In a previous study we reported
In a previous study we reported that the systemic administration of the α1-adrenergic receptor antagonist prazosin attenuates the deficit in Dioscin clinical reward function associated with precipitated nicotine withdrawal (Bruijnzeel et al., 2010). One of the aims of the present experiments was to investigate if the effects of prazosin on nicotine withdrawal were mediated by blocking α1-adrenergic receptors in the CeA. This study demonstrated that the effects of systemically administered prazosin on nicotine withdrawal were not mediated by α1-adrenergic receptors in the CeA. Future studies will explore the role of α1-adrenergic receptors in other brain sites in nicotine withdrawal. A binding study with the selective α1-adrenergic receptor agonist HEAT has shown that high levels of α1-adrenergic receptors are expressed in the bed nucleus of the stria terminalis (Jones et al., 1985). In addition, noradrenergic projections from the A1 and A2 noradrenergic cell groups in the brainstem to the BNST have been implicated in opioid withdrawal-induced place aversion (Delfs et al., 2000). Therefore, it might be possible that α1-adrenergic receptors in the BNST play a role in nicotine withdrawal.
In conclusion, the present findings indicate that the activation of CRF1 receptors in the CeA mediates the elevations in brain reward thresholds associated with nicotine withdrawal. This would suggest that CRF1 receptor antagonists may attenuate the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA. The dysphoria associated with smoking cessation increases craving for cigarettes and contributes to relapse to smoking (Doherty et al., 1995, West et al., 1989). Therefore, CRF1 receptor antagonists may improve smoking cessation rates by attenuating the negative mood state associated with smoking cessation.
Acknowledgements This research was funded by a National Institute on Drug Abuse grant (DA023575) to A. Bruijnzeel. J. Alexander was supported by a Postdoctoral Research Fellowship from the James & Esther King Biomedical Research Program. The authors are grateful to Dr. Shigeyuki Chaki (Taisho Pharmaceutical Co., Saitama, Japan) and Dr. Thomas Steckler (Johnson & Johnson Pharmaceuticals Research & Development, Beerse, Belgium) for generously providing R278995/CRA0450.
Introduction Alcohol is the most ubiquitous recreational drug in the world, causing more than 3 million global deaths in 2012 (World Health Organization, 2014). Anxiety and stress disorders are highly comorbid with alcohol abuse (Lai, Cleary, Sitharthan, & Hunt, 2015), suggesting the possibility of common underlying mechanisms or related circuitry dysfunction. The close relationship between substance use, which acutely elicits feelings of euphoria, and the more unpleasant effects of stress, anxiety, or withdrawal from drug exposure, reflects an important aspect of emotional information processing in the brain: the same circuitry can underlie both rewarding and aversive states. Consistent with this idea, the general experience of stress can also be either rewarding or aversive, depending on the type and duration of stress experienced and the state of the organism. The transition from alcohol use to alcohol abuse is characterized by a change in motivational state from drug reward-dependent intake early in alcohol use to intake motivated by withdrawal-induced aversion as the organism becomes increasingly dependent upon alcohol (Koob & Le Moal, 2001). Investigating the common cellular mechanisms of alcohol and stress in the brain allows for the dissection of specific circuits that underlie seemingly oppositional hedonic states and may provide insight into inherent vulnerability and/or new treatment directions for alcohol use and stress-related disorders, as well as unique strategies for understanding their comorbidity. The amygdala has emerged as a key brain region in the ontogeny of both alcoholism and stress/anxiety disorders. The amygdala is activated by alcohol-related cues in human participants (Dager et al., 2013) and by acute alcohol in rodent models (McBride, 2002), and has been shown to functionally regulate alcohol self-administration (Koob, 2003). Withdrawal from alcohol is associated with both changes in amygdala activity and anxiety-related behaviors (McCool, 2011, Overstreet et al., 2004). The relationship between fear/anxiety and the amygdala is robust. In both naïve rodents and healthy human participants, amygdala activity is associated with fear-paired cues during fear conditioning (Duvarci & Pare, 2014). In the context of anxiety disorders, amygdala activity both at rest and in response to anxiety-associated cues is enhanced in patients with post-traumatic stress disorder (PTSD), and similar amygdala responsivity has been observed in other anxiety disorders in humans (see VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014 for review). The amygdala is therefore a region where alcohol and anxiety-associated circuitry converge and is closely associated with the behavioral manifestations of both disorders.