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

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-HT₇ 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.

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).

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-HT₇ 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-HT₇ 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.

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-HT₇ receptors. These findings provide novel insights into sex-specific serotonergic modulation of neurovascular function.