Abstract
The neuropeptide, corticotropin releasing factor (CRF), has been an enigmatic target for the development of medications aimed at treating stress-related disorders. Despite a large body of evidence from preclinical studies in rodents demonstrating that CRF receptor antagonists prevent stressor-induced drug seeking, medications targeting the CRF-R1 have failed in clinical trials. Here, we provide an overview of the abundant findings from preclinical rodent studies suggesting that CRF signaling is involved in stressor-induced relapse. The scientific literature that has defined the receptors, mechanisms and neurocircuits through which CRF contributes to stressor-induced reinstatement of drug seeking following self-administration and conditioned place preference in rodents is reviewed. Evidence that CRF signaling is recruited with repeated drug use in a manner that heightens susceptibility to stressor-induced drug seeking in rodents is presented. Factors that may determine the influence of CRF signaling in substance use disorders, including developmental windows, biological sex, and genetics are examined. Finally, we discuss the translational failure of medications targeting CRF signaling as interventions for substance use disorders and other stress-related conditions. We conclude that new perspectives and research directions are needed to unravel the mysterious role of CRF in substance use disorders.
Keywords: CRF, Stress, Relapse, Review, Addiction, Substance use disorder
Introduction
The ability to avoid and escape threats in our environment is critical for survival. Moreover, when faced with duress, selection of the most economically viable pattern of behavior is essential for coping and adaptation. To ensure effective responses to threatening stimuli, the influence of stress on the brain is pervasive and includes brain systems that underlie learning, motivation, and affect, thus shaping behavior through a complex coordination of neurotransmission and glial function that influences the brain at the network level. To understand the impact of stress on the brain it is necessary to move beyond basic constructs (e.g., reward and aversion) and consider its influence from the perspective of more complex processes that guide behavior to promote survival and adaptation. Notably, many of these processes also contribute to drug seeking and misuse in those with substance use disorders (SUDs), thus establishing a close link between stress and drug addiction.
Neuropeptides are well-suited to mediate the influence of stress on the brain (see [1] for review). They are co-released with neurotransmitters/monoamines, but under only conditions of higher frequency stimulation. Their release pattern is slower, and their duration of action is prolonged due to reliance on diffusion and proteolysis for clearance. For the same reason, the field of influence of neuropeptides is relatively large and can include extrasynaptic sites as well as adjacent synapses and cells. This, along with the complexity of signaling related to receptor distribution on neurons an astrocytes, receptor/signaling diversity, and peptide processing, positions neuropeptides as effective regional coordinators of network activity. Finally, via transcriptional/translational control, neuropeptide signaling can be scaled via genomic effects of stress hormones independently from the neurotransmitters/modulators with which they are co-released. While a number of neuropeptides are involved in stress/stress-related responses, the neuropeptide corticotropin releasing factor (CRF) has been implicated in many of the behavioral responses to stressors.
CRF, also known as corticotropin releasing hormone (CRH), is a 41 amino acid neuropeptide encoded by the CRH gene. CRF is conserved across species with a seven amino acid difference in sequence between rodents and human. CRF produces acts via two receptors, both of which are primarily Gs G-protein coupled but also signal via other pathways (see [2] and [3] for review): 1) the CRF-R1 receptor, encoded by the CRHR1 gene, which has a higher affinity for CRF and has a relatively widespread expression pattern in the brain and 2) the CRF-R2 receptor, encoded by the CRHR2 gene, which has a lower affinity for CRF and a more restricted pattern of expression. There are two splice variants of CRF-R2: CRF-R2 α and β. The CRF-R2 receptor binds preferentially to a family of CRF-related peptides, the urocortins. CRF also binds to a binding protein with subnanomolar affinity. The 322 amino acid CRF binding protein is a glycoprotein encoded by the CRHBP gene that is widely expressed in the brain and is colocalized with CRF (see [4] for review). Depolarization-dependent release of CRF binding protein from neurons has been reported [5]. In addition to binding to CRF to limit its binding to CRF receptors, there is evidence that CRF binding protein may interact with CRF receptors, specifically CRF-R2, to create a unique signaling complex [6,7].
Beyond parvocellular neurons in the PVN of the hypothalamus which release CRF into the adenohypophyseal microcirculation via the median eminence to regulate anterior pituitary corticotrope adrenocorticotropic hormone (ACTH) secretion, CRF is released into a number of brain structures from both interneurons and projecting neurons that reside in the hypothalamus and non-hypothalamic structures. Subpopulations of neurons co-release CRF with GABA or glutamate (see e.g., [8]). Like other neuropeptides, CRF is released via dense core vesicles under high-frequency stimulation conditions that are distinct from those that release co-neurotransmitters via clear vesicles, thus enabling independent regulation of CRF and co-transmitter release. Moreover, CRF levels can be scaled via changes in transcription/translation and processing. CRF receptors are also expressed by astrocytes (see e.g., [9]). CRF mRNA is expressed in multiple brain regions in addition to the hypothalamus, most notably the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis – brain regions that have been implicated in emotional processing and interface with mesocorticolimbic system [10–12]. Additionally, CRF is evident throughout the neocortex, particularly the prefrontal cortex. Cortical CRF-expressing cells are primarily GABAergic interneurons [13]. CRF production in the ventral tegmental area (VTA) [14] and hindbrain regions, such as locus coeruleus [15] has also been reported. By contrast, urocortin expression is largely confined to the Edinger-Westphal nucleus in the midbrain [16]. Although expression varies by region, CRF receptor binding [17,18] and mRNA [19–21] can be found throughout the brain, including in regions that comprise the extended amygdala and mesocorticolimbic system (e.g., VTA, nucleus accumbens), and, overall, aligns well with the distribution of CRF-immunoreactive axon terminals. The positioning of the CRF system at the interface between brain networks that process negative emotional stimuli and those involved in reward processing and motivation establishes it as an important mechanism through which aversive stimuli in our environment can guide behavior and contribute to SUDs.
CRF contributions to SUDs
While the contribution of CRF to SUDs is complex and involves the regulation/dysregulation of a variety of constructs and corresponding neurocircuits, its influence can be roughly attributed to two domains. First, at least in rodent models, CRF appears to be a critically important mediator of the effects of stressors on drug seeking. Second, it has been proposed that, along with other “anti-reward “ systems (e.g., dynorphin/kappa opioid), CRF signaling in the brain is recruited with repeated drug use, thus establishing an emergent dysphoric state and allostatic dysregulation of hedonic processing that promotes drug seeking and escalates drug intake through negative reinforcement. This intake-dependent recruitment of CRF signaling may also amplify stressor-induced CRF responses, thus augmenting the impact of stress in SUDs, including its effects on relapse susceptibility. The current review examines the contribution of CRF signaling to stressor-induced relapse. First, brain circuitry and CRF mechanisms that contribute to stressor-induced drug seeking are reviewed. Second, evidence that the recruitment of CRF signaling with excessive drug use heightens risk for stressor-induced drug seeking is presented. Third, factors that may influence the impact of CRF in SUDs, including development, biological sex, and genetics are examined. Finally, clinical studies that raise significant questions about whether or not the CRF system is a viable target for pharmacotherapeutic interventions in human populations with SUDs are summarized.
