Review
Corticotropin releasing factor: A key role in the neurobiology of addiction

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Highlights

  • CRF systems have emerged as mediators of the body’s response to stress and, relatedly, the pathophysiology of addiction.

  • CRF systems have a prominent role in driving the addiction via actions in the central extended amygdala.

  • Addiction-related actions are anxious behavior, brain reward deficits, excessive drug use and stress-induced drug-seeking.

  • Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often with stress history.

Abstract

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body’s response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction. The results support the hypothesis that brain CRF–CRF1 systems contribute to the etiology and maintenance of addiction.

Introduction

According to a 2012 report by the Substance Abuse and Mental Health Services Administration, within the past 12 months, approximately 15% of the population aged 12 and older experienced substance use disorders on alcohol, cigarettes, or an illegal drug. Alcohol use disorders alone have an annual prevalence of approximately 10% and account for 4.6% of all disability-adjusted life-years in developed countries (Rehm et al., 2009). Available pharmacotherapies for substance use disorders have only modest long-term efficacy and are underutilized (Heilig et al., 2011). Since the successive discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) (Vale et al., 1981), the structurally-related urocortins (Ucn 1, Ucn 2, Ucn 3), and their cognate receptors (CRF1, CRF2) (Bale and Vale, 2004, Fekete and Zorrilla, 2007), CRF systems have emerged as therapeutic targets for substance abuse.

CRF binds with high and moderate potency to CRF1 and CRF2 receptors, respectively. Ucn 1 is a high-affinity agonist at both of these G-protein coupled receptors, whereas the type 2 urocortins (Ucn 2 and Ucn 3) are selective CRF2 receptor agonists (Bale and Vale, 2004, Zorrilla and Koob, 2004, Fekete and Zorrilla, 2007). Vale and colleagues first demonstrated that CRF initiates the hypothalamic–pituitary–adrenal (HPA) axis neuroendocrine stress response by binding CRF1 receptors in the anterior pituitary after release into portal blood. In addition, however, CRF1 receptors are widely distributed in stress-responsive brain regions, including the neocortex, central extended amygdala, medial septum, hippocampus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei (Grigoriadis et al., 1996, Primus et al., 1997, Sanchez et al., 1999, Van Pett et al., 2000). The brain CRF1 receptor distribution resembles the distribution of its natural ligands CRF (Fig. 1) and Ucn 1 and accounts for the dissociable, non-endocrine role of extrahypothalamic CRF1 systems (i.e., outside the HPA axis) to mediate behavioral and autonomic stress responses (Swanson et al., 1983, Kozicz et al., 1998, Bale and Vale, 2004, Zorrilla and Koob, 2004, Fekete and Zorrilla, 2007).

Extensive preclinical data suggest that extrahypothalamic CRF1 systems subserve negative emotional states. Accordingly, small-molecule CRF1 antagonists are being developed as potential treatments for affective-like disorders, including posttraumatic stress disorder, irritable bowel syndrome, anxiety disorders, and major depression (Zorrilla and Koob, 2004, Zorrilla and Koob, 2010, Holsboer and Ising, 2008, Koob and Zorrilla, 2012, Zorrilla et al., 2013a). Indeed, Dr. Vale was a major force in the pharmaceutical development of drug-like small-molecule CRF1 antagonists. He co-founded Neurocrine Biosciences, which successfully developed a wide range of such compounds, spanning multiple patents.

One proposed clinical indication for CRF1 antagonists is drug addiction (Fig. 1), where the brain stress systems are hypothesized to impact key elements of the addiction cycle. Drug addiction is a chronically relapsing disorder characterized by loss of control over drug intake and emergence of a negative emotional state during abstinence. Drug addiction has been conceptualized as a cycle progressing through three stages—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation—that become worse over time and ultimately lead to a severe neurobiological disorder. CRF systems are hypothesized to play a key role in all three stages of the addiction cycle but particularly in the withdrawal/negative affect stage. Chronic use of a drug of abuse, even if initiated for its rewarding effects, increasingly leads to negative emotional symptoms and negatively reinforced substance use. An extension of the “opponent process theory of affective regulation” (Solomon and Corbit, 1974), this hypothesis of addiction proposes that drugs of abuse initially activate brain structures that subserve positive emotional states (e.g., pleasure, contentment). The positive reinforcing effects of drugs are regulated in part by the ventral striatum and extended amygdala reward system, as well as by dopaminergic and opioid inputs from the ventral tegmental area (VTA) and arcuate nucleus of the hypothalamus, respectively. To maintain emotional homeostasis, however, a counter-regulatory opponent process then decreases mood and increases vigilance/tension via downregulation of brain reward systems (e.g., ventral striatum) and upregulation of brain stress systems, including CRF and norepinephrine systems in the extended amygdala (Heilig and Koob, 2007, Heilig et al., 2010a, Heilig et al., 2010b, Heilig et al., 2011, Koob and Zorrilla, 2010, Koob and Zorrilla, 2012, Breese et al., 2011, Logrip et al., 2011). With continued cycles of intoxication/withdrawal, the opponent process allostatically predominates over the primary rewarding process (Fig. 2). As a result, more substance of abuse is needed simply to maintain euthymia. If drug use stops, negative emotional symptoms emerge (i.e., acute withdrawal: anxiety, dysphoria, irritability). With a sufficient drug use history, stress-like symptoms of dysphoria may episodically and spontaneously resurge even weeks or months after detoxification (i.e., protracted withdrawal). Furthermore, exaggerated responses to otherwise mild stressors may be seen despite continued abstinence. Under this conceptualization of addiction, substance abuse escalates because the drug of abuse mitigates the counter-regulatory negative emotional symptoms of acute and protracted withdrawal (Heilig and Koob, 2007, Koob and Zorrilla, 2010, Zorrilla et al., 2013a).

