COMMENTARY Corticotropin-releasing factor, neuroplasticity (sensitization), and alcoholism George F. Koob* Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037 ensitization is a ubiquitous bio- logical phenomenon that has a role in the neuroadaptation of many different functions, from Slearning and memory to stress respon- sivity. Historically, a specific form of sensitization termed psychomotor sensi- tization (mistermed in my view as ‘‘be- havioral sensitization’’) is induced by repeated administration of drugs of abuse and has been linked to the neuro- adaptive changes associated with increased drug-seeking behavior associ- Fig. 1. CNS actions relevant to alcohol-induced psychomotor sensitization. CRF is a neuropeptide in the ated with addiction. Largely observed brain that controls autonomic, hormonal, and behavioral responses to stressors. New data show that CRF with psychostimulant drugs, also has a role in the neuroplasticity associated with addiction. The present study extends the role of CRF psychomotor sensitization has been con- to the psychomotor sensitization associated with repeated administration of alcohol. The hypothalamic- sidered a model for the increased pituitary-adrenal responses produced by CRF appear to be more involved in the acquisition of sensitiza- incentive salience contributing to the tion, whereas extrahypothalamic CRF systems, likely to be in structures such as the amygdala, appear to increased motivation to seek drugs in be important for the expression of sensitization. These results, combined with previous studies on the role of CRF in the development of alcohol dependence, suggest a key role for CRF in the neuroplasticity individuals with a previous history of associated with addiction. drug use. Psychomotor sensitization also has been observed with repeated admin- istration of ethanol in mice, but not in ized neuronally in brain areas that are ular, the study provides an elegant dem- rats, and psychomotor sensitization to distinct from those of the CRF/urocor- onstration of the power of the molecular ethanol also has been linked to tin 1/CRF1 receptor system and overlaps genetic approach in solving a problem activation of both the hypothalamic- significantly with the distribution of the and provides novel directions for thera- pituitary-adrenal (HPA) system and ex- type 2 urocortins. CRF and urocortin 1 peutic intervention in a chronic relaps- trahypothalamic brain stress systems bind to both the CRF1 and the CRF2 ing disorder. Previous studies using (Fig. 1). However, the exact mechanism receptors. Type 2 urocortins also differ pharmacological approaches showed for stress-induced sensitization has re- from urocortin 1 and CRF with respect that CRF could facilitate psychomotor mained elusive. to their high functional selectivity for sensitization either via the HPA axis (4) Corticotropin-releasing factor (CRF) the CRF2 receptor. or via extrahypothalamic sites (5–7). is a 41-amino-acid polypeptide that con- In this issue of PNAS, Pastor et al. (3) However, the specific CRF-like peptide, trols hormonal, sympathetic, and behav- show that mice lacking CRF1 and CRF2 the specific CRF receptor, and the ioral responses to stressors (1). CRF in receptors (double-constitutive knock- specific functional role had not been the paraventricular nucleus of the hypo- outs) do not show psychomotor sensiti- identified. Here, Pastor et al. (3) dem- thalamus controls the pituitary adrenal zation to ethanol. Further analysis re- onstrates unequivocally that the response to stress (2). Other peptides vealed that knockout of the CRF1 neuropeptide must be CRF and the re- with structural homology to CRF, the receptor also blocked the psychomotor ceptor must be CRF1. Positive results urocortin family of peptides (urocortins sensitization to ethanol. Administration with knockout mice provide a powerful 1, 2, and 3), also modulate behavioral of a CRF1 receptor antagonist attenu- means of testing a hypothesis, and one and autonomic responses to stress and ated the acquisition and blocked the must employ a tortured compensatory may have roles in other homeostatic expression of ethanol-induced psy- logic to argue the contrary. functions, such as appetite. Substantial chomotor sensitization. Knockout of the A parallel ‘‘sensitization’’ phenome- CRF- and urocortin 1-like immunoreac- CRF2 receptor, knockout of urocortin-1, non that is important for alcohol de- tivity is present in the basal forebrain and blockade of glucocorticoid recep- pendence is hypothesized to involve and autonomic midbrain and hindbrain tors failed to block expression of etha- neuroplasticity in the activation of both nuclei. The endogenous selective CRF2 nol-induced psychomotor sensitization. HPA and extrahypothalamic CRF sys- agonists—the type 2 urocortins—include The authors hypothesize that CRF may tems. Progressive changes in the HPA urocortin 2 and urocortin 3 and have have a key role in ethanol-induced psy- axis are observed during the transition neuroanatomical distributions that are chomotor sensitization in acquisition from acute administration to chronic distinct from those of CRF and urocor- (via activation of the HPA axis) and in administration of drugs of abuse. tin 1, notably in hypothalamic nuclei. expression (via the extrahypothalamic Two CRF receptors have been identi- CRF stress system). Author contributions: G.F.K. wrote the paper. fied, CRF1 and CRF2. The CRF1 recep- These results provide new insights tor has abundant, widespread expression into the role of the brain and pituitary The author declares no conflict of interest. in the brain that overlaps significantly stress systems in the neuroadaptations See companion article on page 9070. with the distribution of CRF and uro- associated with chronic administration *E-mail: [email protected]. cortin 1. The CRF2(a) receptor is local- of drugs of abuse and alcohol. In partic- © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0804354105 PNAS ͉ July 1, 2008 ͉ vol. 105 ͉ no. 26 ͉ 8809–8810 Downloaded by guest on September 29, 2021 Acute administration in animals of the CRF system in the extended to return to normal homeostatic most drugs of abuse, including cocaine, amygdala (12). Increases in extrahypo- baseline), setting up a negative rein- opiates, nicotine, and alcohol, activates thalamic CRF drives anxiety-like forcement mechanism and representing the HPA axis and has been hypothe- responses associated with acute with- another form of sensitization (17). The sized to contribute to the acute rein- drawal from ethanol (13), excessive results reported by Pastor et al. (3), forcing effects of these drugs (e.g., drinking during acute and protracted combined with the established role of refs. 8–11). However, as the cycle of withdrawal from ethanol (14, 15), and CRF in drug dependence, provide an drug taking and withdrawal continues, stress-induced reinstatement of etha- even more integrative role for CRF in the HPA axis response shows toler- nol-seeking (16). Engagement of the the neuroplasticity of addiction. The ance, but repeated exposure of the brain stress systems, in contrast to the integrative role for CRF in the neuro- brain to high levels of glucocorticoids HPA axis, may contribute to the nega- plasticity of reward, psychomotor sensi- can continue to have profound effects tive emotional state that dissipates tization, and dependence makes even on the extrahypothalamic brain stress with time after a single injection of a more compelling the argument that the systems. 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