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Published in final edited form as: J Neurosci Res. 2017 Jan 2;95(1-2):320–327. doi: 10.1002/jnr.23860

Impact of sex and gender on corticotropin releasing factor and noradrenergic sensitivity in cocaine use disorder

Aimee L McRae-Clark 1, Angie M Cason 2, Amy S Kohtz 3, Megan Moran-Santa Maria 1, Gary Aston-Jones 3, Kathleen T Brady 1
PMCID: PMC5120611  NIHMSID: NIHMS802411  PMID: 27870396

Abstract

Responses to stress may be important in understanding sex and gender differences in substance use disorders and may also be a target for development of treatment interventions. A growing body of both preclinical and clinical research supports important underlying sex and gender differences in the corticotropin releasing factor (CRF) and noradrenergic systems, which may contribute to drug use. Preclinical models have demonstrated increased sensitivity of females as compared to males to CRF and noradrenergic-induced drug reinstatement, and, consistent with these findings, human laboratory studies have demonstrated greater sensitivity to corticotropin releasing hormone (CRH) and noradrenergic stimulation in cocaine-dependent women as compared to men. Further, neuroimaging studies have demonstrated increased neural response to stressful stimuli in cocaine-dependent women as compared to men, as well as shown significant sex differences in the sensitivity of brain regions responsible for regulating response to CRH. Development of interventions targeting the noradrenergic system and stress response in drug-dependent individuals could have important clinical implications for both women and men.

Keywords: corticotropin releasing hormone, norepinephrine, yohimbine, guanfacine, translational

Introduction

Important gender differences exist in the symptomatology, course and treatment of cocaine use disorder. Approximately 34% of the 3.5 million individuals in the United States who reported cocaine use in 2014 were women (SAMSHA, 2015). Despite the lower prevalence of use, there is evidence that women may actually have increased vulnerability to the development of cocaine dependence and to the deleterious consequences of cocaine use. For example, women meet criteria for drug use disorder more quickly and enter treatment programs earlier as compared to men (Brecht et al., 2004; Cotto et al., 2010; Hernandez-Avila et al., 2004; McCance-Katz, 1999; Ridenour et al., 2005; Westermeyer & Boedicker, 2000). Further, women with cocaine dependence also have greater psychiatric, medical, social/family, and employment problems (Brady & Randall, 1999; Elman et al., 2001; Najavits & Lester, 2008; Wong et al., 2002) and are more likely to attribute relapse to negative emotional states and interpersonal conflict than men (Terry-McElrath et al., 2009). These findings suggest gender differences in cocaine dependence that may have important treatment implications.

Stress is an important predictor of relapse (Back et al., 2010; Cooney et al., 1997; Sinha et al., 2006). A growing body of literature supports underlying sex and gender differences in arousal and stress reactivity, particularly in the corticotropin releasing factor (CRF) and noradrenergic systems. This review will focus first on preclinical models exploring sex differences in substance use disorders, specifically cocaine. Second, evidence for gender differences in stress response from clinical neuroimaging and human laboratory trials involving cocaine-using individuals will be presented. Finally, potential therapeutic interventions targeting stress dysregulation and gender differences in response will be briefly discussed.

CRF and Norepinephrine in stress-induced withdrawal and reinstatement: role of sex differences