The reviewed opponent process putatively of otherwise silent brain CRF1 receptor stress systems of the extended amygdala. For example, in dependent rat models, acute alcohol withdrawal activates CRF systems in the central nucleus of the amygdala (CeA) (Merlo Pich et al., 1995, Zorrilla et al., 2001, Funk et al., 2006, Roberto et al., 2010) and bed nucleus of the stria terminalis (Olive et al., 2002). Extracellular CRF in rats also increased in the CeA during precipitated withdrawal from chronic nicotine (George et al., 2007), withdrawal from binge cocaine self-administration (Richter and Weiss, 1999), and precipitated withdrawal from opioids (Weiss et al., 2001) and cannabinoids (Rodriguez de Fonseca et al., 1997). Nicotine withdrawal in rats also increased CeA CRF mRNA and, especially in females, NAc CRF mRNA levels (Aydin et al., 2011, Torres et al., 2013). Conversely, amygdala CRF tissue content is reduced during acute withdrawal from ethanol exposure (Zorrilla et al., 2001, Funk et al., 2006, Wills et al., 2010) and from binge cocaine self-administration (Zorrilla et al., 2001, Zorrilla et al., 2012), suggesting degradation and depletion after sustained secretion. Supporting a functional role for central extended amygdala CRF1 receptor activation in the negative affect/withdrawal stage, site-specific injections of CRF receptor antagonists into the central amygdala reduce anxiety-like behavior, motivational deficits for other reinforcers, and excessive self-administration of addictive substances during acute withdrawal (Heilig and Koob, 2007, Heilig et al., 2010b, Koob and Zorrilla, 2010, Logrip et al., 2011, Parylak et al., 2011).

The opponent process also may involve pituitary CRF1-dependent activation of the HPA-axis, reflected by elevated ACTH and corticosteroids, because withdrawal from all drugs of abuse studied to date leads to an activated HPA stress response. Interestingly, glucocorticoids, effectors of the HPA-axis, can activate and sensitize CRF–CRF1 systems of the extended amygdala, causally linking the neuroendocrine and extrahypothalamic CRF system stress responses. Consistent with a functional role for the HPA-axis component of the opponent process, glucocorticoid receptor antagonists can reduce the development and expression of excessive alcohol self-administration that results from repeated, intermittent ethanol intoxication (Vendruscolo et al., 2012).

Of preclinical relevance, systemic injections of small molecule CRF1 receptor antagonists that block pituitary and brain CRF1 receptors can also reduce the heightened anxiety-like behavior in dependent rodents acutely withdrawn from alcohol at doses that do not alter the anxiety-like behavior of non-dependent animals (Knapp et al., 2004, Overstreet et al., 2004, Breese et al., 2005a, Breese et al., 2005b, Gehlert et al., 2007, Sommer et al., 2008). Similarly, withdrawal from the repeated administration of cocaine, nicotine, cannabinoids, opiates, and benzodiazepines produces an anxiogenic-like response that can be reversed by intracranial administration of non-selective peptide CRF receptor antagonists (Sarnyai et al., 1995, Rodriguez De Fonseca et al., 1997, Basso et al., 1999, Tucci et al., 2003) or systemic administration of brain-penetrant CRF1-selective nonpeptide receptor antagonists (George et al., 2007, Skelton et al., 2007, Park et al., 2013). Furthermore, the aversive state of opiate withdrawal and the decreased brain reward function associated with nicotine withdrawal are both CRF1 receptor-dependent (Contarino and Papaleo, 2005, Stinus et al., 2005, Bruijnzeel et al., 2007, Bruijnzeel et al., 2009, Bruijnzeel et al., 2012, Garcia-Carmona et al., 2012). Likewise, intracerebroventricular administration of a nonselective CRF1/2 antagonist ameliorated the decreased brain reward function resulting from ethanol withdrawal (Bruijnzeel et al., 2010). Supporting the motivational significance of these effects for addiction, systemic injections of small-molecule CRF1 antagonists reduced the increased alcohol intake of dependent or postdependent rodents (Sabino et al., 2006, Chu et al., 2007, Funk et al., 2007, Gehlert et al., 2007, Gilpin et al., 2008, Richardson et al., 2008) as well as the increased intravenous self-administration of cocaine (Specio et al., 2008), nicotine (George et al., 2007), and heroin (Greenwell et al., 2009) in rats with a history of extended access to the drug of abuse. Similarly, both global (Chu et al., 2007) and conditional brain-specific Crhr1 knockout (Crhr1[NestinCre]) mice (Molander et al., 2012) show reduced ethanol intake during withdrawal in the postdependent state compared with their wildtype littermates.

