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Psychopharmacology (Berl). Author manuscript; available in PMC 2011 November 1.
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PMCID: PMC3192289

Translational and reverse translational research on the role of stress in drug craving and relapse


Rationale and background

High relapse rates during abstinence are a pervasive problem in drug addiction treatment. Relapse is often associated with stress exposure, which can provoke a subjective state of drug craving that can also be demonstrated under controlled laboratory conditions. Stress-induced relapse and craving in humans can be modeled in mice, rats, and monkeys using a reinstatement model in which drug-taking behaviors are extinguished and then reinstated by acute exposure to certain stressors. Studies using the reinstatement model in rats have identified the role of several neurotransmitters and brain sites in stress-induced reinstatement of drug seeking, but the degree to which these preclinical findings are relevant to the human condition is largely unknown.

Objectives and highlights

Here, we address this topic by discussing recent results on the effect of alpha-2 adreno-ceptors and substance P-NK1 receptor antagonists on stress-induced reinstatement in mice and rats and stress-induced craving and potentially stress-induced relapse in humans. We also discuss brain sites and circuits involved in stress-induced reinstatement of drug seeking in rats and those activated during stress-induced craving in humans.


There is evidence that alpha-2 adrenoceptor agonists and NK1 receptor antagonists decrease stress-induced drug seeking in rats and stress-induced craving in humans. Whether these drugs would also prevent stress-induced drug relapse in humans and whether similar or different brain mechanisms are involved in stress-induced reinstatement in non-humans and stress-induced drug craving and relapse in humans are subjects for future research.

Keywords: Corticotropin-releasing factor, Craving Extinction, NK1 receptor, Noradrenaline, Reinstatement, Relapse, Reverse translational research, Stress, Substance P, Translational research, Yohimbine


The high rate of relapse to drug use following periods of forced or self-imposed abstinence is a major clinical problem in addiction treatment (Hunt et al. 1971; O’Brien and Gardner 2005). Clinical studies suggest that stress is among the key factors contributing to these high relapse rates (Brownell et al. 1986; Sinha 2001). Prospective human studies have shown that stress exposure (either acute stressors like an argument with coworkers or more chronic adverse life events like divorce or job loss) is associated with subsequent drug relapse (Baker et al. 2004; Brown et al. 1990; Brown et al. 1995; Epstein et al. 2009a; Hyman et al. 2007; Preston and Epstein 2011; Shiffman 2005; Sinha 2001). While an important strength of these studies over previous correlational studies of stress and relapse has been the prospective assessment of drug relapse in order to predict future relapse risk, these studies have focused on varied assessment of stressful life events, which may have led to some negative results (Hall et al. 1990; O’Doherty and Davies 1987).

Human laboratory studies of stress provocation have also been conducted to provide additional psychobiological measures of stress. These studies have assessed drug use motivation by measuring drug craving (Sinha 2001). The stressors used in these studies include guided imagery stress scripts (Sinha et al. 1999), Trier Social Stress Task (Kirschbaum et al. 1993), and systemic injections of the stress neurohormone corticotropin-releasing factor (CRF) (Vale et al. 1981). These stressors induce physiological (e.g., increased cortisol release and heart rate) and psychological (e.g., increased subjective assessment of anxiety and irritability) stress responses and also increased subjective self-reports of drug craving (Back et al. 2010; Coffey et al. 2002; Sinha 2001; 2009; Sinha et al. 1999). These laboratory studies have established a clear cause–effect relationship between stress exposure and drug craving (Sinha 2001; 2009) and more preliminary evidence for a cause–effect relationship between stress exposure and relapse to drug use in the laboratory (McKee et al. 2011).

Recent studies combining the induction of stress, affect, and related drug craving in the laboratory with a prospective assessment of relapse in the drug user’s environment have shown that stress-induced craving, attenuated subjective response to natural rewards, and physiological stress responses in the laboratory predict drug relapse and intake (Back et al. 2010; Lubman et al. 2009; Sinha et al. 2006; Sinha et al. 2011a, b). Additionally, ecological momentary assessment (EMA) approaches that prospectively measure the relationship between stress exposure in the drug user’s environment and stress-related negative affect with subsequent drug use provide further support for the notion that stress contributes to relapse to drug use (Cooney et al. 2007; Epstein et al. 2009a; Preston and Epstein 2011; Shiffman et al. 1996; Shiffman et al. 2004).

However, while human research has identified that stress contributes to drug relapse, the underlying neurobiological mechanisms are largely unknown. Stress-induced relapse and craving can be modeled in non-humans using two procedural variations of the reinstatement model (Shaham et al. 2000a; Shaham et al. 2003). In the self-administration version, which is based on an operant conditioning paradigm (Skinner 1938), mice, rats, or monkeys are trained to respond for drug infusions (or oral solutions in the case of alcohol), typically by pressing a lever; then, following extinction of the drug-reinforced responding, non-reinforced pressing on the drug-associated lever is induced by certain stressors (Shaham et al. 2000a). These stressors include intermittent unpredictable footshock (Erb et al. 1996; Mantsch and Goeders 1999; Shaham and Stewart 1995), acute food deprivation (Carroll 1985; Shalev et al. 2001b), cold swim stress (Conrad et al. 2010), and the pharmacological stressors yohimbine (Lee et al. 2004; Shepard et al. 2004) and CRF (Erb et al. 2006; Le et al. 2002; Shaham et al. 1997). Yohimbine is a prototypical alpha-2 adrenoceptor antagonist that induces stress- and anxiety-like responses in both humans and laboratory animals (Redmond and Huang 1979); in human laboratory studies, yohimbine also induces opiate and alcohol craving (Stine et al. 2002; Umhau et al. 2011).

In the conditioned place preference (CPP) version of the reinstatement model, which is based on a classical conditioning paradigm (Pavlov 1927), CPP is induced by drug administration, extinguished, and then induced again by stress exposure (Aguilar et al. 2009; Shalev et al. 2002). Stressors reported to reinstate drug preference in the CPP reinstatement version include intermittent unpredictable footshock (Wang et al. 2002; Wang et al. 2006), restraint (Sanchez et al. 2003), conditioned fear (Sanchez and Sorg 2001), social defeat (Ribeiro Do Couto et al. 2006), swim stress (Kreibich and Blendy 2004; Redila and Chavkin 2008), tail pinch (Ribeiro Do Couto et al. 2006), and the pharmacological stressors yohimbine (Mantsch et al. 2010) and the kappa receptor agonist U50,488 (Redila and Chavkin 2008).

It should be noted, however, that stress-induced reinstatement of drug seeking is to some degree both stressor specific and procedure specific. Thus, the established stressors like social defeat (Miczek et al. 1994; Miczek et al. 2008) and restraint (Kvetnansky and Mikulaj 1970) reinstate drug preference in the CPP reinstatement version (Ribeiro Do Couto et al. 2006; Sanchez et al. 2003) but not drug seeking in the self-administration reinstatement version (Funk et al. 2005; Shalev et al. 2000). Additionally, in the case of intermittent footshock, the stressor most often used in reinstatement studies, its effect on reinstatement is dependent on several experimental parameters (Kupferschmidt et al. 2011; Lu et al. 2003), including the context of stress exposure (Shalev et al. 2000), the shock intensity (Shaham 1996), the duration of the withdrawal period (Shalev et al. 2001a), and the amount of drug intake during training (Ahmed et al. 2000; Mantsch et al. 2008).

Studies on stress-induced reinstatement of drug seeking in non-humans have provided mechanistic information on the brain sites and neurotransmitters involved in this reinstatement (Erb 2010; Kalivas and McFarland 2003; Le and Shaham 2002; Shalev et al. 2010); however, the relevance of this information to mechanisms underlying stress-induced craving and relapse in humans is unknown (Epstein et al. 2006). Therefore, an important theoretical issue is the validity of the reinstatement model as an animal model of human drug craving and relapse. This issue has been thoroughly addressed in several reviews (Bossert et al. 2005; Epstein and Preston 2003; Epstein et al. 2006; Katz and Higgins 2003), and thus we do not discuss it in the present review. Instead, we describe translational research on the role of stress in drug craving and relapse that was inspired in part from the results of studies using the reinstatement model. We also describe reverse translational research, in which a finding originally obtained in the human laboratory was assessed in the reinstatement model.

Below, we first discuss studies on the effect of alpha-2 adrenoceptor agonists on stress-induced reinstatement in laboratory animals, which have led to translational clinical studies on the effect of these agonists on stress-induced craving and relapse in heroin and cocaine addicts. We then describe studies on the effect of a neurokinin 1 (NK1) receptor antagonist on stress-induced craving and neuronal activation in alcoholics that have led to a reverse translational preclinical study on the effect of substance P-NK1 receptor blockade on stress-induced reinstatement of alcohol seeking. We subsequently review the brain sites involved in stress-induced reinstatement of drug seeking in rats and the brain sites activated during stress-induced craving in humans. We conclude by proposing future directions of translational research based on findings obtained from preclinical studies using the reinstatement model. Table 1 provides a glossary of several terms used in our review.