Contribution of CRF signaling to stressor-induce drug seeking
Stressor-induced relapse
While there is evidence that stress can facilitate the acquisition of drug self-administration and promote escalating patterns of drug use, much research has focused on the mechanisms through which stressors induce relapse to drug use in those with SUDs (see [22] for review). Indeed, the persistently heightened risk for relapse even after protracted periods of abstinence is perhaps the most significant obstacle to the effective management of SUDs. While the relationship between stress and drug use is complex [23–25], measures of stress during the preceding day can predict drug use [26], and high stress levels upon the initiation of treatment predict poor outcomes (i.e., early dropout; [27,28]). Laboratory studies have consistently demonstrated that personalized stress imagery can induce craving in those with SUDS (see e.g., [29–31]), and the magnitude of stress-induced craving in inpatient abstinent users is predictive of subsequent risk for relapse to drug use [32,33].
Stressor-induced reinstatement in rodents
In rodents, stress-induced drug seeking can be evaluated by assessing the ability of stressors to reinstate extinguished nose poking or lever pressing following self-administration or their capacity to re-establish place preference following cocaine conditioning and extinction (see [22] for review). A variety of stressors have been demonstrated to reinstate drug seeking following self-administration in rats, including intermittent footshock, food restriction, forced swim, intraoral quinine, and social defeat predicting cues. Likewise, various stressors have been found to reinstate place preference following conditioned place preference in mice, including intermittent footshock, social defeat, restraint, forced swim, yohimbine, and conditioned fear-predictive cues. Despite differences in the species typically used, the contingency of drug delivery, the patterns/amounts of drug exposure, and the learning constructs involved, there is quite a bit of overlap between the two approaches in terms of the contributing neurobiological mechanisms. While these approaches have their limitations (e.g., reliance on extinction, lack of alternative reinforcers, etc…), they have been used effectively to examine the contribution of CRF to stress induced drug seeking, despite a general lack of findings that have translated well to SUDs in in humans.
CRF and stressor-induced drug seeking
It is well-established that CRF contributes to stressor-induced drug seeking in animal models of craving/relapse (see Table 1). Following intravenous cocaine self-administration and extinction, systemic or intra-cerebroventricular (icv) delivery of CRF receptor antagonists prevents footshock-induced reinstatement of cocaine [34–36], heroin [34,37], alcohol [38,39], methamphetamine [40] and nicotine [41,42] seeking. Similar effects can be observed with other stressors, including yohimbine administration [43] (but see [44]) and food deprivation [45], following self-administration in rats and forced swim stress following conditioned place preference in mice [46,47] or footshock following conditioned place preference in rats [48]. Moreover, central (icv) administration of CRF is sufficient to induce alcohol [49], heroin [37], and cocaine [50–52] seeking following self-administration and extinction. The contribution of CRF to stressor-induced drug seeking is largely independent of its hypothalamic–pituitary–adrenal (HPA) axis effects. When the corticosterone response is eliminated by surgical adrenalectomy along with physiological corticosterone replacement or by the inhibition of synthesis via the 11 β-hydroxylase inhibitor metyrapone, footshock-induced reinstatement of heroin [37,38], alcohol [38] and cocaine [35,36] seeking persists. Similarly, surgical adrenalectomy/corticosterone replacement fails to prevent the reinstatement of cocaine seeking by icv CRF [36]. Although results have been mixed (see e.g., [39]), it has been reported that reinstatement by drug-associated cues is also CRF-dependent [53]. Notably, the presentation of drug cues also produces anxiety/stress responses in rodents and humans that likely contribute to craving and use [54,55]. In rats, these responses have been reported to be CRF-dependent [56]. Results with drug-primed reinstatement have been mixed with full blockade ([53], methamphetamine), partial blockade ([35], cocaine; [37], heroin), or no effects ([36], cocaine) reported.
Table 1.
Studies demonstrating decreases in stressor-induced reinstatement of drug seeking following CRF receptor antagonism/knockdown.
Drug | Stressor | Species | Sex | Procedure | CRF Ant/Rec | Route | Ref |
---|---|---|---|---|---|---|---|
Alcohol | Footshock | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | icv | [38] |
Alcohol | Footshock | Rat | M | SA/ext | CP-154,526 (R1) | ip | [38] |
Alcohol | Footshock | Rat | M (msP or dep) | SA/ext | MTIP (R1) | ip | [200] |
Alcohol | Footshock | mSP rats | M | SA/ext | Antalarmin (R1) | ip | [239, 336] |
Alcohol | Footshock | Rats | M | SA/ext | d-Phe-CRF (R1/R2) | icv | [38, 39] |
Alcohol | Footshock | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | intra-MRN | [49] |
Alcohol | Yohimbine | Rat | M | SA/ext | Antalarmin (R1) | ip | [43] |
Alcohol | Yohimbine | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | intra-MRN | [140] |
Alcohol | Yohimbine | iP rats | M | SA/ext | CP376395 (R1) | intra-NI | [145] |
Alcohol | U50,488 (KOR agonist) | Rat | M | SA/ext | Antalarmin (R1) | ip | [361] |
Cocaine | Footshock | Rat | M | SA/ext | CP-154,526 (R1) | sc | [34] |
Cocaine | Footshock | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | icv | [35] |
Cocaine | Footshock | Rat | M | SA/ext | α-helical CRF (R1/R2) | icv | [36] |
Cocaine | Footshock | Rat | M | SA/ext | α-helical CRF (R1/R2) | intra-VTA | [75] |
Cocaine | Footshock | Rat | M | SA/ext | Antalarmin (R1) | Intra-VTA | [70, 76] |
Cocaine | Footshock | Rat | M | SA/ext | Antisauvagine-30 (R2) | intra-VTA | [102] |
Cocaine | Footshock | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | intra-BNST | [62] |
Cocaine | Footshock | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | Disconnection: intra-BNST d-Phe-CRF with intra-CeA TTX | [63] |
Cocaine | Footshock | Rat | M | SA/ext | Antalarmin (R1) | Disconnection: intra-VTA antalarmin with intra-BNST ICI118,551 | [70] |
Cocaine | Footshock | Rat | M | SA/ext | Antalarmin (R1) | Disconnection: intra-VTA antalarmin with intra-PFC SCH23390 | [129] |
Cocaine | Food deprivation | Mouse | M | SA/ext | shRNA knockdown (R1) | VTA | [103] |
Cocaine | icv NE | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | icv | [44] |
Cocaine | Intraoral quinine | Rat | M | SA/ext | CP-376395 (R1) | Intra-VTA | [104] |
Cocaine | Forced swim | Mouse | M | CPP/ext | Antalarmin (R1) | ip | [47] |
Heroin | Footshock | Rat | M | SA/ext | CP-154,526 | sc | [34] |
Heroin | Footshock | Rat | M | SA/ext | α-helical CRF (R1/R2) | icv | [37] |
Heroin | Food deprivation | Rat | M | SA/ext | α-helical CRF (R1/R2) | icv | [45] |
Methamphetamine | Footshock | Rat | M | SA/ext | α-helical CRF (R1/R2) | icv | [40] |
Morphine | Forced swim | Rat | M | CPP/ext | NBI 35965 (R1) | Intra-DRN | [139] |
Morphine | Footshock | Rat | M | CPP/ext | CP-154,526 (R1) | Intra-BNST | [48] |
Nicotine | Footshock | Rat | M | SA/ext | d-Phe-CRF (R1/R2) | icv | [41] |
Nicotine | Footshock | Rat | M | SA/ext | R278995/CRA0450 (R1) | icv | [42] |
Nicotine | Footshock | Mouse | M | SA/ext | Antalarmin (R1) | sc | [362] |
Abbreviations: SA: self-administration; CPP: conditioned place preference; ext: extinction; R1: CRF-R1 receptor; R2: CRF-R2 receptor; MRN: medial raphe nucleus; NI: nucleus incertus; VTA: ventral tegmental area; BNST: bed nucleus of the stria terminalis; PFC: prefrontal cortex; DRN: dorsal raphe nucleus; iP: inbred alcohol preferring; mSP: Marchigian Sardinian alcohol-preferring.