CRF1 receptor knockout mice also drink less 20% v/v ethanol under basal conditions (Pastor et al., 2011). Moreover, both CRF and CRF1 knockout mice show reduced ethanol intake and blood ethanol concentrations in a murine model of scheduled, limited access to ethanol (“drinking-in-the-dark”) that can produce binge-like intake (Kaur et al., 2012), suggesting an early role for CRF in neuroadaptations associated with the binge/intoxication stage of the addiction cycle. Perhaps accordingly, systemic administration of small-molecule CRF1 antagonists can reduce binge-like but not non-binge-like ethanol intake in C57BL/6J mice and outbred rats (Lowery et al., 2010, Cippitelli et al., 2012, Simms et al., 2013) (but see Giardino and Ryabinin (2013) for additional findings suggesting that these effects may not be specific for ethanol). Site-specific infusion of CRF1 antagonists into the CeA or VTA likewise could reduce heightened ethanol intake under intermittent access schedules (Lowery-Gionta et al., 2012, Hwa et al., 2013).

Many individuals who suffer from symptoms of anxiety or depression may turn to a substance of abuse for its potential anxiolytic (e.g., alcohol) or mood-enhancing (e.g., cocaine) effects (Pohorecky, 1991). By reducing dysphoria, CRF1 receptor antagonists may help treat individuals who “self-medicate” their anxious or depressed state with a drug of abuse. Consistent with this hypothesis, small-molecule CRF1 receptor antagonists reduce alcohol drinking in rodent models with high innate anxiety, including genetically selected Marchigian Sardinian alcohol-preferring rats (Ciccocioppo et al., 2006, Hansson et al., 2006, Hansson et al., 2007, Heilig and Koob, 2007, Sommer et al., 2008) and isolation-reared Fawn-hooded rats (Lodge and Lawrence, 2003) at doses that do not alter the intake of normal, outbred rodents.

We and others also found evidence that addiction-like activation of CRF systems may play a role in the motivational properties of palatable food. Specifically, rats acutely withdrawn from intermittent access to a high-sucrose, chocolate-flavored diet showed increased anxiety-like behavior (Cottone et al., 2009). As has been seen with substances of abuse, the increased anxiety-like behavior was accompanied by increased mRNA and peptide expression of CRF in the CeA; similar molecular changes were seen by Bale and colleagues in mice withdrawn from high-fat diet (Teegarden et al., 2009). Systemic pretreatment with the selective CRF1 antagonist R121919 blocked food withdrawal-associated anxiety at doses that did not alter the behavior of chow-fed controls. CRF1 antagonist pretreatment also decreased the magnitude of overeating of the palatable sucrose-rich diet by diet-cycled animals at doses that did not alter the food intake of chow-fed controls or of animals fed the sucrose-rich diet, but without a history of diet cycling. Moreover, R121919 reduced evoked inhibitory postsynaptic potentials in the CeA more in diet-cycled rats than in chow-fed controls, suggesting greater control over CeA GABAergic neurotransmission by CRF1 receptors. The findings resemble the enhanced modulatory influence of CRF1 antagonists on CeA GABAergic synaptic transmission that is seen during withdrawal from alcohol (Roberto et al., 2010). When diet-cycled animals had access to the preferred, sucrose-rich diet, both their anxiety-like behavior and CeA CRF levels normalized, supporting the hypothesis that activation of the amygdala CRF–CRF1 system helped subserve the palatable food withdrawal-like state.