Table 1
Glossary of terminology

Effect of alpha-2 adrenoceptor agonists on stress-induced reinstatement in non-humans and stress-induced craving and relapse in humans

Central noradrenergic neurons are activated by different stressors and are thought to play an important role in the mediation of physiological and psychological responses to stress (Bremner et al. 1996a, b; Redmond and Huang 1979; Stanford 1995; Tanaka et al. 1990). There is evidence that brain noradrenaline is a critical mediator of footshock stress-induced reinstatement of drug seeking (Shaham et al. 2000b; Shalev et al. 2002). In several pharmacological studies, investigators have used alpha-2 adrenoceptor agonists (clonidine, lofexidine, guanbenz) that inhibit central noradrenaline cell firing and release (Abercrombie et al. 1988; Aghajanian and VanderMaelen 1982; Carter 1997; Mongeau et al. 1997). In an initial study, Shaham et al. (2000b) reported that systemic injections of low doses of clonidine inhibit the footshock stress-induced reinstatement of heroin seeking. This inhibitory effect of systemic injections of the alpha-2 adrenoceptor agonists on footshock-induced reinstatement of drug seeking has also been observed in rats previously trained to self-administer cocaine, speedball (a heroin–cocaine mixture), alcohol, and nicotine (Table 2) (Erb et al. 2000; Highfield et al. 2001; Le et al. 2005; Zislis et al. 2007).

Table 2
Alpha-2 adrenoceptor agonists that decrease footshock-stress-induced reinstatement of drug seeking or footshock-induced reinstatement of drug CPP in non-humans and stress-induced or stress + cue-induced craving in humans

The effect of the alpha-2 adrenoceptor agonists on footshock-induced reinstatement is centrally mediated. Ventricular injections of clonidine mimic the inhibitory effect of the drug’s systemic injections (Shaham et al. 2000b), while systemic injections of ST-91, a charged analogue of clonidine that does not readily cross the blood–brain barrier (Scriabine et al. 1975), had no effect on footshock-induced reinstatement. Another finding from this series of studies is that systemic injections of the alpha-2 adrenoceptor agonists had no effect on reinstatement of drug seeking induced by drug priming injections or exposure to drug-associated cues (Erb et al. 2000; Highfield et al. 2001).

Additional evidence for a role of alpha-2 adrenoceptors in stress-induced reinstatement is that systemic injections of the prototypical alpha-2 adrenoceptor antagonist yohimbine, which increases noradrenaline cell firing and release (Abercrombie et al. 1988; Aghajanian and VanderMaelen 1982), reinstate methamphetamine, cocaine, heroin, and alcohol seeking in rats (Banna et al. 2010; Feltenstein and See 2006; Le et al. 2005; See and Waters 2010; Shepard et al. 2004), and cocaine seeking in monkeys (Lee et al. 2004). Yohimbine also potently reinstates palatable food seeking in rats (Ghitza et al. 2006; Ghitza et al. 2007; Nair et al. 2009; Nair et al. 2011). Surprisingly, however, the evidence that yohimbine-induced reinstatement of drug seeking is mediated by central noradrenergic systems is mixed. The alpha-2 adrenoceptor agonists clonidine and guanfacine attenuate yohimbine-induced reinstatement of alcohol seeking in rats (Le et al. 2009; Lê et al. 2011) and cocaine seeking in monkeys (Lee et al. 2004). In contrast, clonidine has no effect on yohimbine-induced reinstatement of cocaine seeking in rats (Brown et al. 2009) or yohimbine-induced reinstatement of CPP in mice (Mantsch et al. 2010). Additionally, in rats, 6-hydroxydopamine lesions of the ventral or dorsal noradrenergic bundles have no effect on yohimbine-induced reinstatement of alcohol seeking (Le et al. 2009). Furthermore, yohimbine’s effect on reinstatement of alcohol seeking is not mimicked by RS79948, a selective alpha-2 adrenoceptor antagonist (Le et al. 2009). In contrast, in monkeys, yohimbine’s effect on reinstatement is mimicked by RS79948 (Lee et al. 2004), and in mice this effect of yohimbine is mimicked by another selective alpha-2 adrenoceptor antagonist, BRL44408 (Mantsch et al. 2010). Mantsch et al. (2010) also reported that yohimbine-induced reinstatement of cocaine CPP in mice is attenuated by the beta adrenoceptor antagonist propranolol. Finally, Lê et al. (2011) recently reported that the alpha-1 adrenoceptor antagonist prazosin blocks yohimbine-induced reinstatement of alcohol seeking; prazosin also blocks intermittent footshock-induced reinstatement. A tentative conclusion from the above studies is that both adrenergic and non-adrenergic (possibly serotonergic) mechanisms contribute to the potent effect of yohimbine on reinstatement of drug seeking (Le et al. 2009).

The above findings on the potent inhibitory effect of alpha-2 adrenoceptor agonists on footshock stress-induced reinstatement of drug seeking have led to several laboratory studies on the effect of these agonists on stress-induced craving and relapse in humans. The first human study on the effect of an alpha-2-adrenergic agonist (lofexidine) on stress and drug craving was conducted in opioid-dependent individuals in naltrexone treatment (Sinha et al. 2007). Naltrexone is an opiate receptor antagonist that is approved for the treatment of opioid addiction, but it is not used widely because of poor compliance and high relapse rates (Julius 1976). In rats, naltrexone has no effect on stress-induced reinstatement of heroin or alcohol seeking (Le et al. 1999; Liu and Weiss 2002; Shaham and Stewart 1996). This finding raises the possibility that high relapse rates during naltrexone treatment occur because naltrexone has no effect on stress-induced drug craving and relapse. Indeed, naltrexone-treated opioid-dependent individuals show high levels of guided imagery stress-induced drug craving, physiological arousal, and emotional distress, supporting the notion that naltrexone treatment may not be effective in decreasing stress-related drug craving (Hyman et al. 2007). In a small laboratory and clinical outcomes study, we found that daily administration of 2.4 mg of lofexidine for 4 weeks decreased the guided imagery stress-induced opiate craving, anger ratings, and basal heart rates, as well as improved opiate relapse outcomes in naltrexone-treated opioid-dependent individuals (Sinha et al. 2007).

In a follow-up study, we examined whether chronic 4-week administration of the alpha-2 adrenoceptor agonist guanfacine (up to 3 mg/daily dosing) would decrease guided imagery, stress, cue, and stress + cue-induced drug craving, anxiety, and physiological arousal in cocaine-dependent individuals who also use alcohol and nicotine (Fox et al. under review). Guanfacine (extended release) has been recently approved for attention deficit hyperactivity disorder in children (Sallee and Eaton 2010). Guanfacine decreased basal heart rate and blood pressure. While the placebo group reported significant increases in cocaine and nicotine craving and anxiety following drug cue-related compared with stress-related imagery, such increases were not observed in the guanfacine group. Subjects treated with guanfacine also reported lower nicotine craving, fear, and arousal following drug cue and combined stress + drug cue imagery. These preliminary findings have led to a large scale dose–response study with guanfacine in cocaine-dependent individuals who are also nicotine dependent, which is currently under way.

In another recent study, Jobes et al. (2011) assessed the effect of clonidine on stress- and cue-induced craving in cocaine users that were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg orally under double-blind conditions. The stress and cue manipulations were standard auditory imagery scripts of stress-related and drug cue-related situations. Each subject received clonidine or placebo followed 3 h later by exposure to two pairs of scripts (neutral/stress and neutral/drug). Jobes et al. (2011) reported that both clonidine doses decreased stress-induced cocaine craving while only the high clonidine dose decreased cue-induced craving.

In conclusion, studies using the reinstatement model in rats and mice indicate that stress-induced activation of central noradrenaline systems mediates stress-induced reinstatement of drug seeking. These preclinical studies have led to three human laboratory studies that demonstrated that alpha-2 adrenoceptor agonists (clonidine, lofexidine, and guanfacine), which decrease brain nor-adrenaline cell firing and release, decreased stress-induced drug craving in drug addicts. A question for future research is whether chronic treatment with alpha-2 adrenoceptor agonists would also prevent stress-induced relapse in the addict’s environment. Ongoing studies at both Yale and National Institute on Drug Abuse (NIDA) intramural research program will provide an answer to this question in the near future. Finally, a surprising dissociation has emerged between the rat reinstatement studies and the human laboratory studies. In the rat studies, the alpha-2 adrenoceptor agonists selectively decreased footshock stress-induced reinstatement of drug seeking but not cue or drug priming-induced reinstatement (Erb et al. 2000; Highfield et al. 2001). In contrast, in the human studies, the alpha-2 adrenoceptor agonists consistently decreased cue-induced drug craving (Fox et al. under review; Jobes et al. 2011; Sinha et al. 2007). A possible reason for these different findings is that in the rat, cue exposure likely primarily causes an appetitive motivational state with little or no stress component (Feltenstein and See 2006; See 2005). In contrast, in the human, laboratory cue exposure primarily induces an alpha-2 adrenoceptor agonist sensitive stress-like physiological (e.g., increased cortisol and heart rate) and psychological (e.g., increased subjective ratings of anxiety, anger, and irritability) states that are very similar to those induced by exposure to stressors like guided imagery stress or the Trier Social Stress Test (Back et al. 2010; Sinha et al. 1999; Sinha et al. 2000).

