Modulators of the Brain Stress System
Drugs of abuse are powerful activators of the stress systems, an effect that has important implications for understanding the neurobiology of dependence and relapse, both through the hypothalamic–pituitary–adrenal axis and extensive extrahypothalamic, extra-neuroendocrine CRF systems implicated in behavioral responses to stress. A common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses in animal models. During drug withdrawal, extrahypothalamic CRF systems become hyperactive, with an increase in extracellular CRF within the central nucleus of the amygdala and bed nucleus of the stria terminalis in dependent rats. Withdrawal from repeated administration of cocaine, alcohol, nicotine, and cannabinoids produces an anxiogenic-like response in the elevated plus maze and defensive burying test. One or both of these effects can be reversed by the administration of selective CRF1 receptor antagonists or mixed CRF1/CRF2 receptor antagonists (for further reading see Koob et al., 2008). CRF antagonists block the anxiogenic-like and aversive-like motivational effects of drug withdrawal in animal models of dependence. Systemic injections of small-molecule CRF1 antagonists also block the increase in alcohol intake in alcohol-dependent rats during acute withdrawal and protracted abstinence but not in nondependent rats. CRF antagonists also selectively block the increase in self-administration associated with extended access to cocaine, nicotine, and heroin. These data suggest an important role for CRF, primarily in the central nucleus of the amygdala, in mediating the increased self-administration associated with drug dependence. Several clinical trials have evaluated the effects of CRF1 antagonists on anxiety and depression, but either they have generated negative results or the trials were stopped because of side effects (for further reading, see Koob and Zorrilla, 2012). No human laboratory studies or clinical trials have yet been published that explored the effects of CRF antagonists on drug dependence, largely due to the limited availability of CRF antagonists for human studies on addiction.