Section snippets

Protracted withdrawal

Symptoms of negative affect can persist for weeks and months after detoxification from drugs of abuse (Alling et al., 1982). These negative emotional symptoms of protracted withdrawal, including anger, frustration, sadness, anxiety and guilt, are subacute and appear to be key precipitants of relapse (Hershon, 1977, Lowman et al., 1996, Zywiak et al., 1996, Annis et al., 1998) in the preoccupation/anticipation stage of addiction. Neuroadaptations in amygdala CRF1 systems have been proposed to

Stress-induced reinstatement

Exposure to external stressors can also increase drug craving (Childress et al., 1994, Cooney et al., 1997, Sinha et al., 2000) and lead to relapse. This stress-induced relapse is hypothesized to be motivated by self-medication of the associated negative emotional symptoms of stress (Lowman et al., 1996, Zywiak et al., 1996), in a fashion similar to self-medication of symptoms of protracted withdrawal, but here elicited by external stimuli. Consistent with this hypothesis, systemic injection of

Corticotropin-releasing factor, stress, and the frontal cortex

Converging evidence may link the impairment of medial prefrontal cortex (mPFC) cognitive function, activation of CRF in the PFC, and overactivation of the CeA with the development of compulsive-like responding for drugs of abuse, again suggesting a role for CRF in the binge/intoxication stage of the addiction cycle (Briand et al., 2008a, Briand et al., 2008b, George et al., 2008). Extended access to drugs of abuse, such as cocaine self-administration, can induces a compulsive-like pattern of

Clinical trials of CRF1 receptor antagonists in addiction

Collectively, the reviewed studies demonstrate a key role for brain CRF1 receptors in three addiction-related domains: (1) negative emotional symptoms of acute and protracted withdrawal that can occur sans exteroceptive stress, (2) escalated, compulsive-like substance intake (e.g., with substance dependence), and (3) stress-induced relapse to substance seeking. Accordingly, small-molecule CRF1 antagonists are currently in clinical trials for stress-related aspects of the addiction process.

Functional and genetic heterogeneity of substance use disorders

The effectiveness of medications for substance use disorders differs across individuals and even within individuals at different times of their disease process (Heilig et al., 2010b, Heilig et al., 2011, Koob and Zorrilla, 2010, Logrip et al., 2011, Logrip et al., 2012). Based on the reviewed evidence, CRF1 receptor antagonists would be expected to be most effective if substance use has transitioned to use driven by negative reinforcement (withdrawal/negative affect) and to protect against

CRF2 systems and addiction

Whereas CRF1 systems are generally recognized to exert an overarching, pro-stress-like effect, CRF2 receptor activation may, in addition to suppressing food intake (Spina et al., 1996, Inoue et al., 2003, Fekete et al., 2007), decrease stress responsiveness (Valdez et al., 2002a, Valdez et al., 2003a). In the context of addiction-related behavior, intracerebroventricular infusion of Ucn 3, a selective CRF2 agonist, reduced the heightened anxiety-like behavior and increased ethanol

CRF2 receptors in stress-induced reinstatement

CRF2 receptors outside the extended amygdala have been suggested to act in concert with CRF1 receptors to facilitate aspects of compulsive-like drug seeking. VTA CRF2 receptors have been proposed to facilitate stress-induced reinstatement of cocaine seeking, in which footshock exposure in cocaine-experienced rats elicited the release of extended amygdala-derived CRF into the VTA (Wang et al., 2005). The CRF-mediated stress-induced reinstatement of cocaine seeking is putatively mediated by the

CRF2 receptor and opioid withdrawal

Recent studies have obtained evidence that the CRF2 receptor may play a key role in opiate withdrawal. First, whereas knockout of the CRF1 receptor exacerbated the somatic signs of opiate withdrawal (Papaleo et al., 2007), genetic deletion of the CRF2 receptor blocked the somatic signs of opiate withdrawal (Papaleo et al., 2008). Moreover, CRF2 knockout mice did not manifest the dysphoria-like or anhedonia-like behaviors of opiate withdrawal (Ingallinesi et al., 2012), whereas they showed

Urocortin 1 and alcohol intake

In the brain, Ucn 1, which has equal activity at CRF1 vs. CRF2 receptors, is synthesized principally in cell bodies of the stress-responsive (Korosi et al., 2005) perioculomotor Ucn 1-containing area (pIIIu), now also known as the nonpreganglionic Edinger–Westphal nucleus (Weitemier et al., 2005), and, to a lesser extent, in the lateral superior olive (Vaughan et al., 1995, Ryabinin et al., 2005). Ucn 1 was first implicated in alcohol consumption based on the preferential induction of Fos

Concluding remarks

On a personal note, Wylie Vale was the impetus and driving force behind our early work on the role of CRF in behavioral responses to stressors. We (Floyd Bloom, George Siggins, and myself, George Koob) joined Vale on the NIH program project grant from the National Institute on Diabetes and Digestive and Kidney Diseases when CRF was discovered in 1981. We subsequently injected CRF into the brain of rats and charted their behavioral responses in collaboration with Vale and colleagues (Sutton et

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