Effect of central serotonin depletion on 5-HT receptor-mediated vasomotor responses in the middle meningeal artery of anaesthetized rats

1 It has been hypothesized that craniovascular 5-HT receptors mediating dilatation of cranial vessels undergo sensitization on decreased serotonergic transmission in migraine. This study analysed the effect of chemical lesion of the 5-HT system in the brain with 5,7-dihydroxytryptamine (5,7-DHT) on 5-HT receptor-mediated dilator responses to 5-carboxamidotryptamine (5-CT) in the middle meningeal artery of anaesthetized rats. 5-CT has recently been shown to elicit dilator responses in this cranial vessel via 5-HT₇ receptors and, to a much lesser extent, 5-HT_1B/1D receptors.

2 Pretreatment with 5,7-DHT produced a drastic and selective decrease of 5-HT levels in the brain (78 ± 6% and 94 ± 2% in dorsal raphe and hypothalamic paraventricular nuclei, respectively) compared with controls (1% ascorbic acid).

3 Topical application of 5-CT (1–1000 μm) to exposed dura mater encephali produced concentration-dependent decreases in diastolic blood pressure and dilator responses in the middle meningeal artery that were similar in vehicle- and 5,7-DHT-pretreaed animals.

4 Hypotensive and meningeal dilator responses to 5-CT were unaltered by the 5-HT_1B/1D receptor antagonist, GR-127935 (1 mg kg⁻¹, i.v.), but were strongly inhibited by the 5-HT₇ receptor antagonist, SB-269970 (1 mg kg⁻¹, i.v.), with similar efficacy, in both groups of animals. Treatment with GR-127935 + SB-269970 (1 mg kg⁻¹, i.v. each), produced a stronger inhibitory effect than individual treatments on hypotensive but not on meningeal responses to 5-CT. Meningeal 5-HT₇ receptor-mediated responses (i.e. in GR-127935-pretreated animals) were unchanged by 5,7-DHT pretreatment.

5 Results suggest that the sensitivity of craniovascular 5-HT₇ receptors mediating dilatation is unaffected by a decrease of 5-HT levels in the brain. A neuronal involvement of 5-HT in migraine seems more likely, therefore.