The contribution of CRF signaling to SUDs, most frequently alcohol use disorder, has also been studied using transgenic mice. Although effects on reinstatement have not been reported, studies have examined the effects of CRF, CRFR1, CRFR2, and CRF binding protein knockout, as well as CRF overexpression on alcohol consumption in dependent, non-dependent and stressor exposed mice. CRF knockout mice consume more alcohol, apparently due to reduced sensitivity to alcohol rewarding effects [57], while CRF overexpressing mice consume less alcohol, an effect associated with enhanced alcohol-induced sedation [58]. Although there have been some reports that global CRFR1 knockout reduces high-concentration alcohol consumption ([59] and prevents increased consumption in dependent [60] and sensitized [61] mice, others have found that global CRFR1 knockout increases alcohol consumption following repeated stress [62] and in dependent mice [63]. This unexpected observation is likely attributable to opposing effects of brain and peripheral (e.g., pituitary) CRFR1 receptors as brain-specific deletion of CRFR1 prevents increases in alcohol consumption following stress and in dependent mice [63]. CRFR1 knockout also reduces anxiety-related behaviors during alcohol withdrawal [64]. By contrast, CRFR2 [65] or CRF binding protein [66] knockout alone has little effect on alcohol consumption in dependent or non-dependent mice, although combined CRFR1 and R2 knockout has been reported to prolong the effects of chronic stress on consumption [59]. Fewer studies have used transgenic mice to investigate the contribution of CRF signaling to the consumption of other drugs. CRFR1 knockout mice are more sensitive to cocaine-induced conditioned place preference [67] and less sensitive to opiate withdrawal [68,69].
Pathways and mechanisms that underlie the contribution of CRF to stressor-induced drug seeking
Considering the role of CRF in coordinating adaptive responses to stressors, it is not surprising that the sites at which CRF influences drug seeking involve those that serve as interfaces between brain systems that are implicated in stress and negative affect and those involved in motivation. These sites include structures that comprise the extended amygdala (i.e., BNST, CeA, NAc shell) and midbrain regions that contain cell bodies for monaminergic projections into the corticolimbic system, most notably the VTA and dorsal raphe nuclei. Through actions in these brain regions, CRF coordinates healthy adaptive behaviors across a range of functional domains to promote survival under duress. In the context of SUDs many of these actions are maladaptive and promote drug seeking. The brain regions and CRF mechanisms that have been implicated in stressor-induced drug seeking are summarized briefly below and depicted in Fig. 1.
Fig. 1. Brain regions in which CRF signaling contributes to stressor-induced cocaine seeking in rodents.
Brain regions into which CRF receptor antagonist micro-infusions prevent stressor-induced drug seeking following self-administration or conditioned place preference and extinction (see text and Table 1 for details). Regions are segregated according to the involvement of CRF-R1 and CRF-R2 in stressor-induced cocaine seeking with supporting references listed.
Extended amygdala
The extended amygdala is a network of structures that includes the bed nucleus of the stria terminalis (BNST), the central amygdala (CeA), and the nucleus accumbens (NAc) shell that is involved in emotional processing and closely interfaces with brain networks that mediate reward and motivation. The extended amygdala is heavily influenced by stressors and is rich in neuropeptides, including CRF, as well as neuropeptide signaling molecules, including CRF receptors and CRF binding protein. The BNST, CeA, and NAc shell have all been implicated in stressor-induced drug seeking. Each of these regions shows increased Fos reactivity following stressor-induced drug seeking and pharmacological inactivation of each region prevents swim-induced cocaine seeking following conditioned place preference in mice and/or shock-induced reinstatement following self-administration in rats [70]. The contributions of CRF signaling in each of these regions to stressor-induced drug seeking are summarized below.
BNST.
The BNST functions as an interface between stress and motivational/reward systems and is particularly important for stressor-induced drug seeking. Inactivation of the ventral BNST prevents stressor-induced reinstatement following cocaine self-administration in rats [70] and conditioned place preference in mice [71]. CRF [10–12], CRF receptors [17–20] and CRF binding protein [72] are all expressed in the BNST, and stressor-induced drug seeking is associated with BNST Fos expression. The source of CRF released into the BNST includes both neurons intrinsic to the region and CRF-releasing afferents, most notably from the medial preoptic area, PVN, and medial and central (CeA) regions of the amygdala [73]. CRF mRNA expression in the BNST is increased following swim stress-induced reinstatement of CPP in mice [47] or shock-induced heroin seeking following self-administration in rats [74]. Moreover, intra-BNST (ventral) micro-infusions of the non-selective CRF receptor antagonist, D-Phe CRF(12–41), prevent footshock-induced reinstatement of cocaine seeking following self-administration in rats [75], while intra-BNST administration of the CRFR1 antagonist, CP-154,526, prevents footshock induced reinstatement of morphine seeking following conditioned place preference in rats [48]. The source of CRF in the BNST that mediates stressor-induced drug seeking likely arises, in part, from the CeA. Disconnection of the CeA-to-vBNST CRF pathway by TTX micro-infusion into the CeA in one hemisphere and D-Phe CRF(12–41) micro-infusion into the contralateral ventral BNST attenuates footshock-induced reinstatement of cocaine seeking following self-administration in rats [76]. Notably, this blockade is partial, suggesting contributions of other CRF or non-CRF mechanisms to reinstatement. Moreover, this observation does not preclude involvement of CRF-releasing cells within the BNST.
CRF release in the BNST is influenced by a variety of neuromodulators (reviewed in [77]). The BNST is heavily innervated by noradrenergic projections. Specifically, projections from the A1 and A2 lateral tegmental medullary cell groups via the ventral noradrenergic bundle to the BNST appear to mediate stressor-induced drug seeking, as 6-OHDA lesions of these cell groups attenuate shock-induced drug seeking while pharmacological inhibition of locus coeruleus noradrenergic neurons has no effect [78]. In particular, noradrenergic signaling via beta-adrenergic receptors appears to be critical for stressor-induced drug seeking [79,80]. Beta adrenergic receptors are expressed in the BNST [81], and prior work has found that bilateral micro-infusions of a beta-1/beta-2 adrenergic receptor antagonist cocktail into the BNST attenuates shock-induced reinstatement following self-administration in rats [82]. We have demonstrated that, similar to what is observed with systemically administered receptor antagonists and swim-induced reinstatement following conditioned place preference in mice [47], shock-induced cocaine seeking following self-administration in rats is prevented by intra-BNST micro-infusions of the beta-2 receptor antagonist, ICI-118,551, but not the beta-1 receptor antagonist, betaxolol, and is reproduced by intra-BNST micro-infusions of the beta-2 adrenergic receptor agonist, clenbuterol, but not the beta-1 receptor agonist, dobutamine [83].