Role of NK1 receptors in stress-induced reinstatement in non-humans and stress-induced craving in humans

Substance P (SP) is an 11 amino acid peptide originally isolated from intestinal extracts in 1931 (Euler and Gaddum 1931); this peptide is known to be involved in pain transmission (Payan 1989). SP and its preferred NK1 receptors are expressed in brain areas involved in stress responses, including the hypothalamus and amygdala (Mantyh et al. 1984; Nakaya et al. 1994). Central injection of SP or related peptide agonists is anxiogenic in the elevated plus maze (Teixeira et al. 1996) and causes conditioned place aversion (Elliott 1988). The release of endogenous SP is similarly linked to enhanced stress responses (Ebner et al. 2004; Ebner et al. 2008; Ebner and Singewald 2007). Conversely, NK1 receptor antagonism or genetic deletion of the receptor causes anxiolytic-and antidepressant-like effects in animal models of anxiety and depression (Ballard et al. 2001; File 1997; Kramer et al. 1998b; Papp et al. 2000; Rupniak et al. 2000; Rupniak et al. 2001; Santarelli et al. 2001; Teixeira et al. 1996; Varty et al. 2002).

George et al. (2008) observed that mice with a genetic deletion of the gene encoding the NK1 receptor showed decreased intake of home–cage alcohol drinking after prolonged access to the drug and progressive increases of alcohol concentrations. This finding and the previously established role of the SP–NK1 system in stress responses described above led these investigators to assess the effect of the NK1 receptor antagonist LY686017 (50 mg per day over 3 weeks) on several outcome measures in recently detoxified anxious alcohol dependent subjects. These included alcohol craving and physiological responses after combined exposure to alcohol-related cues (Monti et al. 1993) + the Trier Social Stress task (Kirschbaum et al. 1993). LY686017 suppressed spontaneous alcohol cravings and had a beneficial effect on global measures of well-being in the absence of effects on general psychopathology. LY686017 treatment also reduced both the subjective craving response to the combined cue + stress challenge and the concomitant cortisol response (George et al. 2008).

Additionally, George et al. (2008) used functional magnetic resonance imaging (fMRI) to study the effect of LY686017 treatment on brain responses to standardized affective stimuli from the International Affective Picture System (IAPS) (Lang et al. 1995). Subjects treated with LY686017 showed less brain activation in response to the negative images than the placebo group in several regions associated with emotional response to visual stimuli, including the insula, a part of the brain recently implicated in drug craving and relapse in humans (Naqvi and Bechara 2009; Naqvi et al. 2007). Surprisingly, the LY686017-treated group also showed greater brain activation in the nucleus accumbens and anterior cingulate cortex in response to positive IAPS images than the placebo-treated group, normalizing the deficit in brain responses to positive affective stimuli otherwise found in alcoholics (George et al. 2008). Together, the attenuation of responses to negative affective stimuli and the restoration of responses to positive affective stimuli may reflect an overall shift in the balance between positive and negative emotionality reflected in the subjective improvement detected by the clinical ratings.

The human data by George et al. (2008) on the effect of the NK1 receptor antagonist LY686017 on stress-induced craving and negative affective states inspired us to perform a reverse translational study to determine the role of NK1 receptors in stress-induced reinstatement of alcohol seeking (Schank et al. 2011). In this study, we used a different NK1 receptor antagonist (L822429) that was synthesized to bind with high affinity to the rat NK1 receptor (Ebner et al. 2004; Singewald et al. 2008). We found that systemic injections of L822429 block footshock stress-induced reinstatement of alcohol seeking.

In summary, NK1 receptor antagonism has emerged as a candidate treatment mechanism in alcoholism and illustrates the feasibility of bidirectional translation in developing novel pharmacological treatments for alcohol and drug addiction. A word of caution, however, is that NK1 receptor antagonists were previously assessed for the treatment of depression with mixed results (Ebner and Singewald 2006). While results from some studies were promising (Kramer et al. 1998a; Kramer et al. 2004), results from others were not (Keller et al. 2006). As discussed by Ebner and Singewald (2006), patient selection may be an important factor for these mixed results because it is currently unknown which subpopulation/s of depressed patients may benefit from NK1 receptor antagonist treatment. For example, this treatment may be more suitable for depressed patients with comorbid anxiety, because the administration of an NK1 receptor antagonist decreases social phobia symptoms during a stressful public speaking task (Furmark et al. 2005). We predict that similar mixed results will be obtained in clinical trials with heterogeneous populations of drug addicts in which an unknown proportion of the subjects is prone to stress-induced relapse. On the other hand, more favorable results with NK1 receptor antagonists may be obtained if these drugs are used to treat a subset of drug addicts who are highly anxious and prone to stress-induced relapse.

Brain mechanisms of stress-induced reinstatement in rats and stress-induced craving in humans

Results from neuroanatomical studies have identified brain sites and anatomical projections that are critical for foot-shock stress-induced reinstatement of drug seeking (Kalivas and McFarland 2003; Shaham et al. 2000a; Shalev et al. 2010). An early neuroanatomical model was proposed by Erb et al. (2001b) in which footshock causes initial activation of lateral tegmental (but not locus coeruleus) noradrenergic neurons (Shaham et al. 2000b), which in turn activate CRF projection neurons from the central nucleus of the amygdala to the bed nucleus of stria terminalis (BNST) as well as local CRF interneurons in the BNST (Erb et al. 2001a; Erb and Stewart 1999). Subsequently, CRF-induced activation of excitatory projection neurons from BNST (which possibly contain CRF as a neurotransmitter or cotransmitter) that act in distal brain areas [including dopamine or non-dopamine ventral tegmental area (VTA) neurons] to initiate appetitive approach behaviors that lead to reinstatement of drug seeking.

Neuropharmacological support for this model is provided by the finding that blockade of postsynaptic adrenoceptor antagonists or stimulation of alpha-2 adrenoceptors in BNST or central amygdala decrease footshock stress-induced reinstatement of drug seeking or drug preference (Leri et al. 2002; Wang et al. 2001; Yamada and Bruijnzeel 2011). Anatomical support for this model comes from the identification of glutamate and CRF projection neurons from BNST to VTA (Georges and Aston-Jones 2001; 2002; Rodaros et al. 2007). Potential functional support for the model is provided by the discovery that in the VTA, both CRF and glutamate transmission are critical for footshock-induced reinstatement of cocaine seeking (Wang et al. 2005; Wang et al. 2007). Results from other studies suggest that the neuroanatomical model should be expanded to include the dopaminergic projection from the VTA to dorsal medial prefrontal cortex (mPFC), which interacts with glutamatergic projections from the dorsal mPFC to the nucleus accumbens (Capriles et al. 2003; McFarland et al. 2004; Sanchez et al. 2003; Xi et al. 2004). Results from a comprehensive study, in which discrete brain areas were reversibly inactivated by a mixture of gamma-amino-butyric acid (GABA)a and GABAb agonists, confirm the findings discussed above on the role of the dorsal mPFC, BNST, central amygdala, accumbens, and VTA in foot-shock stress-induced reinstatement, and further indicate that the ventral pallidum plays a role in this reinstatement (McFarland et al. 2004). Finally, the results from two recent studies indicate that BNST neurons of unknown origin and dopamine in the dorsal mPFC play a role in yohimbine-induced reinstatement (Buffalari and See 2011; Nair et al. 2011).

Several recent studies have examined the effect of guided imagery stress, which causes cocaine craving, as well as other stressors (e.g., mental arithmetic subtraction task) on brain activation in humans. These studies demonstrate that with these psychological stressors, healthy individuals show increased medial prefrontal and anterior and posterior cingulate activation along with insula, dorso-medial thalamus, midbrain regions, including the VTA and periaqueductal gray, and in some cases hippocampus and striatal activation (Dedovic et al. 2009; Goldstein et al. 2010; Seo et al. 2011; Sinha et al. 2004; Soufer et al. 1998). On the other hand, there is evidence that with chronic stress, there is a decrease in prefrontal activity during an attention-shifting task (Liston et al. 2009), suggesting that there is an adverse impact of chronic stress on prefrontal regulatory function during stressful and cognitive challenge states (Seo and Sinha 2011).

To apply this research to guided imagery stress-induced drug craving in drug users, brain activation during stress and neutral imagery was examined in an fMRI study. During stress exposure, cocaine users showed decreased activity in the anterior cingulate cortex, hippocampus and parahippo-campus, and insula regions (Sinha et al. 2005). On the other hand, the cocaine users showed increased activity in the caudate and dorsal striatum region during stress and this activation was associated with stress-induced cocaine craving ratings. Thus, guided imagery stress-induced craving is associated with greater activity in the striatum, but decreased activity in the prefrontal cortex and insula.

