Sex-dependent modulation of CGRPergic neurovascular activity by 5-CT in rats

Background and purpose Serotonin modulates vascular tone both directly and indirectly through autonomic and sensory nerves innervating blood vessels. Perivascular sensory nerves release calcitonin gene-related peptide (CGRP), a potent vasodilator strongly implicated in migraine pathophysiology. In male rats, the serotonergic system inhibits CGRPergic vasodepressor responses via 5-HT 1B/1F and 5-HT 7 receptors. Since both serotonergic and CGRPergic pathways exhibit marked sex differences, the present study investigated the 5-HT receptor (sub)types involved in the 5-carboxamydotryptamine (5−CT, 5-HT 1/5/7 receptor agonist) modulation of vascular CGRPergic neurotransmission in rats, focusing on sex-dependent differences. Methods Male and female Wistar rats (14–16 weeks old) were pithed and pretreated with an i.v. continuous infusion of hexamethonium and methoxamine, followed by administration of 5-HT-related drugs. Mean blood pressure (MBP) and heart rate (HR) were continuously recorded throughout the experiments. Vasodepressor CGRPergic responses were elicited by electrical stimulation of the sensory outflow (0.1–5 Hz) or i.v. α-CGRP (0.1–1 μg/kg). Results Basal MBP and HR were lower in females than in males, whereas the methoxamine-induced increase in MBP was greater in females. The electrically evoked vasodepressor responses, as well as their inhibition by 5−CT, were similar in both sexes. In males, the inhibitory effect of 5−CT was reproduced by 5-HT 1B , 5-HT 1F , and 5-HT 7 receptor agonists (CP-93,129, LY344864, and AS-19, respectively) and persisted in the presence of the 5-HT 5A receptor antagonist SB699551. In contrast, in females, 5-CT-induced inhibition was mimicked by 5-HT 1F and 5-HT 7 receptor agonists and was not affected by administration of SB699551. None of the other 5-HT receptor agonists (5-HT 1A/1B/1D ) modified the CGRPergic vasodilator responses in females. Only AS-19 reduced the vasodepressor responses elicited by exogenous α-CGRP in females. Conclusion 5−CT inhibits perivascular sensory CGRPergic neurotransmission in both male and female rats. Unlike males, where the 5−CT effect is mediated by prejunctional 5-HT 1B/1F/7 receptors, in females, this inhibitory effect is mediated by prejunctional 5-HT 1F and pre and/or postjunctional 5-HT 7 receptors. These findings provide novel insights into sex-specific serotonergic modulation of neurovascular function.