Extended access to nicotine leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats

• Published in: Addiction biology Vol. 20; no. 1; pp. 56 - 68
• Main Authors: Cohen, Ami, Treweek, Jennifer, Edwards, Scott, Leão, Rodrigo Molini, Schulteis, Gery, Koob, George F., George, Olivier
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-01-2015; John Wiley & Sons, Inc
• Subjects: addiction; Animals; Anxiety; Anxiety - metabolism; Behavior, Animal - drug effects; emotion; Hyperalgesia - metabolism; Male; Nicotine; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Pyrimidines - pharmacology; Rats; Receptors, Corticotropin-Releasing Hormone - antagonists & inhibitors; Receptors, Corticotropin-Releasing Hormone - metabolism; Rodents; stress; Substance Withdrawal Syndrome - metabolism; Tobacco; Tobacco Use Disorder - metabolism; withdrawal; stress; tobacco; emotion; withdrawal; addiction
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12077

Tobacco dependence is associated with the emergence of negative emotional states during withdrawal, including anxiety and nociceptive hypersensitivity. However, the current animal models of nicotine dependence have focused on the mechanisms that mediate the acute reinforcing effects of nicotine and failed to link increased anxiety and pain during abstinence with excessive nicotine self‐administration. Here, we tested the hypothesis that the activation of corticotropin‐releasing factor‐1 (CRF1) receptors and emergence of the affective and motivational effects of nicotine abstinence only occur in rats with long access (>21 hours/day, LgA) and not short (1 hour/day, ShA) access to nicotine self‐administration. ShA and LgA rats were tested for anxiety‐like behavior, nociceptive thresholds, somatic signs of withdrawal and nicotine intake after 3 days of abstinence. The role of CRF1 receptors during abstinence was tested using systemic or intracerebral infusion of MPZP (N,N‐bis(2‐methoxyethyl)‐3‐(4‐methoxy‐2‐methylphenyl)‐2,5‐dimethyl‐pyrazolo(1,5α)pyrimidin‐7‐amine), a CRF1 receptor antagonist, in the central nucleus of the amygdala (CeA). LgA but not ShA rats exhibited abstinence‐induced increases in anxiety‐like behavior and nociceptive hypersensitivity, which both predicted subsequent excessive nicotine intake and were prevented by systemic administration of MPZP. Intra‐CeA MPZP infusion prevented abstinence‐induced increases in nicotine intake and nociceptive hypersensitivity. These findings demonstrate that the model of short access to nicotine self‐administration has limited validity for tobacco dependence, highlight the translational relevance of the model of extended‐intermittent access to nicotine self‐administration for tobacco dependence and demonstrate that activation of CRF1 receptors is required for the emergence of abstinence‐induced anxiety‐like behavior, hyperalgesia and excessive nicotine intake.
Classic animal models of nicotine dependence have failed to link increased anxiety and pain during abstinence with excessive nicotine self‐administration. Here, we show that rats with long (21 h / day), but not limited (1 h / day) access to nicotine exhibit anxiety‐like behavior and hyperalgesia that predict nicotine intake after abstinence (see Figure). Moreover, anxiety‐like behavior, hyperalgesia and escalation of nicotine intake were dependent on activation of corticotropin releasing factor 1 receptors in the central nucleus of the amygdale.