In the recent study on the effect of guanfacine in cocaine-dependent individuals described above (Fox et al. under review), we also tested patients in an fMRI session to assess guanfacine’s effects on stress-induced brain activation. During guided imagery stress exposure, guanfacine in contrast to placebo treatment increased brain activation in the ventromedial and dorsolateral prefrontal cortex and the insula, while also increasing ventrolateral prefrontal and anterior cingulate activation during drug cue imagery exposure. These data suggest that guanfacine’s positive effects may include reversing the previously documented hypofrontality and insula deficits in drug addicts (Goldstein and Volkow 2002; Naqvi and Bechara 2009).

The literature reviewed above may lead to the counterintuitive conclusion that dissociable neuronal mechanisms mediate stress-induced reinstatement of drug seeking in rats and stress-induced craving in humans. Specifically, in rats, footshock stress exposure activates glutamatergic projection neurons in dorsal mPFC (dorsal prelimbic area and cingulate area) and pharmacological inhibition of dorsal mPFC prevents footshock stress-induced reinstatement of cocaine seeking (Capriles et al. 2003; McFarland et al. 2004). In contrast, in humans, guided imagery stress exposure that induces cocaine craving causes decreased neuronal activity in the anterior cingulate cortex as assessed by BOLD fMRI signal (Sinha et al. 2005). This neuroanatomical dissociation is particularly surprising because as mentioned above, studies using systemic injections of alpha-2 adrenoceptor agonists and NK1 receptor antagonists suggest substantial overlap between the neuronal mechanisms of stress-induced reinstatement in non-humans and stress-induced craving in humans.

At present, we can only speculate on potential reasons for the findings that stress-induced mPFC activation in cocaine-experienced rats and stress-induced mPFC hypo-activation in human cocaine users. One such speculation relates to the nature of the cortical BOLD fMRI signal, which primarily reflects activity of input and local neurons rather than spiking output of projection neurons (Logothetis et al. 2001). Thus, it is often difficult to predict from local BOLD fMRI signal the nature of the activity of output projection neurons. In this regard, the cingulate cortex hypoactivity in cocaine users might reflect decreased local intracortical processing that results in disinhibition of glutamatergic projection neurons. The decreased activity of GABAergic interneurons might be invoked to account for these observations, but this notion is highly speculative, because cortical energy utilization, which correlates with synaptic transmission, is primarily due to glutamatergic neuronal activity (Pan et al. 2000; Sibson et al. 1998). However, the observation that the decreased BOLD fMRI signal in response to stress in cocaine users was associated with a parallel increase in BOLD fMRI signal in the dorsal striatum (Sinha et al. 2005), a major glutamatergic (excitatory) projection area of the cingulate cortex (Voorn et al. 2004), is potentially consistent with our speculation.

Finally, two other factors may contribute to the differential brain response to stress-induced brain activation in cocaine-experienced rats during reinstatement tests and human cocaine users exposed to a craving–inducing stress manipulation. The first is the type of stressor: intermittent footshock in the rat and guided imagery stress in humans. It is well established that even within species, different stressors induce different patterns of brain activation (Sawchenko et al. 2000; Van Loon et al. 1989). The second is the baseline level of stress, which may interact with the individual’s response to stress. Here, it is reasonable to speculate that in the rat, baseline stress levels are very low because they are well habituated to the experimental procedures and the self-administration chambers before footshock exposure during the reinstatement tests. In contrast, for human cocaine users, basal stress levels are likely very high in a novel laboratory environment and novel fMRI magnet procedure that can make subjects quite apprehensive.

Conclusions and future directions

The notion that stress makes people initiate or resume drug use is intuitively appealing to patients, clinicians, and the lay public alike. Yet, clinical observations suffer from major limitations, making it difficult to establish a causal relationship between stress and drug relapse. This is because retrospective recall is biased, and relapse episodes are often associated with the stress related to the resumption of drug use during abstinence (Hall et al. 1990; O’Doherty and Davies 1987). Recently, major advances have been made in parsing out prospective versus retrospective correlative associations between stress and relapse through the use of the EMA methodology (Epstein et al. 2009b; Shiffman and Waters 2004). Another major advance in this line of research is that the magnitude of stress-induced craving in the laboratory can predict both drug relapse in the laboratory (McKee et al. 2011) and future relapse risk in the drug user’s environment (Back et al. 2010; Sinha et al. 2006; Sinha et al. 2011a, b). This finding and recent EMA results on the close temporal relationship between stress-induced drug craving and stress-induced drug relapse (Preston and Epstein 2011) suggest that measures of stress-induced craving can serve as relapse-predictive factor, and that its reduction can offer both a surrogate marker for medication development as well as an objective of novel treatments in its own right.

A future direction of major importance will be to further establish whether results from studies in which stress reinstates drug seeking in mice, rats, and monkeys “translate” to the human condition. The finding that alpha-2 adrenoceptor agonists and NK1 receptor antagonists decrease stress-induced reinstatement in rats and decrease stress-induced craving in humans is encouraging. However, a critical missing piece concerning the “translational” value of these findings is whether alpha-2 adrenoceptor agonists and NK1 receptor antagonists would prevent stress-induced drug relapse in the drug user’s environment. Results from clinical studies currently conducted at Yale University and the NIDA–IRP in which the effects of alpha-2 adrenoceptor agonists on drug relapse are being assessed will provide this missing piece.

Another promising future research direction is the assessment of the effect of small molecule CRF1 receptor antagonists, which passed phase I toxicity screening and can be given to humans (Zorrilla and Koob 2010), on stress-induced craving and relapse in drug addicts. Data from these studies will be informative on the utility of translational research based on the reinstatement model as well as other preclinical addiction models. This is because multiple studies have shown that blockade of CRF receptors decreases both footshock-induced reinstatement (Bruijnzeel et al. 2009; Erb et al. 1998; Gehlert et al. 2007; Le et al. 2000; Shaham et al. 1997) and yohimbine-induced reinstatement (Marinelli et al. 2007) of drug seeking. Additionally, extended access to cocaine and alcohol upregulates the expression levels of CRF and CRF1 receptors in the amygdala (Sommer et al. 2008; Zorrilla et al. 2001), and CRF1 receptor antagonists decrease alcohol dependence induced increases in alcohol consumption (Funk et al. 2007; Gehlert et al. 2007; Heilig and Koob 2007), as well as escalation of heroin, cocaine, or nicotine self-administration in rats given extended access to these drugs (George et al. 2007; Greenwell et al. 2009; Specio et al. 2008).

An important future research direction that is only in its infancy is the understanding of individual differences in medication response. Genetic as well as experiential factors are likely to be the determinants of treatment response for drugs targeting the stress mechanisms reviewed here. For example, in both laboratory animals and humans, some individuals may be more sensitive to CRF blockade as a means of preventing stress-induced relapse or excessive alcohol and drug intake than others. This may be related to genetic factors, as suggested by human (Blomeyer et al. 2008; Nelson et al. 2010; Treutlein et al. 2006), rat (Hansson et al. 2006), and non-human primate (Barr et al. 2009) studies. Unless these individual differences are understood, treatment studies targeting unselected patient populations may dilute any effects and fail, leading to discontinuations of development efforts with treatments that would have the potential to be successful in the right patient population. Assessing the drug user’s vulnerability to stress may be particularly important in future studies assessing the effect of CRF1 receptor antagonists on drug craving and relapse, because these compounds failed in double-blind phase II clinical trials of depression using non-selected patient populations (Binneman et al. 2008).

Another important future issue from the perspective of translational research is concerned with medication effects in males versus females. In this regard, there is evidence from many non-humans studies for sex differences as well as a role of ovarian hormones in reinstatement of drug seeking induced by cues or drug priming (Becker and Hu 2008; Carroll et al. 2004; Kippin et al. 2005; Lynch 2006) and stress responses (Bale 2006; Becker et al. 2007; Shors 2006). However, with the exception of the first publication on stress-induced reinstatement of drug (heroin) seeking that included both male and female rats (Shaham and Stewart 1995) and a very recent report (Feltenstein et al. 2011), to our knowledge, preclinical research on the mechanisms of stress-induced reinstatement has primarily been performed in male rats. Additionally, while there is evidence for gender differences in physiological and psychological responses to stress in drug addicts (Fox et al. 2009; Fox and Sinha 2009), systematic studies on the effect of potential medications on stress-induced craving and relapse in males and females are yet to be conducted.

In summary, we reviewed data that support the notion that the frequently observed association between stress and relapse in patients with addictive disorders is causal rather than correlational. We further reviewed evidence that despite the numerous differences between the experimental conditions used to assess stress-induced reinstatement of drug seeking in non-humans and stress-induced craving in humans, there is a good concordance between the pharmacological agents that decrease stress effects across species. We conclude with a word of caution that in all likelihood, stress-related medication will not be effective in preventing relapse in all patients; however, the translational research reviewed here suggests potential pharmacological targets that may have considerable potential in selected stress vulnerable patient populations whose drug use and relapse is driven by stress.


The writing of this review was supported in part by the Intramural Research Programs of NIDA (YS) and NIAAA (MH), and extramural NIH grants (RS).

