Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Conclusion In conclusion the current

    2020-07-08


    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 Anacardic acid 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). Although the aforementioned studies indicate that increased CRF and noradrenergic transmission plays a role in drug withdrawal, very few studies have investigated the role of CRF and noradrenergic transmission in the central nucleus of the amygdala (CeA) in nicotine dependence. The present studies investigated the effect of the CRF1 receptor antagonist R278995/CRA0450 (Ki CRF1=53.2nM; CRF2 >10,000nM), the α1-adrenergic receptor antagonist prazosin (IC50 α1=0.6nM, α2=5000nM), and the α2-adrenergic receptor agonist clonidine (Ki α1=713nM, α2=3.2nM) in the CeA on precipitated nicotine withdrawal (Chaki et al., 2004, Van Meel et al., 1981, Virtanen et al., 1988). Both prazosin and clonidine inhibit noradrenergic transmission in the brain; prazosin by blocking postsynaptic α1-adrenergic receptors and clonidine by stimulating presynaptic α2-adrenergic receptors. In a separate experiment, R278995/CRA0450 was administered into the basolateral nucleus of the amygdala (BLA) before precipitating nicotine withdrawal. This control experiment was conducted to rule out the possibility that R278995/CRA0450 affected nicotine withdrawal by blocking CRF1 receptors in brain sites in close proximity to the CeA. The negative mood state associated with nicotine withdrawal was investigated using a discrete-trial intracranial self-stimulation (ICSS) procedure. Previous studies have shown that this ICSS procedure provides a quantitative measure of the emotional aspects of drug withdrawal (Bruijnzeel et al., 2006, Schulteis et al., 1995, Wise and Munn, 1995).