br Conclusion In conclusion the current study showed that

Conclusion In conclusion, the current study showed that central CRF signals have crucial roles in behavioral changes, such as locomotor activity and anxiety behavior. In contrast, the hormonal regulation of CRF through HPA axis can be primarily modulated at the peripheral level. CRF1 receptor antagonists that block CRF signaling in the CNS, like Compound A, are expected to show anxiolytic effects.
Funding This work was funded by Takeda Pharmaceutical Company Limited.
Acknowledgements
Introduction Tobacco addiction is a chronic disorder that is characterized by compulsive smoking and relapse after periods of abstinence (American Psychiatric Association, 2000). The positive reinforcing effects of cigarettes have been suggested to play a pivotal role in the initiation of smoking (Chen et al., 2003, Finkenauer et al., 2009). The positive reinforcing effects of smoking include mild euphoria, relaxation, and improved cognitive functioning (Ague, 1973, Benowitz, 1988, Wesnes and Warburton, 1983). Smoking induces adaptations in the FLAG Peptide that may cause the negative mood state, increased anxiety, and impaired cognitive function associated with smoking cessation (Bruijnzeel, 2009, Bruijnzeel and Gold, 2005, Hughes et al., 1991). The negative affective symptoms associated with smoking cessation have been suggested to play an important role in relapse to smoking (Koob and Le Moal, 2005). Corticotropin-releasing factor (CRF) and norepinephrine play a pivotal role in the regulation of mood states. CRF levels are elevated in depressed patients and treatment with antidepressant drugs improves mood states and decreases brain CRF levels (De Bellis et al., 1993, Nemeroff et al., 1984). Furthermore, chronic treatment with noradrenergic reuptake inhibitors improves mood states in depressed patients (Nelson, 1999). More recent studies have provided evidence for a role of CRF and norepinephrine in drug addiction. The administration of the non-specific CRF1/CRF2 receptor antagonist d-Phe CRF (12–41) and the CRF1 receptor antagonist R278995/CRA0450 into the lateral ventricles attenuates the negative mood state associated with nicotine withdrawal (Bruijnzeel et al., 2007, Bruijnzeel et al., 2009). Blockade of CRF1 receptors also attenuates stress-induced reinstatement of nicotine seeking and increased nicotine intake after a period of abstinence (Bruijnzeel et al., 2009, George et al., 2007). Numerous studies have provided evidence for a role of noradrenergic transmission in drug addiction. The α1-adrenergic receptor antagonist prazosin attenuates the negative mood state associated with nicotine withdrawal in rats (Bruijnzeel et al., 2010). Prazosin also reduces heroin and cocaine self-administration in rats with extended access (6–12h/day) to these drugs (Greenwell et al., 2009, Wee et al., 2008). The α2-adrenergic receptor agonist clonidine attenuates the morphine withdrawal-induced decrease in operant responding for food and prevents naloxone-induced conditioned place aversion in morphine dependent animals (Kosten, 1994, Sparber and Meyer, 1978). Clonidine also improves smoking cessation rates (Glassman et al., 1988, Gourlay et al., 2004) and attenuates opioid withdrawal symptoms in humans (Gold et al., 1978).