Contributor Information

Rajita Sinha, Department of Psychiatry, Yale University, New Haven, CT, USA.

Yavin Shaham, Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, Baltimore, MD, USA.

Markus Heilig, Laboratory of Clinical and Translational Studies, IRP/NIAAA/NIH/DHHS, Bethesda, MD, USA.


  • Abercrombie ED, Keller RW, Jr, Zigmond MJ. Characterization of hippocampal norepinephrine release as measured by micro-dialysis perfusion: pharmacological and behavioral studies. Neuroscience. 1988;27:897–904. [PubMed]
  • Aghajanian GK, VanderMaelen CP. Alpha 2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science. 1982;215:1394–1396. [PubMed]
  • Aguilar MA, Rodriguez-Arias M, Minarro J. Neurobiological mechanisms of the reinstatement of drug-conditioned place preference. Brain Res Rev. 2009;59:253–77. [PubMed]
  • Ahmed SH, Walker JR, Koob GF. Persistent increase in the motivation to take heroin in rats with history of drug escalation. Neuropsychopharmacology. 2000;22:413–421. [PubMed]
  • Back SE, Hartwell K, DeSantis SM, Saladin M, McRae-Clark AL, Price KL, Moran-Santa Maria MM, Baker NL, Spratt E, Kreek MJ, Brady KT. Reactivity to laboratory stress provocation predicts relapse to cocaine. Drug Alcohol Depend. 2010;106:21–27. [PMC free article] [PubMed]
  • Baker TB, Piper ME, McCarthy DE, Majeskie MR, Fiore MC. Addiction motivation reformulated: an affective processing model of negative reinforcement. Psychol Rev. 2004;111:33–51. [PubMed]
  • Bale TL. Stress sensitivity and the development of affective disorders. Horm Behav. 2006;50:529–533. [PubMed]
  • Ballard TM, Sanger S, Higgins GA. Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist. Eur J Pharmacol. 2001;412:255–264. [PubMed]
  • Banna KM, Back SE, Do P, See RE. Yohimbine stress potentiates conditioned cue-induced reinstatement of heroin-seeking in rats. Behav Brain Res. 2010;208:144–148. [PMC free article] [PubMed]
  • Barr CS, Dvoskin RL, Gupte M, Sommer W, Sun H, Schwandt ML, Lindell SG, Kasckow JW, Suomi SJ, Goldman D, Higley JD, Heilig M. Functional CRH variation increases stress-induced alcohol consumption in primates. Proc Nat Acad Sci USA. 2009;106:14593–14598. [PubMed]
  • Becker JB, Hu M. Sex differences in drug abuse. Front Neuroendocrinol. 2008;29:36–47. [PMC free article] [PubMed]
  • Becker JB, Monteggia LM, Perrot-Sinal TS, Romeo RD, Taylor JR, Yehuda R, Bale TL. Stress and disease: is being female a predisposing factor? J Neurosci. 2007;27:11851–11855. [PubMed]
  • Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry. 2008;165:617–620. [PubMed]
  • Blomeyer D, Treutlein J, Esser G, Schmidt MH, Schumann G, Laucht M. Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biol Psychiatry. 2008;63:146–151. [PubMed]
  • Bossert JM, Ghitza UE, Lu L, Epstein DH, Shaham Y. Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol. 2005;526:36–50. [PubMed]
  • Bouton ME, Swartzentruber D. Sources of relapse after extinction in Pavlovian and instrumental learning. Clin Psychol Rev. 1991;11:123–140.
  • Bremner JD, Krystal JH, Southwick SM, Charney DS. Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse. 1996a;23:28–38. [PubMed]
  • Bremner JD, Krystal JH, Southwick SM, Charney DS. Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse. 1996b;23:39–51. [PubMed]
  • Brown SA, Vik PW, McQuaid JR, Patterson TL, Irwin MR, Grant I. Severity of psychosocial stress and outcome of alcoholism treatment. J Abnorm Psychol. 1990;99:344–348. [PubMed]
  • Brown SA, Vik PW, Patterson TL, Grant I, Schuckit MA. Stress, vulnerability and adult alcohol relapse. J Stud Alcohol. 1995;56:538–545. [PubMed]
  • Brown ZJ, Tribe E, D’Souza NA, Erb S. Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat. Psychopharmacology. 2009;203:121–130. [PubMed]
  • Brownell KD, Marlatt GA, Lichtenstein E, Wilson GT. Understanding and preventing relapse. Am Psychol. 1986;41:765–782. [PubMed]
  • Bruijnzeel AW, Prado M, Isaac S. Corticotropin-releasing factor-1 receptor activation mediates nicotine withdrawal-induced deficit in brain reward function and stress-induced relapse. Biol Psychiatry. 2009;66:110–117. [PMC free article] [PubMed]
  • Buffalari DM, See RE. Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine. Psychopharmacology. 2011;213:19–27. [PMC free article] [PubMed]
  • Cannon WB. Stresses and strains of homeostasis. Am J Med Sci. 1935;189:1–14.
  • Capriles N, Rodaros D, Sorge RE, Stewart J. A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2003;168:66–74. [PubMed]
  • Carroll ME. The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats. Drug Alcohol Depend. 1985;16:95–109. [PubMed]
  • Carroll ME, Lynch WJ, Roth ME, Morgan AD, Cosgrove KP. Sex and estrogen influence drug abuse. Trends Pharmacol Sci. 2004;25:273–279. [PubMed]
  • Carter AJ. Hippocampal noradrenaline release in awake, freely moving rats is regulated by alpha-2 adrenoceptors but not by adenosine receptors. J Pharmacol Exp Ther. 1997;281:648–654. [PubMed]
  • Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992;267:1244–1452. [PubMed]
  • Coffey SF, Saladin ME, Drobes DJ, Brady KT, Dansky BS, Kilpatrick DG. Trauma and substance cue reactivity in individuals with comorbid posttraumatic stress disorder and cocaine or alcohol dependence. Drug Alcohol Depend. 2002;65:115–127. [PubMed]
  • Cohen F, Horowitz MJ, Lazarus RS, Moos RH, Robbins LN, Rose RM, Rutter M. Panel report on psychosocial and modifiers of stress. In: Eliott GR, Eisdorfer C, editors. Stress and human health. Springer; New York: 1982. pp. 147–188.
  • Cohen S, Evans GW, Stokols D, Krantz DS. Behavior, health, and environmental stress. Plenum Press; New York: 1986.
  • Conrad KL, McCutcheon JE, Cotterly LM, Ford KA, Beales M, Marinelli M. Persistent increases in cocaine-seeking behavior after acute exposure to cold swim stress. Biol Psychiatry. 2010;68:303–305. [PMC free article] [PubMed]
  • Cooney NL, Litt MD, Cooney JL, Pilkey DT, Steinberg HR, Oncken CA. Alcohol and tobacco cessation in alcohol-dependent smokers: analysis of real-time reports. Psychol Addict Behav. 2007;21:277–286. [PMC free article] [PubMed]
  • Dedovic K, Duchesne A, Andrews J, Engert V, Pruessner JC. The brain and the stress axis: the neural correlates of cortisol regulation in response to stress. Neuroimage. 2009;47:864–871. [PubMed]
  • Ebner K, Singewald N. The role of substance P in stress and anxiety responses. Amino Acids. 2006;31:251–272. [PubMed]
  • Ebner K, Singewald N. Stress-induced release of substance P in the locus coeruleus modulates cortical noradrenaline release. Naunyn Schmiedebergs Arch Pharmacol. 2007;376:73–82. [PubMed]
  • Ebner K, Rupniak NM, Saria A, Singewald N. Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci USA. 2004;101:4280–4285. [PubMed]
  • Ebner K, Singewald GM, Whittle N, Ferraguti F, Singewald N. Neurokinin 1 receptor antagonism promotes active stress coping via enhanced septal 5-HT transmission. Neuropsychopharmacology. 2008;33:1929–1941. [PubMed]
  • Elliott PJ. Place aversion induced by the substance P analogue, dimethyl-C7, is not state dependent: implication of substance P in aversion. Exp Brain Res. 1988;73:354–356. [PubMed]
  • Epstein DH, Preston KL. The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology. 2003;168:31–41. [PMC free article] [PubMed]
  • Epstein DH, Preston KL, Stewart J, Shaham Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology. 2006;189:1–16. [PMC free article] [PubMed]
  • Epstein DH, Marrone GF, Heishman SJ, Schmittner J, Preston KL. Tobacco, cocaine, and heroin: craving and use during daily life. Addict Behav. 2009a;35:318–324. [PMC free article] [PubMed]
  • Epstein DH, Willner-Reid J, Vahabzadeh M, Mezghanni M, Lin JL, Preston KL. Real-time electronic diary reports of cue exposure and mood in the hours before cocaine and heroin craving and use. Arch Gen Psychiatry. 2009b;66:88–94. [PMC free article] [PubMed]
  • Erb S. Evaluation of the relationship between anxiety during withdrawal and stress-induced reinstatement of cocaine seeking. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:798–807. [PubMed]
  • Erb S, Stewart J. A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on stress-induced reinstatement of cocaine seeking. J Neurosci. 1999;19:RC35. [PubMed]
  • Erb S, Shaham Y, Stewart J. Stress reinstates cocaine-seeking behavior after prolonged extinction and drug-free periods. Psychopharmacology. 1996;128:408–412. [PubMed]
  • Erb S, Shaham Y, Stewart J. The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats. J Neurosci. 1998;18:5529–5536. [PubMed]
  • Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J. Alpha-2 adrenergic agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology. 2000;23:138–150. [PubMed]
