Functional interaction between orexin/CRF and orexin/dynorphin transmission in the infralimbic cortex modulates the stress-induced reinstatement of alcohol-seeking behavior in male and female Wistar rats

Stress contributes to the chronic relapsing nature of alcohol use disorder (AUD), given its ability to elicit craving and precipitate relapse, even after long periods of self-imposed abstinence. Although not thoroughly understood, anatomical, pharmacological, and behavioral data suggest orexin (OX), corticotropin-releasing factor (CRF), and dynorphin (DYN) interact, particularly in the infralimbic cortex (IL). Functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects, rendering them vulnerable to relapse. Male and female Wistar rats were trained to self-administer 10% alcohol for 3 weeks and then made dependent via chronic intermittent alcohol vapor exposure for 6 weeks. Following extinction training (12 sessions), rats received an intra-IL microinfusion of the OX_1/2 receptor antagonist suvorexant (15 μg/0.5 μl/side), the CRF₁ receptor antagonist CP154,526 (0.6 μg/0.5 μl/side), the κ-opioid receptor antagonist nor-binaltorphimine (norBNI; 4 μg/0.5 μl/side), or a combination of suvorexant + CP154,526 or suvorexant + norBNI. Rats were then tested for footshock stress-induced reinstatement of alcohol-seeking behavior. In nondependent rats, only CP154,526 prevented the reinstatement of alcohol-seeking behavior, an effect that was reversed by suvorexant co-administration. In dependent rats, suvorexant, CP154,526, and norBNI attenuated alcohol-seeking behavior. Interestingly, the co-administration of suvorexant + CP154,526 or suvorexant + norBNI attenuated suvorexant's effect. Increases in Hcrtr1 mRNA expression in the IL were found in alcohol-dependent rats only. These results demonstrate a functional interaction between OX/CRF and OX/DYN receptor signaling in the IL in subjects with a history of alcohol dependence.