The corticotropin releasing factor (CRF) system plays an essential role in the response to stress. In general, female rats display greater hypothalamic pituitary adrenal (HPA) axis activation and greater norepinephrine (NE) response to stressors compared to male rats (Heinsbrook et al., 1990; Heinsbroek et al 1991). Recent findings indicate that sex differences in the CRF system may contribute to sex differences in substance use. Chronic exposure to drugs of abuse produces increased anxiety-like behaviors that are associated with increased CRF receptor expression and increased locus coeruleus (LC)-NE activation in female compared to male rats (Valentino et al., 2012; Reston et al., 2015). During drug withdrawal, intact female rats exhibit increased anxiety-like behaviors and increased CRF gene expression compared to ovarectomized females (Torres et al., 2015). Following abstinence, stress drives reinstatement of drug seeking in a CRF-dependent manner; female rats are more sensitive to the effect of stress on drug seeking than males, and show greater stress-induced reinstatement than males (Shaham et al., 1997; Erb et al., 1998; Shaham et al., 1998; Le et al., 2000; Anker and Carroll, 2010; Buffalari et al., 2012). Collectively, these findings indicate that stress-associated drug use is regulated in a sex-dependent manner that is modulated by ovarian hormones in the female rat.

It is well known that interactions between the brain’s NE and CRF systems play an important role in stress response. LC-NE neurons in females are more sensitive to CRF and CRF receptor activation than in males; interestingly, this effect is independent of estrous cycle (Curtis, Bethea, & Valentino, 2006). In animal models, stress drives reinstatement of cocaine-seeking in a CRF-dependent manner (Erb et al., 1998, Shaham et al., 1998), and females show greater stress-induced reinstatement than males following the administration of the pharmacological stressor, yohimbine, or intracranial infusions of CRF (Anker and Carroll, 2010; Buffalari et al., 2012; Feltenstein et al., 2011). Notably, greater stress-induced reinstatement in females is dependent upon estrous cycles with females in proestrus demonstrating the highest levels of stress-induced reinstatement in response to yohimbine (Feltenstein et al., 2011).

In addition to showing increased cocaine seeking following a period of abstinence, females show increased responding during initial abstinence, extinction day one (ED1), following a period of chronic cocaine exposure compared to males (Fuchs et al., 2005; Kippin et al., 2005; Feltenstein et al., 2011). It is unclear if increased responding on ED1 in females is dependent upon estrous cycle of the female rat (Feltenstein and See, 2007; Feltenstein et al., 2009). In a recent study, the authors hypothesized that the initiation of abstinence, ED1, is stressful due to the absence of drug thereby engaging the CRF and NE systems to promote increased cocaine seeking (Cason et al. 2016; Kohtz and Aston-Jones, under revision). This hypothesis was tested by blocking CRF1 signaling using a selective CRF1 receptor antagonist, CP-154,526 (CP) and investigating the impact on drug seeking on ED1 measured by responding on an active lever previously associated with cocaine self-administration. Following chronic cocaine self-administration, female and male rats underwent a test for extinction responding by measuring lever pressing in the absence of cocaine after injection with vehicle or the selective CRF1 antagonist (CP). Findings from this study indicate that pretreatment with CP decreased cocaine seeking on ED1 more effectively in female compared to male rats (Cason et al., 2016). Moreover, increased responding on ED1 was associated with increased Fos activation in LC-NE on ED1 compared to control animals and control regions, including noradrenaline cells in A1 and A2/nucleus of solitary tract (Cason et al., 2016). Together, these findings indicate that signaling at CRF receptors in LC is involved in increased drug seeking during initial abstinence.