Beta adrenergic receptor activation in the BNST regulates CRF to induce drug seeking. Reinstatement of cocaine seeking by icv norepinephrine following self-administration in rats [44] or by systemic administration of the beta-2 receptor agonist clenbuterol following conditioned place preference in mice [47] is blocked by CRF receptor antagonism. In mice, systemic clenbuterol administration also increases CRF mRNA levels in the BNST [47], while intra-BNST administration of the CRF-R1 receptor antagonist, antalarmin, prevents reinstatement of cocaine seeking in response to intra-BNST administration of clenbuterol [83]. A series of studies by Winder and colleagues have demonstrated that beta adrenergic receptors promote excitatory regulation of key BNST output pathways involved in cocaine seeking via a mechanism that likely requires CRF release from a local population of neurons intrinsic to the BNST and BNST CRF-R1 receptor activation [84,85]. These pathways include CRF-positive neurons that innervate the VTA [85–87], where CRF receptor activation is required for stressor-induced cocaine seeking ([88,89]; see below). Indeed, bath application of the non-selective beta-adrenergic receptor agonist, isoproterenol, promotes excitatory synaptic regulation of retro-labeled VTA-projecting CRF-positive neurons via CRF-R1-dependent glutamate release in the BNST [85]. The BNST-VTA projection is comprised of both GABAergic and glutamatergic neurons [90]. However, it has been reported that CRF-positive neurons that project from the BNST to VTA [83,87] are primarily GABAergic [8]. To confirm that beta-2 adrenergic receptor regulation of a projection from the ventral BNST that releases CRF into the VTA mediates stressor-induced cocaine seeking, we deployed a pharmacological disconnection approach in which we administered the beta-2 adrenergic receptor antagonist, ICI-118,551, into the BNST in one hemisphere and the CRF-R1 antagonist, antalarmin, into the contralateral VTA. Using this approach, we confirmed that the ability of footshock to reinstate cocaine seeking in rats following self-administration requires beta-2 adrenergic receptor activation of a vBNST pathway that releases CRF into the VTA and activates CRF-R1 receptors [83].
CeA.
CRF as well as its receptors and binding protein are expressed in the CeA. Activation of the CeA is required for footshock-induced cocaine seeking [70] and stressor-induced drug seeking are associated with increased CeA Fos expression [91]. CRF mRNA levels also increase with stressor-induced drug seeking [74]. While there are CRF-positive CeA projections to the VTA [87], it has been proposed that a CRF-releasing excitatory pathway from the CeA to the BNST is critical for stressor-induced drug seeking [76]. Consistent with findings that beta-1 adrenergic receptors are expressed on CRF-positive neurons in the CeA and regulate CRF expression [92], it has been found that CeA beta-adrenergic receptor activation is required for shock-induced cocaine seeking [82] and that drug seeking in response to centrally administered norepinephrine [44] or systemic administration of a beta-2 adrenergic receptor agonist [47] is blocked by pretreatment with a CRF-R1 antagonist. CRF-R1 in the CeA has been heavily implicated in SUDs (see e.g., [93] for review). However, while roles for CRF-R1 signaling in withdrawal-related dysphoria (see e.g., [94, 95]) and escalating patterns of drug intake (see e.g., [96–98]) have been identified, the contribution of CRF-R1 receptors to stressor-induced drug seeking has not been well-characterized. Erb et al [75] reported that intra-CeA administration of the CRF receptor antagonist, D-Phe CRF(12–41), failed to affect footshock-induced cocaine seeking following self-administration in rats. However, recently, it has been demonstrated that targeted overexpression of CRFR1 in CaMKII neurons the CeA augments stressor-induced alcohol seeking [99]. Moreover, it has been found that intra-CeA micro-infusions of the CRF-R1 antagonist, CP-154,526, prevent drug-primed but not footshock-induced reinstatement of morphine seeking following conditioned place preference in rats [48].
Nucleus accumbens.
One region in which the contribution of CRF signaling to drug seeking has been surprising understudied is the nucleus accumbens (NAc). The NAc receives CRF-positive inputs from the BNST [100] and, likely, the CeA [101], and NAc expression of CRF [102,103] and its receptors [18] has been reported. NAc CRFR1 and R2 expression is both pre- and post-synaptic [104] and includes localization to cholinergic interneurons [105]. Recently, it has been reported that optical stimulation of CRF neurons in the NAc can increase incentive motivation for a non-drug reward [106], similar to the effects of intra-NAc CRF micro-infusions [107]. Moreover, intra-NAc CRF can influence effortful choice [108]. Further, in naïve rats, CRF micro-infusions into the NAc produce arousal [109] increase dopamine [104], and support place preference [104]. Despite, these observations, the contribution of NAc CRF signaling to stressor-induced cocaine seeking is unclear. One study has reported an enhancement of nicotine self-administration by CRF-R1 overexpression in the NAc core [110], while the CRF projection from the CeA to the NAc core appears to attenuate alcohol drinking [101].
Ventral tegmental area
The VTA is key site for CRF regulation of drug seeking. Both CRF-R1 and CRF-R2 receptors [21,111,112] as well as the CRF binding protein [113] are expressed in the region. The VTA receives CRF-releasing inputs from several brain regions implicated in stress-related hormonal and behavioral responses, most notably the CeA, the paraventricular nucleus of the hypothalamus, and BNST [87]. There is also evidence for local VTA CRF release [14]. During footshock-induced reinstatement of cocaine seeking, extracellular levels of CRF in the VTA are elevated in rats [88]. Moreover, intra-VTA CRF delivery is sufficient to reinstate cocaine seeking [88,89,114].
There is evidence for involvement of both CRF-R1 and CRF-R2 receptors in the VTA in stress-induced drug seeking. We have found that, following self-administration and extinction in rats, VTA CRF-R1 but not CRF-R2 receptors are necessary for CRF- and footshock-induced reinstatement. VTA micro-infusions of the CRF-R1-selective antagonists antalarmin or CP-376395 blocked reinstatement following in intra-VTA CRF or footshock while micro-infusions of the CRF-R2 antagonists astressin2B or antisauvagine-30 had no effect. Moreover, activation of VTA CRF-R1 receptors alone was sufficient to reinstate cocaine seeking [89]. Intra-VTA micro-infusions of the selective CRF-R1 receptor agonist cortagine but not the selective CRF-R2 agonist, rat urocortin 2, reproduced the reinstating effects of stress and CRF on cocaine seeking. Consistent with these reports, it has been found that knockdown of CRF-R1 receptors in the VTA blocks cocaine seeking following acute food deprivation or cocaine cues in mice [115]. We have also found that VTA CRF-R1 antagonism prevents cocaine seeking in response to intraoral delivery of the aversive tastant, quinine [116]. VTA CRF-R2 receptors have also been implicated in stressor-induced drug seeking. Others have reported that footshock-induced reinstatement of cocaine seeking following self-administration and extinction requires CRF-R2 but not - R1 receptors in the VTA [88,114]. In line with findings that CRF can potentiate NMDA receptor mediated synaptic transmission in the VTA via a mechanism that requires interaction with the CRF binding protein [6], it has been reported that binding protein interactions in the VTA are also required for stressor-induced cocaine seeking and associated neurochemical effects [114]. The reasons for the disparate findings regarding CRF mechanisms of action in the VTA are unclear but may be related to differences in the mode and duration of CRF/antagonist delivery, the self-administration history of the rats, and other experimental parameters.
As noted above, the VTA receives CRF-positive projections from several brain regions, most notably the CeA, paraventricular nucleus of the hypothalamus, and the BNST [87]. We have found that that BNST projections to the VTA are critical for stressor-induced drug seeking. Overall, these projections are comprised of both GABAergic and glutamatergic neurons [90,117]. However, the CRF-positive neurons that project from the BNST to the VTA are primarily GABAergic [8]. Consistent with reports that that stressor-induced cocaine seeking requires beta-2 adrenergic [83] and CRF-R1 [75,83] receptor activation in the BNST, it has been found that ex vivo beta adrenergic receptor agonist application to brain slices containing BNST promotes excitatory synaptic regulation of retro-labeled VTA-projecting CRF-positive neurons via CRF-R1-dependent glutamate release [85]. We have used a pharmacological disconnection approach in which we micro-infused the beta-2 adrenergic receptor antagonist, ICI-118,551, into the BNST in one hemisphere and the CRF-R1 antagonist, antalarmin, into the contralateral VTA and demonstrated that a beta-2 receptor regulated CRF-releasing projection from the BNST to the VTA is required for shock-induced reinstatement of cocaine seeking following self-administration in rats [83]. Although a role for CRF release from neurons originating in other brain regions in stressor-induced drug seeking has not been confirmed, it has been demonstrated that CeA inhibition prevents stress-induced cocaine seeking, suggesting that there may be a potential contribution of CeA-VTA projection CRF release [70].
