Blockade of corticotropin-releasing factor-1 receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol seeking in male Wistar rats: Evidence of interaction between CRF 1 and orexin receptor signaling

• Published in: Neuropharmacology 2022-06, Vol.210, p.109046
• Main Authors: Flores-Ramirez, Francisco J, Matzeu, Alessandra, Sánchez-Marín, Laura, Martin-Fardon, Rémi
• Format: Article
• Language: English
• Subjects: Animals; Corticotropin-Releasing Hormone - metabolism; Hypothalamo-Hypophyseal System - metabolism; Male; Orexin Receptors - metabolism; Orexins - metabolism; Pituitary-Adrenal System - metabolism; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - metabolism; Self Administration
• ISSN: 1873-7064

Alcohol use dysregulates responsivity to stress, which is mediated by corticotropin-releasing factor (CRF). With repeated cycles of alcohol use, the hypothalamic-pituitary-adrenal axis becomes hyporesponsive, rendering individuals vulnerable to the reinstatement of alcohol-seeking behavior during stressful episodes. Orexin (Orx; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and interacts with CRF. The infralimbic cortex (IL) is a CRF-rich region. Anatomical evidence suggests that CRF and Orx interact in this area. To test the behavioral implication of CRF and Orx transmission in the IL during the stress-induced reinstatement of alcohol-seeking behavior, male Wistar rats were trained to self-administer 10% alcohol for 3 weeks. The rats then underwent two weeks of extinction training (identical to the alcohol self-administration sessions, but alcohol was withheld). The day after the last extinction session, the rats received a bilateral intra-IL injection of the CRF receptor antagonist CP154,526 (0.6 μg/0.5 μl/side), the dual Orx receptor antagonist TCS1102 (15 μg/0.5 μl/side), or their combination and then were tested for the footshock stress-induced reinstatement of alcohol-seeking behavior. CP154,526 significantly prevented reinstatement, but TCS1102 did not produce such an effect. Interestingly, the co-administration of TCS1102 and CP154,526 reversed the effect of CP154,526 alone, and footshock stress induced a significant increase in Crhr1 and Hcrtr2 mRNA expression in the IL. These results demonstrate a functional interaction between Orx receptor and CRF receptor signaling and suggest that CRF receptor antagonism may ameliorate stress-induced alcohol-seeking behavior.