Noradrenergic contributions to stress-related drug seeking has been predominantly studied in male rats, despite the fact that female rats have higher expression of adrenergic receptors in brain regions that modulate motivation and drug seeking behaviors (Ferris et al., 2007; Espana et al., 2016). Systemic α1 and β-adrenergic receptor antagonists, or auto-receptor agonists such as clonidine that decrease NE release, block stress-induced reinstatement of drug seeking in male rats (Amit et al., 1977; Brown et al., 1977; Erb et al 2000; Weinshenker et al., 2000; Shaham et al., 2000; Leri and Stewart, 2002; Ventura et al., 2005; Lê et al., 2005; Lê et al., 2011; Smith and Aston-Jones 2011). In clinical studies, administration of beta blockers, such as carvedilol or propranolol, reduced cocaine self-administration, increased treatment retention, and promoted periods of abstinence in cocaine-dependent individuals (Sofuoglu, et al. 2000, Kampman, et al. 1999; 2001). A recent study by Kohtz and Aston-Jones tested the hypothesis that NE systems are involved in sex differences in drug-seeking behavior on ED1 using previously published methods (Cason, et al. 2016). Prior to the ED1 test session, rats were injected with S-propranolol (10mg/kg, intraperitoneally), a β–adrenergic receptor (β-AR) antagonist, to measure the effects of NE antagonism on cocaine-seeking during early abstinence. The findings indicate that S-propranolol was more effective in reducing ED1 drug seeking in female compared to male rats (F(1,56)=10.59, p <0.01; Fig 1b). In addition, female rats had higher levels of corticosterone on ED1 compared to male rats (t=2.013, df=12, p<0.05; Fig. 1a; Cason et al., 2016). Taken together with previous findings, these results suggest that interaction with CRF and LC-NE signaling mechanisms may influence aspects of sex differences in stress-induced drug seeking, particularly during initial abstinence.

Figure 1.

Figure 1

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Effects of adrenergic antagonists on ED1 drug-seeking. Rats were trained to self-administer cocaine on a fixed-ratio 1 schedule for 10 days prior to ED1 testing. On ED1, rats were returned to the context in which they previously acquired drug, with cues and cocaine or other rewards absent. Active lever pressing over a 90-minute period was recorded as a measure of cocaine-seeking behavior as per prior methods (Cason et al. 2016). Panel A. Extinction Day 1: Stress Response. Immediately following the 90-minute ED1 session, whole blood was extracted via catheter blood draw. Plasma was processed via previously reported methods (Cason, et al. 2016) and analyzed for corticosterone concentration utilizing the Enzo Sciences ELISA kit. ED1 exposure increased corticosterone levels compared to homecage controls. * indicates significant difference in females compared to males (P <0.05). Panel B. Extinction Day 1: Systemic Antagonists. Systemic administration of S-propranolol, a beta-adrenergic antagonist, at 10mg/kg ip 30-minutes prior to the start of the ED1 session decreased drug-seeking behavior on ED1. S-propranolol was more effective in reducing ED1 drug-seeking among females (** P <0.01) compared to males (* P <0.05). C. Extinction Day 1: Intrahippocampus Antagonists. S-propranolol infused directly to the dorsal hippocampus 10-minutes prior to the start of the ED1 session reduced drug-seeking behavior on ED1 among males (* P <0.05). A cocktail of specific b1 and b2 antagonists, betaxolol + ICI 118–551, or S-propranolol infused to the dorsal hippocampus 10-minutes prior to the ED1 session, reduced cocaine-seeking amongfemales (** P <0.05). These data suggest that adrenergic actions may drive drug-seeking among females, in particular via the dorsal hippocampus, however there may be alternative signaling in males.

LC-NE and Downstream Neural Targets in Drug-Seeking

LC-NE neurons have widespread projections across the forebrain that actively regulate arousal and stress reactivity. The dorsal hippocampus (DH) is a prominent focal region in stress circuitry and receives strong input from LC-NE neurons (Foote et al., 1983; Robertson et al., 2013). The DH has a number of structural and biochemical sex differences that modulate stress and can be altered by exposure to stressors. For example, females show greater CRF receptor binding affinity, increased serotonin synthesis, and increased adrenergic-, corticosterone-, and GABA-receptor expression as compared to males (Turner, 1992; Madeira and Paula-Barbosa, 1993; Galea et al., 1997; Rhodes and Rubin, 1999; Shors et al., 2001). In addition, findings from a recent study by Kohtz and Aston-Jones demonstrate that selective inhibition of β-ARs with S-propranolol or with a cocktail of selective β-AR antagonists betaxolol+ICI-118,551 microinjected into the DH attenuates drug seeking during initial abstinence (ED1; ED1; (F(1,40)=5.083, p<0.05). Post-hoc analyses reveal that the betaxolol+ICI-118,551 cocktail was effective in female (t=2.144, df=15, p<0.05), but not male rats (t=0.5156, df=11, p=0.6164; Fig 1c). Thus, in the dorsal hippocampus, β-ARs may play a larger role in drug-seeking behaviors among females compared to males (Kohtz & Aston-Jones, under revision).