A detailed overview of CRF actions in the VTA is beyond the scope of this review. Consistent with its proposed role as a regional coordinator of adaptive responses and with the heterogeneity of the VTA, CRF regulates a variety of cell types (dopaminergic non-Ddopaminergic, interneurons, glia) at both pre- and post-synaptic sites in a manner that appears to vary across synapses defined according to VTA inputs and outputs, signaling contexts, and pharmacological/environmental histories. CRF has been reported to promote both excitatory [6,112,118,119] and inhibitory [120] transmission in the VTA and alter synaptic integration via intracellular calcium mobilization in dopaminergic cells [121]. Additionally, CRF promotes glutamate release in the VTA [88], a finding that is consistent with reports that CRF also increases the frequency of AMPAR-mediated spontaneous miniature EPSCs in dopaminergic cells in slice preparations [119] and can attenuate GABA release via CRFR2 receptors [122]. The effects of CRF signaling on VTA outputs that lead to drug seeking have been largely assumed to be a function of enhanced excitatory transmission [123]. Accordingly, intra-VTA CRF delivery increases local DA release measured during reinstatement testing [88], and glutamate receptor antagonism in the VTA prevents both increases in local dopamine levels and stressor- and CRF-induced reinstatement [88]. However, stressor effects on neuronal firing in VTA are not uniform and firing patterns and downstream dopamine release can vary according to output pathway. Whereas stressors reliably produce robust activation of VTA neurons that project to the PFC [124–127], effects on NAc dopamine are more complex (see [128] for review) with reports of increases, reductions, or no effect, depending on the NAc subregion, stressor, context, and timeframe [116,129–138].
Shock-induced cocaine seeking is associated with CRF-dependent increases in extracellular dopamine in the VTA [88]. However, CRFR1 expression on VTA neurons varies depending on output pathway [139] while midbrain CRF-R1 deletion selectively reduces dopamine release in the PFC [140]. CRF micro-infusions into the VTA have been reported to reduced NAc dopamine signaling [137]. We reported that VTA CRF-R1 antagonism prevents quinine-induced cocaine seeking and corresponding reductions in NAc shell dopamine [116]. Moreover, we found that reinstatement by intra-VTA CRF administration is prevented by intra-VTA pretreatment with a GABA-B receptor antagonist [141], suggesting that aversive stimuli may produce CRF-R1 dependent drops in NAc dopamine that can promote drug seeking, potentially by removing inhibitory regulation of medium spiny neurons by D2 receptors.
By contrast we have found that CRF-R1 receptor activation of VTA dopamine neurons the project to the prelimbic prefrontal cortex is required for stressor-induced cocaine seeking [142]. Consistent with findings by our lab and others that shock-induced cocaine seeking in rats is blocked by dopamine D1 receptor antagonist micro-infusions into the prelimbic cortex [70,143] and by chemogenetic (Designer Receptor Exclusively Activated by Designer Drug-based) inhibition of prelimbic PFC-projecting VTA neurons [142], we have found that pharmacological disconnection of the VTA-prelimbic cortex pathway by administration of the CRF-R1 antagonist, antalarmin, into the VTA in one hemisphere, and administration of the D1 receptor antagonist SCH 23390 into the prelimbic cortex of the contralateral hemisphere prevents shock-induced cocaine seeking following self-administration in rats [142].
Altogether findings from our laboratory suggest that CRF-releasing inputs from the BNST produce CRF-R1 dependent activation of VTA neurons that project to the prelimbic PFC resulting in D1-dependent augmentation of excitatory regulation of pyramidal neuron PFC outputs, most notably those projecting to the NAc core [70] to induce cocaine seeking. At the same time, CRF-R1 mediated inhibition of NAc-projecting neurons, potentially through effects on GABAergic transmission, reduce NAc dopamine levels, thus reducing tone on D2Rs and dis-inhibiting medium spiny neuron outputs.
Raphe nuclei
The medial and dorsal raphe nuclei (MRN and DRN), localized to the midbrain, are among the most rostral nuclei of the raphe cluster and send serotonergic projections throughout the brain, including to structures in the extended amygdala and mesocorticolimbic system. The contribution of serotonin to drug seeking is complex and varies with receptor and context (see e.g., [144,145]). CRF, CRF receptors, and CRF binding protein are expressed in the MRN and DRN and regulate serotonergic signaling, particularly in response to stressors (see [146,147] for review). Overall, CRF application decreases 5-HT neuronal firing [148,149] via CRFR1-dependent reductions in GABA release and CRFR-2-dependent enhancement of post-synaptic GABA sensitivity [150]. Indeed, muscimol or 5-HT1A receptor agonist-induced suppression of DRN neurons is sufficient to reinstate alcohol seeking in rats [49,151]. Accordingly, CRF micro-infusions into the MRN [49] or CRF-R1 agonist micro-infusions into the DRN [152] are sufficient to induce alcohol [49] or opioid [152] seeking. Likewise, CRF receptor antagonism in the MRN blocks footshock- [49] or yohimbine- [153] induced alcohol seeking following self-administration or forced swim-induced reinstatement of morphine seeking following conditioned place preference [152]. Although the downstream targets that are affected by CRF-dependent reductions in serotonergic signaling to promote drug seeking are not well-defined, a likely site of action is the nucleus accumbens where stressor-induced reduction in 5-HT and signaling via 5-HT1B receptors gave been shown to promote cocaine preference [154,155].
Other brain regions
CRF actions that influence drug seeking extend beyond the regions and functions described above and will be briefly summarized here. First, CRF-R1 signaling in the basolateral amygdala has recently been implicated in reconsolidation of cocaine context memories as demonstrated by disruption of context-induced reinstatement of cocaine seeking when CRF-R1 receptors are blocked during earlier reconsolidation [156]. Second, cue induced cocaine seeking is disrupted when CRF-R1 receptors are blocked in the anterior dorsal agranular subregion of the insular cortex [157]. Third, CRF-R1 but not CRF-R2 antagonism in the nucleus incertus prevents yohimbine-induced alcohol seeking in alcohol-preferring rats [158]. Finally, while CRF effects in the prefrontal cortex on alcohol self-administration have been reported [159], the contribution of CRF signaling in subregions of the PFC to stress-induced drug seeking remains unexplored.
CRF signaling mechanisms
A comprehensive overview of all of the signaling mechanisms with which CRF interacts is beyond the scope of this review (see e.g., [140,141,160–170]). As is the case with other neuropeptides, CRF is co-released with neurotransmitters and other neuromodulators (including neuropeptides) and signals interactively with these partners in target cells. Moreover, in many cases the field of influence of CRF extends to adjacent synapses and cell populations, thus allowing CRF to regionally influence signaling via mediators beyond those with which it is co-released. Several areas of particular interest that require additional investigation have emerged related to CRF signaling.
a. CRF receptor-containing heteromers.
