Site-specific role of CRF1 receptors along the rostrocaudal axis of the insular cortex in cardiovascular responses evoked by acute and repeated restraint stress in rats

The present study investigated the contribution of corticotropin-releasing factor (CRF) neurotransmission acting through local CRF₁ receptors in the anterior (aIC), rostral-posterior (rpIC), and caudal-posterior (cpIC) subregions of the insular cortex (IC) to the modulation of cardiovascular responses during acute and repeated (10th session) restraint stress in rats. To this end, we performed targeted microinjections of the selective CRF₁ receptor antagonist CP376395 or the agonist CRF into the IC subregions; and assessed changes in arterial pressure, heart rate, and tail skin temperature (TST). We observed that microinjection of CP376395 into the aIC reduced tachycardia and enhanced TST drop during acute restraint stress, whereas the same pharmacological approach into the rpIC attenuated the pressor response and enhanced the TST drop. CRF₁ receptor antagonism within the cpIC decreased both pressor and tachycardiac responses during acute restraint stress, without affecting the TST drop. Comparisons between acutely and chronically stressed animals showed that repeated restraint stress altered CRF control of cardiovascular responses in the rpIC and cpIC, but not in the aIC. In chronically stressed animals, these alterations were primarily characterized by an attenuation of the effects observed with CRF₁ receptor antagonism, whereas local CRF administration elicited effects not observed in animals subjected to acute restraint. Repeated restraint stress did not alter CRF₁ receptor expression in any of the IC subregions. These results indicate that CRF neurotransmission in the IC plays a critical role in controlling cardiovascular responses to stress. This control is site-specific across rostrocaudal IC subregions and is affected by previous stress experience.