Other structures, such as the medial prefrontal cortex (mPFC), receive NE solely from LC, which is implicated in drug seeking and may play a role in sex differences in stress-induced reinstatement (Andén et al., 1966; Lindvall and Bjorklund, 1984; McFarland and Kalivas, 2001; McLaughlin and See, 2003; Kalivas and Volkow, 2005; Koya et al., 2008). Inhibition of PFC neural activity blocks cue- or drug-induced reinstatement of cocaine seeking suggesting that the PFC may be a site where NE modulates reinstatement of drug seeking behaviors (Capriles et al., 2003; McLaughlin and See, 2003). Unfortunately, studies on how NE action in the PFC affects drug reinstatement have not been performed in females; however, sex differences in basal function of PFC may provide some insight into how NE activity in the mPFC might influence sex differences in stress-induced reinstatement of drug seeking. Adult female rats have higher expression of adrenergic receptors in mPFC compared to male rats (Ferris et al., 2007). In response to stressors, there is enhanced dendritic branching in females compared to atrophy in males and increased activation of intracellular stress signaling pathways in females compared to males (Arnsten, 2009; Garrett and Wellman 2009). Therefore, it seems likely that NE projections to mPFC may account for some sex differences in stress-induced reinstatement. In conclusion, sex differences in drug seeking associated with stress may involve interactions between CRF-NE systems in LC, and involve NE projections from LC to mPFC and DH in addition to CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala (Mantsch et al., 2016).

Human Laboratory Paradigms Investigating Gender Differences in Stress and Cocaine Use Disorder

Human laboratory paradigms have been utilized in systematic investigations of gender differences in cocaine use disorders. In response to physical, cognitive, or social stress tasks, cocaine-dependent women demonstrate greater subjective reactivity, as evidenced by significantly higher ratings of stress, nervousness, and pain as compared to men (Back et al., 2005; Fox et al. 2006; Fox et al. 2008). Laboratory studies have also demonstrated gender differences in basal neuroendocrine tone. During early abstinence, cocaine dependent women have been shown to have lower ACTH and cortisol levels than cocaine dependent men (Fox et al. 2006; Fox et al. 2009). Our previous work has demonstrated that cocaine-dependent women experience greater cocaine craving following a social stressor as compared to cocaine-dependent men (Waldrop et al., 2010). We also observed greater dysregulation in the HPA-axis response to CRH administration in cocaine-dependent women as compared to cocaine-dependent men or control men and women (Brady et al., 2009). In addition, subjective response to CRH in the laboratory correlated with relapse to cocaine use (Back et al., 2010).

Gender specific sensitivity to noradrenergic dysregulation in cocaine using individuals has also been demonstrated in a human laboratory paradigm. In a double-blind placebo-controlled cross-over study, cocaine-dependent men and women received either yohimbine, an α2-noradrenergic receptor antagonist, or placebo prior to cocaine cue exposure. Cocaine-dependent women, as compared to cocaine-dependent men, reported greater anxiety and craving in response to yohimbine and cue exposure (Moran-Santa Maria et al., 2014), suggesting that noradrenergic mediated stress may increase the salience of cocaine cues for women more so than for men.

Together, these studies suggest gender-specific alterations in underlying neuroendocrine tone, HPA-axis responsivity, and stress-induced craving in individuals with cocaine use disorder. In particular, the HPA axis and noradrenergic systems in women may be more sensitive to disruption resulting from chronic cocaine use. This difference could explain an increased sensitivity to stress-induced relapse in women.