GPCRs can interact in heteromers, macromolecular complexes consisting of at least two different receptor types [170]. When part of a heteromeric complex, GPCRs often signal distinctly than then they do in isolation. Thus far, putative heteromeric complexes comprised of the CRF-R2 and dopamine D1 receptors [171,172], the CRFR1 and CRFR2β receptors [173], the CRFR1 and vasopressin V1b receptors [174], the CRFR2 and orexin OX1 receptors [175], and the CRFR1, the orexin OX1, and σ1R receptors [176] have been identified. In several cases, it has been demonstrated that activation of one receptor in these heteromeric complexes alters signaling via the other [175–177]. It has been reported that signaling via CRF receptor-containing heteromers can be influenced by cocaine [176] or amphetamine [175]. In the case of the CRFR1-OX1σ1R complex, cocaine may directly influence CRF signaling via its interaction with σ1R [176]. The contribution of these heteromers to the effects of CRF on drug seeking remains to be determined.
b. CRF-BP:
The CRF-BP is a secreted glycoprotein with no transmembrane domains that binds CRF with an equal or greater affinity than the CRF receptors [178–181]. Its expression is tissue-specific, with human CRF-BP detected in plasma, pituitary, and brain [182]. Rodent CRF-BP is detected only in brain and pituitary [183]. Within the CNS, CRF-BP is expressed in cerebral cortex (including the PFC), hippocampus, the amygdaloid complex, BNST, and VTA [113,182–184]. Rat CRF and CRF-BP co-localize in a number of regions, including BNST and CeA [183], key sites implicated in SUDs and stress. CRF-BP is also detected in a number of CRF target sites (BLA, VTA and anterior pituitary), where CRF-BP and CRF receptors are often co-expressed [113,183,185]. CRF-BP mRNA levels in pituitary and amygdala are increased by stress [185–187]. Multiple functions have been suggested for the CRF-BP. Approximately 40–60% of CRF in human brain is bound by CRF-BP, supporting a role for CRF-BP in limiting CRF bioavailability [188]. In pituitary corticotrope cultures, CRF-BP binds CRF and neutralizes its ACTH-releasing activity via CRF-R1 [178,183]. CRF-BP deficient mice exhibit increased anxiety-like behaviors, consistent with elevated “free” CRF levels [189], supporting an inhibitory role for the CRF-BP, at least for CRF actions at CRF-R1. However, other studies have suggested alternative roles for the CRF-BP, including a facilitative role for CRF-BP in VTA via actions with CRF-R2 in stress-induced cocaine seeking [6,114,123] or CRF receptor independent actions [184]. The possibility that the CRF-BP can modulate CRF signaling, particularly in VTA and other sites within the stress/reward pathways, has important physiological significance and warrants further studies to address its role in stress induced drug seeking.
c. Effects of CRF on astrocytes:
Electron microscopy has revealed CRF-positive axon terminals in close apposition to astrocytic processes [190], and CRF has been found to regulate astrocytic calcium signaling in culture [191] and astrocyte proliferation [192]. Both CRFR1 and CRFR2 receptors [9,193–196] and the CRF binding protein [197] are expressed by astrocytes, and it has been reported that astrocytic CRFR2 expression in the midbrain can be regulated by repeated cocaine or methamphetamine administration [195]. It is likely that, during periods of stress, CRF influences astrocytic glucose utilization and promotes lactate release to fuel neurons in under conditions of high energy demand. However, the relevance of CRF regulation of astrocytes to SUDs is not clear. Astrocytes in the nucleus accumbens have been demonstrated to play a critical role in regulating drug seeking, in part via the management of extrasynaptic glutamate levels and signaling via extrasynaptic metabotropic glutamate and NMDA receptors (see e.g., [198–202]). Astrocytes can also release ATP which can directly influence neuronal function via purinergic receptors or be converted to adenosine which signals through adenosine receptor subtypes [203–205]. Notably, A2A adenosine receptors in the nucleus accumbens [206–208] and prefrontal cortex [209] regulate drug seeking, although their contribution to drug seeking during periods of stress is unknown. Understanding the relevance of CRF effects on astrocytes to drug seeking will require further investigation.
Recruitment of CRF signaling and stressor-induced drug seeking
Drug addiction has been conceptualized as a surfeit disorder wherein “anti-reward “ systems, including those that mediate stress-related signaling, are recruited with repeated cycles of drug use and abstinence/withdrawal, resulting in an allostatic negative emotional state/hyperkatifeia that promotes drug seeking and use through negative reinforcement [210]. CRF systems are among those that contribute to a range of persistent dysphoric effects that emerge with repeated drug use and likely fuel SUDs. Indeed, key dysphoria-related aspects of withdrawal from cocaine (see e.g., [211,212]), opioids (see e.g., [68,213–215]), alcohol (see e.g., [64,215–219]), and other abused drugs (e.g., nicotine: [220,221]; cannabinoids: [222]; benzodiazepines: [223]) are mediated by heightened CRF signaling.
A detailed overview of alterations in CRF signaling that emerge with chronic drug exposure is beyond the scope of this review. However, changes in CRF signaling in a variety of brain regions including the amygdala (see e.g., [97,224–232]), hippocampus (see e.g., [233]), BNST (see e.g., [85,234–236]), septum (see e.g., [237]), prefrontal cortex (see e.g., [238]), nucleus accumbens (see e.g., [239,240]), serotonergic raphe nuclei (see e.g., [241–243]), noradrenergic cell groups (see e.g., [244,245]), and VTA [88,119,120,246–248] have been demonstrated. The functional consequences of altered CRF signaling likely extend beyond dysphoric effects and may include CRF-dependent alterations in decision making [249], reward conditioning [250], drug memory reconsolidation [156] and cognition [251].
CRF and escalating patterns of drug self-administration
One consequence of the recruitment of CRF signaling with repeated drug use may be the emergence of escalating patterns of drug self-administration. Escalation of drug self-administration in rats occurs with high levels of drug exposure resulting from extended or protracted drug access and can be observed across drug classes (alcohol: [252]; cocaine: [253,254]; heroin: [255]; methamphetamine: [256]; nicotine: [257]. It has been demonstrated that CRF receptor antagonism selectively attenuates escalated cocaine [258], ethanol [259–261], or heroin [262] self-administration and corresponding indicators of hyperkatifeia (e.g., mechanical allodynia; [215]) without producing effects under “non-escalated” conditions. Altogether, these findings suggest that drug-induced recruitment of brain CRF systems escalates future self-administration, thus establishing a vicious cycle of drug-taking behavior.
Recruitment of CRF signaling and stressor-induced drug seeking
The recruitment of CRF signaling with excessive drug use also increases susceptibility to CRF-dependent stressor-induced reinstatement of drug seeking (Fig. 2). Although stress has been identified as a contributor to relapse, its relationship with drug seeking is complex. The onset of stress does not always serve as a reliable trigger for cocaine use [23,24]. A key determinant of stress-induced cocaine seeking is the extent/pattern of prior use. High-frequency cocaine users show heightened drug craving, anxiety and associated physiological responses upon exposure to stress imagery compared with lower-frequency users in a laboratory setting [263] and display stronger relationships between daily stress and cocaine/opioid craving as assessed via smartphone monitoring [264]. Consistent with these observations, we find that reliable stress-induced cocaine seeking is observed in male rats with a history of long-access cocaine self-administration (14 × 6–10 h/day) but not rats with a history of short-access self-administration (14 × 1–2 h/day) [51]. Similar findings of heightened stressor-induced reinstatement following long-access self-administration have been reported with heroin [255].
Fig. 2. Glucocorticoid-dependent recruitment of CRF-R1 receptors in the VTA establishes stressor-induced regulation of mesocortical dopamine neurons and cocaine seeking.
