Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF₁receptors. Overactivation of the CRF–CRF₁system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.

Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF ₁ ) receptor antagonist-reversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF ₁ electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahypothalamic CRF-CRF ₁ systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented.