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Vol. 53, Issue 2, 209-244, June 2001
Laboratory of Neuroendocrinology and Laboratory of Biology of
Addictive Diseases, Rockefeller University, New York, New York (Z.S.);
PsychoGenics, Inc., Hawthorne, New York (Z.S.); Behavioral Neuroscience
Branch, Intramural Research Program, National Institute on Drug Abuse,
National Institutes of Health, Baltimore, Maryland (Y.S.); and
Department of Psychology, Boston College, Chestnut Hill, Massachusetts
(S.C.H.)
I. Introduction
II. Overview of Corticotropin-Releasing Factor and Brain Function
A. Anatomical Distribution of the Corticotropin-Releasing Factor
Family of Peptides and Binding Sites
1. Corticotropin-Releasing Factor and Urocortin.
2. Corticotropin-Releasing Factor Binding Sites.
a. Corticotropin-Releasing Factor-1 Receptor.
b. Corticotropin-Releasing Factor-2 Receptors.
c. Corticotropin-Releasing Factor Binding Protein.
B. Role of Corticotropin-Releasing Factor in the Coordination of
Hormonal and Behavioral Stress Responses
1. Hormonal Effects of Corticotropin-Releasing Factor and
Urocortin.
2. Behavioral Effects of Corticotropin-Releasing Factor and
Urocortin.
3. Behavioral Effects of Corticotropin-Releasing Factor Receptor
Antagonists.
C. Role of Corticotropin-Releasing Factor in Neuropsychiatric
Disorders
III. Role of Corticotropin-Releasing Factor in Behavioral and
Hormonal Effects of Drugs of Abuse
A. Drug-Induced Activation of the
Hypothalamic-Pituitary-Adrenocortical Axis
1. Psychostimulant Drugs.
2. Opioids.
3. Alcohol and Benzodiazepines.
4. Nicotine.
5. Cannabinoids.
6. Differential Adaptation of the
Hypothalamic-Pituitary-Adrenocortical Axis to Chronic Drug
Administration.
a. Psychostimulants.
b. Opioids.
c. Alcohol and Benzodiazepines.
d. Nicotine.
e. Cannabinoids.
7. Summary.
B. Unconditioned and Conditioned Behavioral Effects of Drugs
1. Psychostimulant Drugs.
2. Alcohol and Benzodiazepines.
3. Cannabinoids.
4. Summary.
C. Drug Self-Administration and Reward
1. Cocaine.
2. Alcohol.
3. Summary.
D. Drug Withdrawal
1. Psychostimulant Drugs.
2. Opioids.
3. Alcohol and Benzodiazepines.
4. Nicotine.
5. Cannabinoids.
6. Summary.
E. Relapse to Drug-Taking Behavior
1. Cocaine.
2. Alcohol.
3. Heroin and Morphine.
4. Summary.
IV. Alterations in Brain Corticotropin-Releasing Factor Systems in
Response to Drug Exposure and Withdrawal
A. Psychostimulant Drugs
B. Opioids
C. Alcohol and Benzodiazepines
D. Nicotine and Cannabinoids
E. Summary
V. Discussion
A. Summary of Main Findings
B. Neuroanatomical Considerations
C. Drug-Induced Neuroadaptations, Corticotropin-Releasing Factor,
and Vulnerability to Drug Addiction
D. Therapeutic Implications
Acknowledgments
References
The goal of this article is to summarize available data examining the physiological significance of brain corticotropin-releasing factor (CRF) systems in mediating the behavioral and physiological effects of several classes of abused drugs, including opioid and psychostimulant drugs, alcohol and sedative hypnotics, nicotine, and cannabinoids. An initial discussion of CRF neurobiology is followed by consideration of the role of CRF in drug-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, the behavioral effects of drugs (e.g., locomotor activity, anxiogenic-like responses), drug self-administration, drug withdrawal, and relapse to drug-seeking. Subsequently, neurochemical changes in brain CRF in response to acute and chronic drug exposure are examined. A major conclusion derived from the data reviewed is that extrahypothalamic brain CRF systems are critically involved in behavioral and physiological manifestations of drug withdrawal and in relapse to drug-taking behavior induced by environmental stressors. On the other hand, it appears that hypothalamic CRF, via its action on the HPA axis, is involved in the reinforcing effects of cocaine and alcohol, and the locomotor activating effects of psychostimulant drugs. These preclinical data may provide a rationale for the development of CRF-based pharmacotherapies for the treatment of compulsive drug use in humans.
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