Neuroimaging Evidence for Sex and Gender Differences in Cocaine Use Disorder

Dysregulation in corticolimbic brain activity has been implicated in drug craving and relapse, and could be specifically involved in stress-induced relapse (Childress et al., 1999; Kilts et al., 2001). For example, functional uncoupling between the prefrontal cortex and limbic brain regions, including the amygdala, has been associated with depression, anxiety and time to relapse in cocaine-dependent males (Kim et al., 2011; McHugh et al., 2014). Despite the well documented sex differences in corticolimbic structure, function and neurochemistry (Cahill, 2006), few studies have assessed sex differences in corticolimbic brain activity in substance use disorders, and even fewer studies have directly assessed the contributions of the noradrenergic and CRH stress systems to corticolimbic dysregulation in clinical populations.

One study of cocaine-dependent men and women and sex matched controls found significant sex differences in stress-related brain activity with cocaine-dependent women exhibiting hyperactivity in the amygdala, hippocampus, insula and regions of the prefrontal cortex during guided imagery of a stressful event (Potenza et al., 2012). Interestingly, these findings were not observed in cocaine-dependent men. Thus, dysregulation in corticolimbic reactivity to stress may play a greater role in stress-related craving and relapse in cocaine-dependent women as compared to cocaine-dependent men. Given data from previous studies that demonstrate corticolimbic uncoupling is associated with anxiety and relapse, we measured corticolimbic connectivity during a social stress task (Montreal Imaging Stress Task (MIST)) and a control condition in cocaine-dependent and control women. In cocaine-dependent women, the left amygdala exhibited significantly greater functional connectivity with the posterior cingulate cortex during the stress condition as compared to the control condition (Figure 2A). In the control group, the left amygdala exhibited significantly greater functional connectivity with the orbitofrontal cortex during the stress condition as compared to the control condition. Cocaine-dependent women also reported significantly greater anxiety in response to the MIST as compared to control women (Figure 2B). These data suggest that dysregulation in corticolimbic connectivity may play a role in the vulnerability of cocaine-dependent women to stress-related craving and relapse. Altered central noradrenergic tone has not been investigated in neuroimaging studies of substance-dependent men and women. However, yohimbine administration increases amygdala activity and decreases prefrontal activity in healthy control women, but not men, who are exposed to faces depicting fearful affect (van Stegeren et al., 2005). These data suggest that women are more sensitive to perturbations in central noradrenergic tone than men and are consistent with human laboratory data demonstrating that cocaine-dependent women have greater craving and anxiety following yohimbine administration, as previously discussed. Future neuroimaging studies of yohimbine and/or alpha-2 agonists on corticolimbic brain activity in substance dependent women and men and sex matched controls are warranted.

Figure 2.

Figure 2

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The effect of corticotropin releasing hormone (CRH) on the BOLD signal in cocaine dependent men and women. Mean percent BOLD signal change following CRH administration (relative to saline) in the left and right (A) amygdala, (B) caudate nucleus, (C) insular cortex, and (D) anterior cingulate cortex in cocaine dependent men (black bars) and women (gray bars). * Denotes significant treatment effect. # Denotes significant treatment x sex interaction.

Plasticity within corticolimbic CRH stress sensitive brain regions is hypothesized as one of the neurobiologic underpinnings of compulsive drug seeking (Kreek & Koob, 1998). Based on our findings of altered noradrenergic and HPA axis responses to CRH in cocaine-dependent women discussed above (Brady et al., 2009), we conducted a pilot neuroimaging study to examine the impact of a CRH (1 ug/kg) challenge on brain activity in cocaine-dependent men (n=10) and women (n=10). A significant (p<0.05) reduction in activity was found in bilateral caudate, insula, and anterior cingulate cortices. The magnitude of the reduction was significantly (p<0.05) greater in women in bilateral anterior cingulate cortices, left caudate and insula (Figure 3) as compared to men. However, there was no influence of CRH on activity in the left or right amygdala. These data suggest significant sex differences in the sensitivity of brain regions responsible for regulating the emotional response to CRH. Moreover, these findings support the extant literature describing a sexually dimorphic brain which may underscore some of the sex/gender differences in stress sensitivity in substance-dependent populations (Brady et al. 1993; Brienza and Stein 2002; McCance-Katz et al. 1999; McKay et al. 1996).