The ability of a stressor, electric footshock, to reinstate extinguished cocaine seeking is intake-dependent [51], requires elevated glucocorticoids during self-administration [36], and involves increased CRF-R1 expression in the VTA and the establishment of CRF regulation of mesocortical dopamine neurons [89,142]. A. In rats with a history of short-access cocaine self-administration (1–2 h/day), footshock does not reinstate cocaine seeking. B. Elevated glucocorticoids during long-access self-administration (6+ hrs/day) [277] likely contribute to an upregulation of VTA CRF-R1 receptors on dopamine neurons that project to the prelimbic (PL) prefrontal cortex [142]. C. As a result, the ability of CRF to regulate PL-projecting dopamine neurons [142] and produce CRF-R1 dependent cocaine seeking during stress [89] in response to activation of CRF-releasing afferents from the BNST [83] is established. Abbreviations: CRF (corticotropin releasing factor), DA (dopamine), D1R (dopamine D1 receptor), GR (glucocorticoid receptor), BNST (bed nucleus of the stria terminalis), VTA (ventral tegmental area), PFC (prefrontal cortex), SA (self-administration).
As is the case with stressor-induced reinstatement, drug seeking in response to icv CRF delivery is also only observed following long-access cocaine self-administration and extinction, indicating that drug-induced adaptations in CRF signaling may establish the ability of stress to trigger relapse [51]. In general, these findings are consistent with clinical reports that subjective and physiological responses to CRF infusions are heightened in cocaine-dependent individuals [265]. We have found that a key region at which CRF signaling is recruited to promote stressor-induced drug seeking is the VTA. In line with findings that repeated cocaine administration increases CRF binding in the VTA [111], enhances CRF-R1 dependent regulation of excitatory transmission in the VTA [119], and establishes CRF control of VTA dopaminergic signaling [88], we have found that self-administration under long-access conditions establishes CRF-dependent regulation of cocaine-seeking behavior in male rats [89]. As is observed with icv CRF, the ability of VTA micro-infusions into the VTA to reinstate extinguished cocaine seeking is only observed when rats have a history of long-access cocaine self-administration [89]. More recently, we have found that the establishment of CRF-dependent stressor-induced cocaine seeking is associated with increased CRF-R1 mRNA levels in the VTA and a heightened CRF-R1 dependent Fos response in the prelimbic cortex [142]. Along with findings that a stressor-induced cocaine seeking requires CRF-R1 receptor regulation of a dopaminergic projection from the VTA to the prelimbic PFC and prelimbic D1 receptor activation [142], these findings suggest that excessive cocaine use produces persistent increases in CRF-R1 expression in VTA dopamine neurons that project to the prelimbic cortex to establish susceptibility to stress triggered relapse (Fig. 2).
Chronic stress effects on CRF signaling and drug self-administration/reinstatement
Chronic stress can also escalate drug use via processes that involve recruitment of CRF signaling. For example, chronic social defeat stress can persistently escalate alcohol [266–268] and cocaine [269–272] self-administration in mice and rats as a result of enhanced CRF actions in the VTA [267,269–272]. Social defeat-escalated cocaine self-administration is associated with increased VTA CRF tone and may involve both CRF-R1 and CRF-R2 receptor signaling in subregions of the VTA [271]. Exposure to predator odor can also escalate alcohol drinking in a manner that can be blocked by CRF-R1 antagonism in the CeA [98]. Although not directly demonstrated, the effects of chronic stress in combination with self-administration are also likely evident as CRF-dependent heightened susceptibility to stressor-induced drug seeking in relapse models. We have reported that daily footshock at the time of drug self-administration escalates cocaine intake [273]. Recently, we have found that footshock escalated cocaine self-administration is also associated with a persistently increased stressor-induced reinstatement following extinction (J. McReynolds and J. Mantsch, unpublished observations).
Glucocorticoid regulation of CRF signaling
Using experiments examining the effects of long-access cocaine self-administration on reinstatement, our laboratory has begun to explore the neurobiological processes through excessive drug use recruits CRF signaling and stress-triggered cocaine seeking. It is well-established that self-administered cocaine elevates corticosterone levels in plasma [274,275] and in the brain [276]. These elevations are prolonged and exaggerated when rats self-administer cocaine under daily long-access conditions [277]. Prior work has demonstrated that chronically elevated glucocorticoids can promote brain CRF signaling via allostatic alterations that may contribute to neuropathology [278]. Consistent with this, we have demonstrated that when rats undergo surgical adrenalectomy and along with basal (diurnal) corticosterone replacement prior to a 14-day long-access cocaine self-administration period, reinstatement of cocaine seeking in response to footshock or icv CRF (both of which require prior long-access self-administration [51]) is not observed [36]. By contrast, when rats undergo adrenalectomy/corticosterone replacement after long-access self-administration but prior to testing for reinstatement, cocaine seeking in response to icv CRF or footshock is comparable to sham-operated controls. Altogether, these findings suggest that the adrenal response during periods of excessive drug use, but not thereafter, is necessary for establishing adaptations in CRF signaling that underlie susceptibility to stressor-induced drug seeking (Fig. 2). Surprisingly, while the adrenal response during long-access self-administration is required for subsequent stressor-induced cocaine seeking, elevated corticosterone alone is not sufficient to establish susceptibility to reinstatement. We have found that daily corticosterone administration during short-access self-administration, at a dose that reproduces plasma patterns observed during long-access self-administration, fails to alter later reinstatement [279]. We speculate that other adrenal hormones likely contribute to neuroadaptations that establish CRF-dependent stressor-induced cocaine seeking. One hormone of interest is epinephrine, which can stimulate vagal afferents into the brain [280] and has been demonstrated function cooperatively with corticosterone to contribute to cocaine-induced behavioral plasticity [281].
Factors that influence the contribution of CRF to SUDs
Various factors can influence the relationship between CRF signaling and SUDs. In particular, CRF effects have been reported to vary across development and between sexes and are likely defined by genetic differences. Evidence that these factors can determine the contribution of CRF to SUDs is provided below.
Development
Early-life trauma and adversity are key determinants of SUD risk and severity later in life [282]. In humans, genetic variation in CRF receptors is associated with the impact of early-life adversity on adult SUD outcomes (see e.g., [283]). Neonatal and adolescent stress has also been shown to increase susceptibility to adult drug self-administration and seeking and related behaviors in rodents (see [284,285]). Studies have implicated CRF signaling in many of these effects of stress (see e.g., [286,287] for reviews). For example, the ability of social defeat stress during adolescence to promote escalating patterns of cocaine self-administration during adulthood is prevented by administration of a CRF-R1 antagonist into the VTA [288] while the enhancement of adult responses to cocaine by removal of enrichment during adolescence in mice is associated with increases CRF mRNA in the BNST and prevented by the blocking CRF-R1 receptors [289]. Moreover, early post-natal stress disrupts connectivity between stress- and reward/motivation-related networks in a manner that is prevented by attenuating CRF signaling in the amygdala [290,291]. Conversely, drug use during adolescence can alter CRF signaling during adulthood, thereby increasing the risk for stress-related psychopathology in adults (see e.g., [292–295]). Altogether, these findings establish CRF signaling during early life as a determinant of adult SUDs and suggest that early life events may influence CRF signaling in adulthood to promote SUD risk.