  • Erb S, Salmaso N, Rodaros D, Stewart J. A role for the CRF-containing pathway projecting from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology. 2001a;158:360–365. [PubMed]
  • Erb S, Shaham Y, Stewart J. Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala. Stress. 2001b;4:289–303. [PubMed]
  • Erb S, Petrovic A, Yi D, Kayyali H. Central injections of CRF reinstate cocaine seeking in rats after postinjection delays of up to 3 h: an influence of time and environmental context. Psychopharmacology. 2006;187:112–120. [PubMed]
  • Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol. 1931;72:74. [PubMed]
  • Feltenstein MW, See RE. Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine. Behav Brain Res. 2006;174:1–8. [PubMed]
  • Feltenstein MW, Henderson AR, See RE. Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Psychopharmacology. 2011 (in press) [PMC free article] [PubMed]
  • File SE. Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test. Pharmacol Biochem Behav. 1997;58:747–752. [PubMed]
  • Fox HC, Sinha R. Sex differences in drug-related stress-system changes: implications for treatment in substance-abusing women. Harv Rev Psychiatry. 2009;17:103–119. [PMC free article] [PubMed]
  • Fox HC, Hong KI, Siedlarz KM, Bergquist K, Anderson G, Kreek MJ, Sinha R. Sex-specific dissociations in autonomic and HPA responses to stress and cues in alcohol-dependent patients with cocaine abuse. Alcohol Alcohol. 2009;44:575–585. [PMC free article] [PubMed]
  • Funk D, Harding S, Juzytsch W, Le AD. Effects of unconditioned and conditioned social defeat on alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology. 2005;183:341–349. [PubMed]
  • Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol Psychiatry. 2007;61:78–86. [PMC free article] [PubMed]
  • Furmark T, Appel L, Michelgard A, Wahlstedt K, Ahs F, Zancan S, Jacobsson E, Flyckt K, Grohp M, Bergstrom M, Pich EM, Nilsson LG, Bani M, Langstrom B, Fredrikson M. Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol Psychiatry. 2005;58:132–142. [PubMed]
  • Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, Lu J, Hembre EJ, Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo R, Heilig M. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl- imidazo[1,2-b]pyrida-zine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci. 2007;27:2718–2726. [PubMed]
  • George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O’Dell LE, Richardson HN, Koob GF. CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci USA. 2007;104:17198–17203. [PubMed]
  • George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science. 2008;319:1536–1539. [PubMed]
  • Georges F, Aston-Jones G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. J Neurosci. 2001;21:RC160. [PubMed]
  • Georges F, Aston-Jones G. Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: a novel excitatory amino acid input to midbrain dopamine neurons. J Neurosci. 2002;22:5173–5187. [PubMed]
  • Ghitza UE, Gray SM, Epstein DH, Rice KC, Shaham Y. The anxiogenic drug yohimbine reinstates palatable food seeking in a rat relapse model: a role of CRF(1) receptors. Neuropsychopharmacology. 2006;31:2188–2196. [PMC free article] [PubMed]
  • Ghitza UE, Nair SG, Golden SA, Gray SM, Uejima JL, Bossert JM, Shaham Y. Peptide YY3-36 decreases reinstatement of high-fat food seeking during dieting in a rat relapse model. J Neurosci. 2007;27:11522–11532. [PMC free article] [PubMed]
  • Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159:1642–1452. [PMC free article] [PubMed]
  • Goldstein JM, Jerram M, Abbs B, Whitfield-Gabrieli S, Makris N. Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci. 2010;30:431–438. [PMC free article] [PubMed]
  • Greenwell TN, Funk CK, Cottone P, Richardson HN, Chen SA, Rice KC, Zorrilla EP, Koob GF. Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long- but not short-access rats. Addict Biol. 2009;14:130–143. [PMC free article] [PubMed]
  • Hall SM, Havassy BE, Wassermann DA. Commitment to abstinence and acute stress in relapse to alcohol, opiates and nicotine. J Counsel Clin Psychol. 1990;58:175–181. [PubMed]
  • Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Bjork K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R. Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci USA. 2006;103:15236–15241. [PubMed]
  • Heilig M, Koob GF. A key role for corticotropin-releasing factor in alcohol dependence. Trend Neurosci. 2007;30:399–406. [PMC free article] [PubMed]
  • Highfield D, Yap J, Grimm J, Shalev U, Shaham Y. Repeated lofexidine treatment attenuates stress-induced, but not drug cues-induced reinstatement of a heroin-cocaine mixture (speedball) seeking in rats. Neuropsychopharmacology. 2001;25:320–331. [PubMed]
  • Hunt WA, Barnett LW, Branch LG. Relapse rates in addiction programs. J Clin Psychol. 1971;27:455–456. [PubMed]
  • Hyman SM, Fox H, Hong KI, Doebrick C, Sinha R. Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment. Exp Clin Psychopharmacol. 2007;15:134–143. [PMC free article] [PubMed]
  • Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL. Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology. 2011 (in press) [PMC free article] [PubMed]
  • Julius D. NIDA’s naltrexone research program. NIDA Res Monogr. 1976;9:5–11. [PubMed]
  • Kalivas PW, McFarland K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology. 2003;168:44–56. [PubMed]
  • Katz JL, Higgins ST. The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology. 2003;168:21–30. [PubMed]
  • Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, Hargreaves R, Hietala J, Lines C, Beebe K, Reines S. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry. 2006;59:216–223. [PubMed]
  • Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, See RE. Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology. 2005;182:245–252. [PubMed]
  • Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81. [PubMed]
  • Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998a;281:1640–1645. [PubMed]
  • Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Rupniak NM. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998b;281:1640–1645. [PubMed]
  • Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild AJ, Snavely D, Ghosh K, Ball WA, Reines SA, Munjack D, Apter JT, Cunningham L, Kling M, Bari M, Getson A, Lee Y. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology. 2004;29:385–392. [PubMed]
  • Kreibich AS, Blendy JA. cAMP response element-binding protein is required for stress but not cocaine-induced reinstatement. J Neurosci. 2004;24:6686–6692. [PubMed]
  • Kupferschmidt DA, Brown ZJ, Erb S. A procedure for studying the footshock-induced reinstatement of cocaine seeking in laboratory rats. J Vis Exp. 2011 doi: 10.3791/2265. [PubMed] [Cross Ref]
  • Kvetnansky R, Mikulaj L. Adrenal and urinary catecholamines in rats during adaptation to repeated immobilization stress. Endocrinology. 1970;87:738–743. [PubMed]
  • Lang PJ, Bradley MM, Cuthbert BN. International affective picture system (IAPS): technical manual and affective ratings. The Center for Research in Psychophysiology, University of Florida; 1995.
  • Le A, Shaham Y. Neurobiology of relapse to alcohol in rats. Pharmacol Ther. 2002;94:137–156. [PubMed]
  • Le AD, Poulos CX, Harding S, Watchus W, Juzytsch W, Shaham Y. Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress in rats. Neuropsychopharmacology. 1999;21:435–444. [PubMed]
  • Le AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y. The role of corticotropin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology. 2000;150:317–324. [PubMed]
  • Le AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y. The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J Neurosci. 2002;22:7844–7849. [PubMed]
  • Le AD, Harding S, Juzytsch W, Funk D, Shaham Y. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology. 2005;179:366–373. [PubMed]
  • Le AD, Funk D, Harding S, Juzytsch W, Fletcher PJ. The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats. Psychopharmacology. 2009;204:477–488. [PMC free article] [PubMed]
  • Lê AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, Shaham Y. Effects of prazosin and guanfacine on yohimbine-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology. 2011 (in press) [PMC free article] [PubMed]
  • Lee B, Tiefenbacher S, Platt DM, Spealman RD. Pharmacological blockade of alpha(2)-arenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsycho-pharmacology. 2004;29:686–693. [PubMed]
  • Leri F, Flores J, Rodaros D, Stewart J. Blockade of stress-induced, but not cocaine-induced reinstatement, by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci. 2002;22:5713–5718. [PubMed]