Therapeutic Interventions Targeting Sex-Specific Stress Dysregulation in Cocaine Use Disorder

Given the basic science, human laboratory and neuroimaging evidence supporting the roles of CRF and noradrenergic systems in cocaine craving and relapse, these systems are potential targets for therapeutic development. Moreover, the gender differences in dysregulation in these systems suggest that that a gender differential might be seen in response to interventions targeting these systems. The α2-receptor agonist guanfacine is an antihypertensive agent which reduces noradrenergic tone. In a human laboratory study, Fox and colleagues (2012) demonstrated that administration of guanfacine (up to 3mg daily) reduced cocaine cue-induced craving, anxiety, and arousal. A follow-up trial evaluated the impact of three weeks of guanfacine treatment on stress- and cue-response in forty early abstinent cocaine-dependent individuals (Fox et al., 2014). Guanfacine treatment attenuated both stress- and cue-induced craving, anxiety, and negative emotion in women, but not in men. Although preliminary, these findings support the fact that interventions targeting noradrenergic dysregulation may be more efficacious in reducing cocaine use in women as compared to men due to sex differences in stress-related sensitization. In another recent clinical trial, 118 opiate-dependent subjects on buprenorphine maintenance were randomized to adjunctive treatment with placebo or clonidine, another antihypertensive agent which decreases noradrenergic tone (Kowalczyk et al., 2015). The clonidine treated group had longer periods of illicit opioid abstinence and reported decreased association between daily life stressors and episodes of craving and relapse. While there was no analysis of gender difference in response reported, this study further supports the exploration of therapeutic interventions targeting the noradrenergic system in substance use disorders.

Discussion

In summary, evidence from basic science studies, human laboratory paradigms, neuroimaging studies and clinical trials are converging to suggest that substance use disorders are associated with dysregulation of the CRF and noradrenergic systems, and these changes may be particularly critical in stress-induced relapse. Important sex and gender differences have also been observed, with preclinical models demonstrating increased sensitivity of females as compared to males to CRH and noradrenergic-induced drug reinstatement. Consistent with these findings, human laboratory studies have demonstrated greater sensitivity to CRH and noradrenergic stimulation in cocaine-dependent women as compared to men. In addition, neuroimaging studies have demonstrated greater neural response to stressful stimuli in cocaine-dependent women as compared to men. The evolution of knowledge in this area has been driven forward by a series of complementary translational research studies conducted by both basic and clinical scientists. This synergistic work has led to the development of interventions targeting the noradrenergic system and stress response in drug-dependent individuals which may have important clinical implications for both women and men.

Significance Statement.

Gender differences in cocaine use disorder may be important in understanding precipitants of relapse and have significant treatment implications. Growing evidence from both preclinical and clinical investigations suggest that substance use disorders are associated with dysregulation of stress response, in particular within the corticotropin releasing factor and noradrenergic systems. This review focuses on preclinical models exploring sex differences in substance use disorders, specifically cocaine, evidence for gender differences in stress response from clinical neuroimaging and human laboratory trials involving cocaine-using individuals, and potential therapeutic interventions targeting stress dysregulation.

Acknowledgments

Supported by NIH grants P50DA016511 (Brady) and K24DA038240 (McRae-Clark)

Footnotes

Conflict of interest.

None of the authors have any conflict of interest related to this work.

Role of Authors.

All authors contributed to the drafting and revision of this review, and have approved the final manuscript.

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