Sex differences
Sex differences in stress reactivity and vulnerability have been identified (see [296–299] for reviews) and females have been reported to be more vulnerable to stress-related drug seeking/craving and related responses [300–305]. Indeed, findings of sex differences in the effects of medications on drug craving (see e.g., [306]) have emphasized the need for consideration of sex as a biological variable when developing medications that target the influence of stress in SUDs [307]. Sex differences in CRF signaling have also been well-documented [308–311]. Importantly, CRF delivery differentially influences functional connectivity in networks that include the extended amygdala, prefrontal cortex, and nucleus accumbens in female rats [312,313]. These differences appear to translate to sex differences in the contribution of CRF to drug seeking. Indeed, rodent studies have found that female rats are more susceptible to reinstatement of cocaine seeking following icv CRF delivery [52]. Moreover, alcohol-induced neuroadaptations in CRF signaling in the central amygdala are sex dependent [311,314]. These findings parallel those from clinical studies which have found that cocaine-dependent women display heightened CRF reactivity [265].
Genetic linkages
The risk for and severity of SUDs involves a complex intersection of multiple genes with environmental determinants and drug-effects. There is evidence for genetic links between components of CRF signaling and drug misuse. Variants of or haplotypes involving variants of the CRHR1, CRHR2 or CRFBP genes have been associated with various aspects of SUDs. Variants of CRHR1 have been associated with binge alcohol drinking [315], the overall lifetime prevalence of drinking [315], habitual alcohol intake [316], and adolescent drinking initiation and progression [317]. Associations between CRHR1 variants and nicotine dependence [318] and heroin addiction [319] have also been reported. CRHR2 variants have been associated with heroin use [319,320] while variants in CRHBP have been associated with the use of heroin [321,322] and cocaine [321,323]. Genetic variation in the CRF system appears to be a particularly important determinant of the influence of environmental factors in SUDs, especially the impact of early-life stress. CRHR1 polymorphisms/variant-containing haplotypes are associated with heightened stress-related alcohol consumption in adolescents [283,317] and are predictive of the impact of childhood sexual abuse [324] and early-life trauma [325] on adult drinking/AUD. Strong associations with the effects of stress in SUDs are also observed with genetic variation related to the CRHBP gene. CRHBP variants have been associated with heightened stress-related alcohol craving [326] and heroin relapse [327]. These associations may be attributable to altered PFC processing of emotional stimuli, as CRHR1 variants appear to influence negative emotionality and corresponding ventrolateral PFC function [328] while CRHBP variants are associated with alterations in cortical EEG [329]
Genetic associations between the CRF system and SUD-related behaviors can also be observed in rodents. Most notably, differences in CRF signaling are observed in rat lines genetically selected for high alcohol preference (see [330] for review), including Sardinian alcohol preferring (sP) and non-preferring (sNP) rats developed from a Wistar foundation stock at the University of Cagliari, Italy and subsequently bred at Scripps, and the Marchigian subline of Sardinian Preferring (msP) (reviewed in [331]) and the alcohol-preferring (P) and non-preferring (NP) lines developed at the Walter Reed Army Hospital, also derived from a Wistar stock and transferred to the University of Indiana (reviewed in [332]). The msP rats have two G-to-A substitutions in the promoter region of the Crhr1 gene that leads to increased brain expression and are associated with CRF-R1 associated anxiety-related behaviors [333,334], heightened CRFR1-dependent stressor-induced alcohol seeking [261,335,336], and the establishment of CRFR1-mediated alcohol self-administration under both dependent and non-dependent conditions [261,335,336]. Compared to Wistar controls, these rats also display altered CRFR1 regulation of both inhibitory and excitatory synaptic transmission in the CeA [337,338]. By contrast CRFR1 antagonist effects on alcohol consumption under dependence or non-dependence conditions are not observed in sP rats [339,340], which lack the A alleles in the Crhr1 promoter [341]. Alcohol consumption in P rats is sensitive to CRFR1 antagonism, despite the absence of the alleles, but only in dependent animals [342], an effect that may be attributed to changes in both CRF [343] and its receptors [344,345]. Overall, these observations are consistent with human data suggesting that genetic alterations in CRF signaling can confer susceptibility to SUDs, particularly during periods of stress.
Section IV: therapeutic implications
The effectiveness of CRF receptor antagonists in preclinical rodent models inspired efforts to develop oral, non-peptide brain penetrant CRF antagonists for clinical use in individuals diagnosed with anxiety, depression, PTSD, and SUDs. Unfortunately, after some early indications of potential utility, more recent clinical trials using the newest generation of CRF-R1 antagonists (pexacerfont and verucerfont) have failed to demonstrate efficacy, despite evidence of neuroendocrine effectiveness, CNS penetrance, and functional brain effects (see [346] for commentary). An initial study published in 2015 reported that the CRF-R1 antagonist, pexacerfont, did not attenuate alcohol craving, emotional responses, anxiety or corresponding neural activity [347]. Subsequently, similar findings were reported in women using the CRF-R1 antagonist, verucerfont, which blocked the HPA response to CRF and the amygdala responses to negative affective stimuli [348]. These outcomes are consistent with those from clinical trials investigating the efficacy of CRF receptor antagonists in individuals with generalized anxiety disorder [349], major depression [350]; GlaxoSmithKline, CRS106139), or PTSD [351]. The translational failure of CRF antagonists may be attributable to a number of factors, including lack of sufficient target engagement in the human brain, lack of universal effectiveness in all subpopulations of individuals with SUDs, and the need for co-administration with other medications. However, these studies raise serious questions about the translatability of preclinical finding in rodents to humans and, potentially, the models used to define the neurobiological mechanisms through which stress influences drug seeking. To date, our understanding of the potential contribution of CRF signaling to SUDs has relied heavily on rodent-based approaches in which the ability of stimuli to trigger drug seeking in rodents following drug self-administration and extinction has been used as an indicator of relapse susceptibility. Limitations to these approaches include the use of forced abstinence/extinction-based versus voluntary abstinence protocols, the absence of assessment of drug seeking in the context of other relevant stimuli and alternative reinforcers, and the lack of adequate consideration of subpopulations of users with varying vulnerability based on factors such as co-morbidity, early-life experience (e.g., childhood trauma), biological sex, and genetic background. The application of approaches that better capture the complex role of stress in drug craving and seeking (e.g., the interactive effects of stress with other stimuli [352]) and use of models guided by reverse translation [353–355], including those that incorporate voluntary abstinence [356,357], have the potential to reveal more relevant targets for interventions. Importantly, our ability to effectively leverage mechanisms them will rely on our capacity to diagnosis those with cocaine use disorder whose drug seeking is stress-related.
Conclusions
In conclusion, the contribution of CRF to SUDs in humans remains enigmatic. Despite an abundance of evidence that CRF signaling is fundamental to behaviors in rodent models assumed to be relevant to human addiction, medications designed to target CRF have repeatedly failed in clinical trials. Considering that CRF and its receptors are expressed in the human brain and dysregulated in stress-related disorders [358–360] and SUDs [265], these failures have been puzzling. New perspectives and additional research are needed to unravel the mysterious role of CRF in SUDs.
Acknowledgments
Supported by NIH R01s DA048280 and DA052169 to JRM. Erik Van Newenhizen is acknowledged for his support with figure preparation. No conflict of interest is declared.
Abbreviations:
- SUDs
substance use disorders
- CRF
corticotropin releasing factor
- VTA
ventral tegmental area
- ACTH
adrenocorticotropic hormone
- BNST
bed nucleus of the stria terminalis
- CeA
central nucleus of the amygdala
- NAc
nucleus accumbens
- MRN
medial raphe nucleus
- DRN
dorsal raphe nucleus
- PTSD
post-traumatic stress disorder
- HPA
hypothalamic pituitary adrenal
- CRF-BP
CRF binding protein
Footnotes
Declaration of Competing Interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data Availability
No data were used for the research described in the article.
References
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