Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jul 15;66(2):110-7.
doi: 10.1016/j.biopsych.2009.01.010. Epub 2009 Feb 12.

Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse

Adrie W Bruijnzeel  1 , Melissa Prado, Shani Isaac
Affiliations

Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse

Adrie W Bruijnzeel et al. Biol Psychiatry. .

Abstract

Background: Tobacco addiction is a chronic brain disorder that is characterized by a negative affective state upon smoking cessation and relapse after periods of abstinence. Previous research has shown that blockade of corticotropin-releasing factor (CRF) receptors with a nonspecific CRF1/CRF2 receptor antagonist prevents the deficit in brain reward function associated with nicotine withdrawal and stress-induced reinstatement of extinguished nicotine-seeking in rats. The aim of these studies was to investigate the role of CRF1 and CRF2 receptors in the deficit in brain reward function associated with precipitated nicotine withdrawal and stress-induced reinstatement of nicotine-seeking.

Methods: The intracranial self-stimulation (ICSS) procedure was used to assess the negative affective state of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. Stress-induced reinstatement of nicotine-seeking was investigated in animals in which responding for intravenously infused nicotine was extinguished by substituting saline for nicotine.

Results: In the ICSS experiments, the nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-dependent rats but not those of the control rats. The CRF1 receptor antagonist R278995/CRA0450 but not the CRF2 receptor antagonist astressin-2B prevented the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. Furthermore, R278995/CRA0450 but not astressin-2B prevented stress-induced reinstatement of extinguished nicotine-seeking. Neither R278995/CRA0450 nor astressin-2B affected operant responding for chocolate-flavored food pellets.

Conclusions: These studies indicate that CRF(1) receptors but not CRF(2) receptors play an important role in the anhedonic-state associated with acute nicotine withdrawal and stress-induced reinstatement of nicotine-seeking.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Effect of the CRF1 receptor antagonist R278995/CRA0450 (saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine-precipitated nicotine withdrawal (A). Effect of R278995/CRA0450 on the response latencies of rats chronically treated with saline (n = 12) or nicotine (n = 14) and acutely treated with mecamylamine (B). Brain reward thresholds and response latencies are expressed as a percentage of the pre-test day values. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 μg of R278995/CRA0450). Data are expressed as means ± SEM.
Figure 1
Figure 1
Effect of the CRF1 receptor antagonist R278995/CRA0450 (saline, n = 12; nicotine, n = 14) on the elevations in brain reward thresholds associated with mecamylamine-precipitated nicotine withdrawal (A). Effect of R278995/CRA0450 on the response latencies of rats chronically treated with saline (n = 12) or nicotine (n = 14) and acutely treated with mecamylamine (B). Brain reward thresholds and response latencies are expressed as a percentage of the pre-test day values. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Plus signs (+ P<0.05, ++ P<0.01) indicate lower brain reward thresholds compared to those of rats chronically treated with nicotine and acutely treated with mecamylamine and vehicle (0 μg of R278995/CRA0450). Data are expressed as means ± SEM.
Figure 2
Figure 2
Effect of the CRF2 receptor antagonist astressin-2B (saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine-precipitated nicotine withdrawal (A). Effect of astressin-2B on the response latencies of rats chronically treated with saline (n = 8) or nicotine (n = 8) and acutely treated with mecamylamine (B). Brain reward thresholds and response latencies are expressed as a percentage of the pre-test day values. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Data are expressed as means ± SEM.
Figure 2
Figure 2
Effect of the CRF2 receptor antagonist astressin-2B (saline, n = 8; nicotine, n = 8) on the elevations in brain reward thresholds associated with mecamylamine-precipitated nicotine withdrawal (A). Effect of astressin-2B on the response latencies of rats chronically treated with saline (n = 8) or nicotine (n = 8) and acutely treated with mecamylamine (B). Brain reward thresholds and response latencies are expressed as a percentage of the pre-test day values. Asterisks (* P<0.05, ** P<0.01) indicate elevations in brain reward thresholds compared to those of the corresponding saline-treated control group. Data are expressed as means ± SEM.
Figure 3
Figure 3
Responding on the active and inactive lever during nicotine self-administration (A, n = 12), extinction training, and relapse (B, n = 12). In figure 3A, asterisks (* P<0.05, ** P<0.01) indicate a decrease in responding on the active lever or an increase in responding on the inactive lever compared to the first day of nicotine self-administration. In figure 3B, asterisks (** P<0.01) indicate a decrease in responding on the active lever compared to baseline responding (last day of nicotine self-administration). Plus signs (++ P<0.01) indicate a footshock-induced increase in responding on the active lever compared to day 9 of extinction training. Abbreviations: B, baseline; Sh, footshocks. Data are expressed as means ± SEM.
Figure 3
Figure 3
Responding on the active and inactive lever during nicotine self-administration (A, n = 12), extinction training, and relapse (B, n = 12). In figure 3A, asterisks (* P<0.05, ** P<0.01) indicate a decrease in responding on the active lever or an increase in responding on the inactive lever compared to the first day of nicotine self-administration. In figure 3B, asterisks (** P<0.01) indicate a decrease in responding on the active lever compared to baseline responding (last day of nicotine self-administration). Plus signs (++ P<0.01) indicate a footshock-induced increase in responding on the active lever compared to day 9 of extinction training. Abbreviations: B, baseline; Sh, footshocks. Data are expressed as means ± SEM.
Figure 4
Figure 4
Effects of the CRF1 receptor antagonist R278995/CRA0450 (A, n = 12) and the CRF2 receptor antagonist astressin-2B (B, n = 16) on footshock-induced reinstatement of nicotine-seeking behavior. Asterisks (* P<0.05) indicate a decrease in responding on the active lever compared to rats that were pretreated with vehicle. Data are expressed as means ± SEM.
Figure 4
Figure 4
Effects of the CRF1 receptor antagonist R278995/CRA0450 (A, n = 12) and the CRF2 receptor antagonist astressin-2B (B, n = 16) on footshock-induced reinstatement of nicotine-seeking behavior. Asterisks (* P<0.05) indicate a decrease in responding on the active lever compared to rats that were pretreated with vehicle. Data are expressed as means ± SEM.
See this image and copyright information in PMC

References

    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Press; Washington, DC: 2000. text revision ed.
    1. Markou A, Kosten TR, Koob GF. Neurobiological similarities in depression and drug dependence: a self-medication hypothesis. Neuropsychopharmacology. 1998;18:135–174. - PubMed
    1. Koob GF, Caine SB, Parsons L, Markou A, Weiss F. Opponent process model and psychostimulant addiction. Pharmacol Biochem Behav. 1997;57:513–521. - PubMed
    1. Swan GE, Denk CE, Parker SD, Carmelli D, Furze CT, Rosenman RH. Risk factors for late relapse in male and female ex-smokers. Addict Behav. 1988;13:253–266. - PubMed
    1. Cohen S, Lichtenstein E. Perceived stress, quitting smoking, and smoking relapse. Health Psychol. 1990;9:466–478. - PubMed

Publication types

MeSH terms

Substances