Blockade of orexin receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats

Background and Purpose: A major problem managing alcohol use disorder is the high vulnerability to relapse, even after long periods of abstinence. Chronic alcohol use dysregulates stress responsivity, rendering this system hyporesponsive and making individuals vulnerable to relapse. Orexin (hypocretin) plays a role in diverse physiological processes, including stress. Orexin neurons in the hypothalamus, project to the infralimbic cortex. This study asked does infralimbic cortex orexin transmission play a significant role in stress-induced reinstatement of alcohol-seeking behaviour in alcohol-dependent rats. Experimental Approach: Male and female rats were trained to self-administer 10% alcohol (3 weeks) and then made dependent via chronic intermittent alcohol vapour exposure. Following extinction (5 days·week⁻¹ at 8 h abstinence for 10 sessions), rats received an intra- infralimbic cortex microinfusion of the OX_1/2 antagonist TCS 1102 (15 μg/0.5 μl per side) and then tested for footshock stress-induced reinstatement of alcohol seeking. In a separate cohort, orexin regulation of infralimbic cortex neuronal activity at the time of reinstatement was investigated using ex vivo electrophysiology. Key Results: TCS 1102 prevented reinstatement in dependent animals only. Moreover, Hcrtr mRNA expression in the hypothalamus and Hcrtr1/2 in the infralimbic cortex increased in alcohol-dependent animals at the time of testing. Dependence dampened basal orexin/OX receptor influence over infralimbic cortex GABAergic synapses (using TCS 1102) allow for greater stimulated orexin effects. Conclusion and Implications: Infralimbic cortex transmission is implicate in stress-induced reinstatement of alcohol-seeking behaviour in subjects with a history of alcohol dependence and show maladaptive recruitment of infralimbic cortex transmission by alcohol dependence.