  • Liston C, McEwen BS, Casey BJ. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc Nat Acad Sci USA. 2009;106:912–917. [PubMed]
  • Liu X, Weiss F. Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci. 2002;22:7856–7861. [PubMed]
  • Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature. 2001;412:150–157. [PubMed]
  • Lu L, Shepard JD, Scott Hall F, Shaham Y. Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci Biobehav Rev. 2003;27:457–491. [PubMed]
  • Lubman DI, Yucel M, Kettle JW, Scaffidi A, Mackenzie T, Simmons JG, Allen NB. Responsiveness to drug cues and natural rewards in opiate addiction: associations with later heroin use. Arch Gen Psychiatry. 2009;66:205–212. [PubMed]
  • Lynch WJ. Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol. 2006;14:34–41. [PubMed]
  • Mantsch JR, Goeders NE. Ketoconazole blocks the stress-induced reinstatement of cocaine-seeking behavior in rats: relationship to the discriminative stimulus effects of cocaine. Psychopharmacology. 1999;142:399–407. [PubMed]
  • Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP. Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats. Psychopharmacology. 2008;195:591–603. [PubMed]
  • Mantsch JR, Weyer A, Vranjkovic O, Beyer CE, Baker DA, Caretta H. Involvement of noradrenergic neurotransmission in the stress- but not cocaine-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: role for beta-2 adrenergic receptors. Neuropsychopharmacology. 2010;35:2165–2178. [PMC free article] [PubMed]
  • Mantyh PW, Hunt SP, Maggio JE. Substance P receptors: localization by light microscopic autoradiography in rat-brain using [3H]Sp as the radioligand. Brain Res. 1984;307:147–165. [PubMed]
  • Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, Le AD. The CRF(1) receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology. 2007;195:345–355. [PubMed]
  • McFarland K, Davidge SB, Lapish CC, Kalivas PW. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci. 2004;24:1551–1560. [PubMed]
  • McKee S, Sinha R, Weinberger AH, Sofuoglu M, Harrison EL, Lavery M, Wanzer J. Stress decreases the ability to resist smoking and potentiates smoking intensity and reward. J Psychopharmacol. 2011;4:490–502. [PubMed]
  • Miczek KA, Weerts E, Haney M, Tidey J. Neurobiological mechanisms controlling aggression: preclinical developments for pharmacotherapeutic interventions. Neurosci Biobehav Rev. 1994;18:97–110. [PubMed]
  • Miczek KA, Yap JJ, Covington HE., 3rd Social stress, therapeutics and drug abuse: preclinical models of escalated and depressed intake. Pharmacol Ther. 2008;120:102–128. [PMC free article] [PubMed]
  • Mongeau R, Blier P, de Montigny C. The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments. Brain Res Rev. 1997;23:145–195. [PubMed]
  • Monti PM, Rohsenow DJ, Rubonis AV, Niaura RS, Sirota AD, Colby SM, Abrams DB. Alcohol cue reactivity: effects of detoxification and extended exposure. J Stud Alcohol. 1993;54:235–245. [PubMed]
  • Nair SG, Adams-Deutsch T, Epstein DH, Shaham Y. The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog Neurobiol. 2009;89:18–45. [PMC free article] [PubMed]
  • Nair SG, Navarre BM, Cifani C, Pickens CL, Bossert JM, Shaham Y. Role of dorsal medial prefrontal cortex dopamine D1-family receptors in relapse to high-fat food seeking induced by the anxiogenic drug yohimbine. Neuropsychopharmacology. 2011;36:497–510. [PMC free article] [PubMed]
  • Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J Comp Neurol. 1994;347:249–274. [PubMed]
  • Naqvi NH, Bechara A. The hidden island of addiction: the insula. Trends Neurosci. 2009;32:56–67. [PubMed]
  • Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science. 2007;315:531–534. [PubMed]
  • Nelson EC, Agrawal A, Pergadia ML, Wang JC, Whitfield JB, Saccone FS, Kern J, Grant JD, Schrage AJ, Rice JP, Montgomery GW, Heath AC, Goate AM, Martin NG, Madden PA. H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence. Addict Biol. 2010;15:1–11. [PMC free article] [PubMed]
  • O’Brien CP, Gardner EL. Critical assessment of how to study addiction and its treatment: human and non-human animal models. Pharmacol Ther. 2005;108:18–58. [PubMed]
  • O’Doherty F, Davies BJ. Life events and addiction: a critical review. Br J Addict. 1987;82:127–137. [PubMed]
  • Pan JW, Stein DT, Telang F, Lee JH, Shen J, Brown P, Cline G, Mason GF, Shulman GI, Rothman DL, Hetherington HP. Spectroscopic imaging of glutamate C4 turnover in human brain. Magn Reson Med. 2000;44:673–679. [PubMed]
  • Papp M, Vassout A, Gentsch C. The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats. Behav Brain Res. 2000;115:19–23. [PubMed]
  • Pavlov IP. Conditioned reflexes. Oxford University Press; UK: 1927.
  • Payan DG. Neuropeptides and inflammation: the role of substance P. Annu Rev Med. 1989;40:341–352. [PubMed]
  • Perry W, Minassian A, Paulus MP, Young JW, Kincaid MJ, Ferguson EJ, Henry BL, Zhuang X, Masten VL, Sharp RF, Geyer MA. A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men. Arch Gen Psychiatry. 2009;66:1072–1780. [PMC free article] [PubMed]
  • Piazza PV, Le Moal M. The role of stress in drug self-administration. Trends Pharmacol Sci. 1998;19:67–74. [PubMed]
  • Preston KL, Epstein DH. Stress in the daily lives of cocaine and heroin users: Relationship to mood, craving, relapse triggers, and cocaine use. Psychopharmacology. 2011 in press. [PMC free article] [PubMed]
  • Redila VA, Chavkin C. Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology. 2008;200:59–70. [PMC free article] [PubMed]
  • Redmond DEJ, Huang YH. Locus coeruleus and anxiety. Life Sci. 1979;25:2149–2162. [PubMed]
  • Ribeiro Do Couto B, Aguilar MA, Manzanedo C, Rodriguez-Arias M, Armario A, Minarro J. Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice. Psychopharmacology. 2006;185:459–470. [PubMed]
  • Rodaros D, Caruana DA, Amir S, Stewart J. Corticotropin-releasing factor projections from limbic forebrain and para-ventricular nucleus of the hypothalamus to the region of the ventral tegmental area. Neuroscience. 2007;150:8–13. [PubMed]
  • Rupniak NM, Carlson EC, Harrison T, Oates B, Seward E, Owen S, De Felipe C, Hunt S, Wheeldon A. Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology. 2000;39:1413–1421. [PubMed]
  • Rupniak NMJ, Carlson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, De Felipe C, Hunt SP, Oates B, Wheeldon A. Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol. 2001;12:497–508. [PubMed]
  • Sallee FR, Eaton K. Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD) Expert Opin Pharmac-other. 2010;11:2549–2556. [PubMed]
  • Sanchez CJ, Sorg BA. Conditioned fear stimuli reinstate cocaine-induced conditioned place preference. Brain Res. 2001;908:86–92. [PubMed]
  • Sanchez CJ, Bailie TM, Wu WR, Li N, Sorg BA. Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior. Neuroscience. 2003;119:497–505. [PubMed]
  • Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, Hen R, Heath MJ. Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci USA. 2001;98:1912–1917. [PubMed]
  • Sawchenko PE, Li HY, Ericsson A. Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res. 2000;122:61–78. [PubMed]
  • Schank JR, Pickens CL, Rowe KE, Cheng K, Thorsell A, Rice KC, Shaham Y, Heilig M. Stress-induced reinstatement of alcohol seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L822429. Psychopharmacology. 2011 (in press) [PMC free article] [PubMed]
  • Scriabine A, Sweet CS, Ludde CT, Stavorski JM, Wenger HC, Bohidar NR. Some cardiovascular effects of ST-91 and clonidine. Eur J Pharmacol. 1975;43:333–341. [PubMed]
  • See RE. Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol. 2005;526:140–146. [PubMed]
  • See RE, Waters RP. Pharmacologically-induced stress: a cross-species probe for translational research in drug addiction and relapse. Am J Transl Res. 2010;3:81–89. [PMC free article] [PubMed]
  • Selye H. The stress of life. McGraw-Hill; New York: 1956.
  • Seo D, Sinha R. Neuroimaging stress in addiction. In: Adinoff B, Stein E, editors. Neuroimaging and addiction. Wiley and Sons; 2011. (in press)
  • Seo D, Jia Z, Lacadie C, Tsou K, Bergquist K, Sinha R. Sex differences in neural response to stress and alcohol context cues. Human Brain Mapping. 2011 (in press) [PMC free article] [PubMed]
  • Shaham Y. Effect of stress on opioid-seeking behavior: evidence from studies with rats. Ann Behav Med. 1996;18:255–263. [PubMed]
  • Shaham Y, Stewart J. Stress reinstates heroin self-administration behavior in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology. 1995;119:334–341. [PubMed]
  • Shaham Y, Stewart J. Effects of opioid and dopamine receptor antagonists on relapse induced by stress and reexposure to heroin in rats. Psychopharmacology. 1996;125:385–391. [PubMed]
