 ml 100 g(-1) min(-1) in MDA-pretreate d rats with similar levels of hypercapnia. In some brain areas of hype rcapnic MDA-pretreated rats, blood Bows 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 inne rvation that becomes manifest when, as in hypercapnia, cerebrovascular tone is low.