Background <p>Atogepant is a small-molecule non-competitive calcitonin gene-related peptide (CGRP) receptor antagonist efficacious in preventing episodic migraine. Cortical spreading depolarization (CSD) is a slowly propagating depolarization wave underlying migraine aura. We investigated whether the efficacy of atogepant in migraine is mediated by CSD suppression.</p> Method <p>We used Sprague-Dawley rats (<i>n</i> = 28 males, 28 females) to determine the electrical stimulation intensity threshold for CSD induction and the frequency of CSDs induced by continuous topical 1&#xa0;M KCl application sequentially in the same animal, using intracortical glass microelectrodes under isoflurane anesthesia and full systemic physiological monitoring, including arterial blood pressure and blood gases. In a separate cohort, we disrupted the BBB by inducing three CSDs in the contralateral hemisphere using 1&#xa0;M KCl daily for 2 days before CSD susceptibility testing. Both cohorts received atogepant (30&#xa0;mg/kg, once daily oral gavage) or vehicle for four days. CSD susceptibility was examined 1&#xa0;h after the last atogepant dose.</p> Results <p>Atogepant did not affect the CSD threshold, frequency, propagation speed, amplitude, or duration compared with vehicle, either without or with preceding CSDs. Systemic physiological parameters did not differ between groups.</p> Conclusions <p>These data suggest that atogepant efficacy in migraine is not mediated via CSD suppression, even when BBB permeability is increased.</p>