  • Shaham Y, Funk D, Erb S, Brown TJ, Walker CD, Stewart J. Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci. 1997;17:2605–2614. [PubMed]
  • Shaham Y, Erb S, Stewart J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev. 2000a;33:13–33. [PubMed]
  • Shaham Y, Highfield D, Delfs JM, Leung S, Stewart J. Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of the locus coeruleus noradrenergic neurons. Eur J Neurosci. 2000b;12:292–302. [PubMed]
  • Shaham Y, Shalev U, Lu L, De Wit H, Stewart J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology. 2003;168:3–20. [PubMed]
  • Shalev U, Highfield D, Yap J, Shaham Y. Stress and relapse to drug seeking in rats: studies on the generality of the effect. Psychopharmacology. 2000;150:337–346. [PubMed]
  • Shalev U, Morales M, Hope B, Yap J, Shaham Y. Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology. 2001a;156:98–107. [PubMed]
  • Shalev U, Yap J, Shaham Y. Leptin attenuates food deprivation-induced relapse to heroin seeking. J Neurosci. 2001b;21:RC129. [PubMed]
  • Shalev U, Grimm JW, Shaham Y. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev. 2002;54:1–42. [PubMed]
  • Shalev U, Erb S, Shaham Y. Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking. Brain Res. 2010;1314:15–28. [PMC free article] [PubMed]
  • Shepard JD, Bossert JM, Liu SY, Shaham Y. The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry. 2004;55:1082–1089. [PubMed]
  • Shiffman S. Dynamic influences on smoking relapse process. J Pers. 2005;73:1715–1748. [PubMed]
  • Shiffman S, Waters AJ. Negative affect and smoking lapses: a prospective analysis. J Consult Clin Psychol. 2004;72:192–201. [PubMed]
  • Shiffman S, Paty JA, Gnys M, Kassel JA, Hickcox M. First lapses to smoking: within-subjects analysis of real-time reports. J Consult Clin Psychol. 1996;64:366–379. [PubMed]
  • Shiffman S, Waters A, Hickcox M. The nicotine dependence syndrome scale: a multidimensional measure of nicotine dependence. Nicotine Tob Res. 2004;6:327–348. [PubMed]
  • Shors TJ. Stressful experience and learning across the lifespan. Annu Rev Psychol. 2006;57:55–85. [PMC free article] [PubMed]
  • Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG. Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci USA. 1998;95:316–321. [PubMed]
  • Singewald N, Chicchi GG, Thurner CC, Tsao KL, Spetea M, Schmidhammer H, Sreepathi HK, Ferraguti F, Singewald GM, Ebner K. Modulation of basal and stress-induced amygdaloid substance P release by the potent and selective NK1 receptor antagonist L-822429. J Neurochem. 2008;106:2476–2488. [PubMed]
  • Sinha R. How does stress increase risk of drug abuse and relapse. Psychopharmacology. 2001;158:343–359. [PubMed]
  • Sinha R. Modeling stress and drug craving in the laboratory: implications for addiction treatment development. Addict Biol. 2009;14:84–98. [PMC free article] [PubMed]
  • Sinha R, Catapano D, O’Mally S. Stress-induced craving and stress responses in cocaine dependent individuals. Psychopharmacology. 1999;142:343–351. [PubMed]
  • Sinha R, Fuse T, Aubin LR, O’Malley SS. Psychological stress, drug-related cues and cocaine craving. Psychopharmacology. 2000;152:140–148. [PubMed]
  • Sinha R, Lacadie C, Skudlarski P, Fulbright RK, Kosten TR, Rounsaville BJ, Wexler BE. Neural activity associated with stress-induced cocaine craving: an fMRI study. Annal N Y Acad Sci. 2004;1032:254–257.
  • Sinha R, Lacadie C, Skudlarski P, Fulbright RK, Rounsaville BJ, Kosten TR, Wexler BE. Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study. Psychopharmacology. 2005;183:171–180. [PubMed]
  • Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ. Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry. 2006;63:324–331. [PubMed]
  • Sinha R, Kimmerling A, Doebrick C, Kosten TR. Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings. Psychopharmacology. 2007;190:569–574. [PubMed]
  • Sinha R, Fox HC, Hong KI, Siedlarz K, Tuit K, Kreek MJ. Effects of adrenal sensitivity, stress and cue induced alcohol craving and anxiety on subsequent relapse and treatment outcomes. Archives of General Psychiatry. 2011a (in press) [PubMed]
  • Sinha R, Hong KA, Seo D, Fox H, Bergquist K. Neural and endocrine predictions of alcohol relapse risk. Alcoholism: Clin Exp Res. 2011b (in press)
  • Skinner BF. Appleton-Century-Crofts, Appleton-Century-Crofts. 1938. The behavior of organisms.
  • Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, Heilig M. Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence. Biol Psychiatry. 2008;63:139–145. [PubMed]
  • Soufer R, Bremner JD, Arrighi JA, Cohen I, Zaret BL, Burg MM, Goldman-Rakic P. Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease. Proc Natl Acad Sci USA. 1998;95:6454–6459. [PubMed]
  • Specio SE, Wee S, O’Dell LE, Boutrel B, Zorrilla EP, Koob GF. CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharmacology. 2008;196:473–482. [PMC free article] [PubMed]
  • Stanford SC. Central noradrenergic neurones and stress. Pharmacol Ther. 1995;68:297–342. [PubMed]
  • Stine SM, Southwick SM, Petrakis IL, Kosten TR, Charney DS, Krystal JH. Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients. Biol Psychiatry. 2002;51:642–651. [PubMed]
  • Tanaka M, Tsuda A, Yokoo H, Yoshida M, Yoshishige I, Nishimura H. Involvement of the brain noradrenaline system in emotional changes caused by stress in rats. Annal N Y Acad Sci. 1990;597:159–174. [PubMed]
  • Teixeira RM, Santos AR, Ribeiro SJ, Calixto JB, Rae GA, De Lima TC. Effects of central administration of tachykinin receptor agonists and antagonists on plus-maze behavior in mice. Eur J Pharmacol. 1996;311:7–14. [PubMed]
  • Treutlein J, Kissling C, Frank J, Wiemann S, Dong L, Depner M, Saam C, Lascorz J, Soyka M, Preuss UW, Rujescu D, Skowronek MH, Rietschel M, Spanagel R, Heinz A, Laucht M, Mann K, Schumann G. Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Mol Psychiatry. 2006;11:594–602. [PubMed]
  • Umhau JC, Schwandt ML, Usala J, Geyer C, Singley E, George TD, Heilig M. Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology. 2011;60:303–311. [PMC free article] [PubMed]
  • Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 1981;213:1394–1397. [PubMed]
  • Van Loon GR, Kvetnansky R, McCarty R, Axelrod J. Stress: neurochemical and humoral mechanisms. Gordon & Breach; New York: 1989.
  • Varty GB, Cohen-Williams ME, Morgan CA, Pylak U, Duffy RA, Lachowicz JE, Carey GJ, Coffin VL. The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists. Neuropsychopharmacology. 2002;27:371–379. [PubMed]
  • Voorn P, Vanderschuren LJ, Groenewegen HJ, Robbins TW, Pennartz CM. Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci. 2004;27:468–474. [PubMed]
  • Wang X, Cen X, Lu L. Noradrenaline in the bed nucleus of the stria terminalis is critical for stress-induced reactivation of morphine-conditioned place preference in rats. Eur J Pharmacol. 2001;432:153–161. [PubMed]
  • Wang B, Luo F, Ge XC, Fu AH, Han JS. Effects of lesions of various brain areas on drug priming or footshock-induced reactivation of extinguished conditioned place preference. Brain Res. 2002;950:1–9. [PubMed]
  • Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB. Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci. 2005;25:5389–5396. [PubMed]
  • Wang J, Fang Q, Liu Z, Lu L. Region-specific effects of brain corticotropin-releasing factor receptor type 1 blockade on footshock-stress- or drug-priming-induced reinstatement of morphine conditioned place preference in rats. Psychopharmacology. 2006;185:19–28. [PubMed]
  • Wang B, You ZB, Rice KC, Wise RA. Stress-induced relapse to cocaine seeking: roles for the CRF(2) receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacology. 2007;193:283–294. [PubMed]
  • Wikler A. Dynamics of drug dependence, implication of a conditioning theory for research and treatment. Arch Gen Psychiatry. 1973;28:611–616. [PubMed]
  • Xi ZX, Gilbert J, Campos AC, Kline N, Ashby CR, Jr, Hagan JJ, Heidbreder CA, Gardner EL. Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats. Psychopharmacology. 2004;176:57–65. [PubMed]
  • Yamada H, Bruijnzeel AW. Stimulation of alpha2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats. Neuropharmacology. 2011;60:303–311. [PMC free article] [PubMed]
  • Zislis G, Desai TV, Prado M, Shah HP, Bruijnzeel AW. Effects of the CRF receptor antagonist D-Phe CRF(12–41) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats. Neuropharmacology. 2007;53:958–966. [PMC free article] [PubMed]
  • Zorrilla EP, Koob GF. Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today. 2010;15:371–383. [PMC free article] [PubMed]
  • Zorrilla EP, Valdez GR, Weiss F. Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats. Psychopharmacology. 2001;158:374–381. [PubMed]