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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 (Orx; also called hypocretin) plays a role in diverse physiological processes, including stress. Orexin neurons, exclusively produced in the hypothalamus, project to the infralimbic cortex (IL). This study tested the hypothesis that IL-Orx transmission plays a significant role in stress-induced reinstatement of alcohol-seeking behavior in alcohol dependent rats.Male and female rats were trained to self-administer 10% alcohol (3 weeks) and then made dependent via chronic intermittent alcohol vapor exposure. Following extinction (5 days/week at 8 h abstinence for 10 sessions), rats received an intra-IL microinfusion of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg/0.5 μl/side) and then tested for footshock stress-induced reinstatement of alcohol seeking. In a separate cohort, Orx regulation of IL neuronal activity at the time of reinstatement was investigated using ex vivo electrophysiology.TCS1102 prevented reinstatement in dependent animals only. Moreover, Hcrtr mRNA expression in the hypothalamus and Hcrtr1/2 in the IL increased in alcohol-dependent animals at the time of testing. Lastly, dependence dampened basal Orx/OrxR influence over IL GABAergic synapses (using TCS1102) allowing for greater stimulated Orx effects.These results implicate IL-Orx transmission during stress-induced reinstatement of alcohol-seeking behavior in subjects with a history of alcohol dependence and show maladaptive recruitment of IL-Orx transmission by alcohol dependence. |
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