Targeting the Noradrenergic System for Gender-Sensitive Medication Development for Tobacco Dependence

Abstract

Introduction:

Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research.

Methods:

We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence.

Results:

We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms.

Conclusions:

Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems.

Introduction

Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, with 440,000 deaths per year attributable to smoking-related causes.¹ Compared to male smokers, female smokers appear to be at a greater risk of a number of health-related consequences including lung cancer,^2,3 oral cancer,³ and coronary heart disease.⁴ Women also experience sex-specific smoking consequences such as dysmenorrhea, early natural menopause, spontaneous abortion, and preterm delivery.⁵ Thus, women experience significant health-related disparities regarding tobacco use, underscoring the need to develop effective treatments for women smokers.

Smoking cessation can prevent and reduce many of the harmful consequences of smoking, and successful smoking cessation exerts greater cardiovascular⁶ and respiratory⁷ benefits for women compared to men. However, smokers often fail to maintain long-term abstinence. Seventy percent or more of smokers relapse within 1 year even with our most effective treatments.⁸ Despite being more likely to report a quit attempt than men,⁹ women are less successful in quitting smoking^10,11 (see also Jarvis et al.¹²) and may be more likely to relapse to smoking after a period of abstinence.¹³ Further, some smoking cessation medications have demonstrated differential efficacy across gender. Women may be less responsive to nicotine replacement therapy (NRT) as a cessation aid,^14,15 and findings for sex differences in bupropion efficacy have been mixed.¹⁶

In light of evidence for sex differences in medication efficacy, sex-sensitive treatments show promise for improving success rates for both women and men. Yet, current treatment guidelines for tobacco dependence¹⁷ provide little guidance for incorporating sex-specific factors into treatment decisions. Supported by the U.S. National Institutes of Health’s Office of Research on Women’s Health and the Federal Drug Administration’s Office on Women’s Health, there is a growing awareness, supported by federal regulation, to consider sex and gender in treatment development and efficacy. With regard to smoking cessation, sex-specific studies conducted thus far have focused on behavioral interventions related to weight gain^18,19 or exercise.¹⁹ Pharmacological development targeted at gender-sensitive aspects of smoking behavior is a critical, yet underdeveloped area of research.

In the following sections, we review the preclinical and clinical evidence for gender differences in the inability to quit smoking examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We present preliminary evidence supporting our hypothesis that noradrenergic targets differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms.

Smoking for Negative Affect Regulation

Negative affect and stress are associated with smoking initiation, maintenance, and relapse to cigarette smoking.^20,21 While stress and negative affect are related to the smoking behavior of women and men, the role of affect is especially critical in women’s smoking and the ability of women to maintain abstinence after a quit attempt. In a cohort of ~130,000 smokers, self-reported smoking to alleviate negative affect was a more important dimension of nicotine dependence for women than men, and this sex difference has increased in magnitude over the past 10 years.²²

Women smokers are more likely to experience greater levels of negative affect, including depression,²³ are more likely to expect that smoking will improve their mood,²⁴ and are more likely to report smoking to reduce and manage negative affect compared to men.^10,25 In human laboratory studies, female smokers smoked more quickly following a negative mood induction compared to males,²⁶ and females with faster accessibility to negative affect reduction beliefs smoked more cigarettes, had longer puff durations, greater puff volume, and shorter inter-puff intervals compared to men²⁷ (see also Fucito and Juliano²⁸).

Our group and others have shown that stress and negative affect (including depression) appear to exert a greater negative impact on the ability of women to quit smoking compared to men^29,30 (see also Hitsman et al.³¹). Prior to a quit attempt, women anticipated greater negative affect associated with smoking cessation compared to men, which reduced their odds of successfully quitting by a factor of 4.³² Following a quit attempt, women experience greater increases in negative affect,³³ greater stress-induced distress and cravings to smoke,³⁴ and greater relief of abstinence-induced negative affect by smoking.³⁵ Females, compared to males, also have a higher propensity to relapse following stressful events.²⁹

Gender-sensitive relationships between negative affect and smoking also extend to smokers with depression. In a nationally representative study, both current and lifetime major depressive disorder were associated with a lower likelihood of quitting smoking and a higher probability of relapse.³⁶ As depression is twice as common in women compared to men, these associations had a greater impact on women smokers. In a systematic review of clinical trials examining smoking cessation in depressed smokers, depression had a greater negative impact on treatment outcomes for women than men,³⁷ although it is important to note that only 10% of these studies examined outcomes by gender.

In the preclinical literature, there is a well-established connection between the nicotinic acetylcholine receptor (nAChR) system and depression. Dysregulation of the cholinergic system has been associated with increased negative affect and depression,^38,39 a key precipitant of smoking in women. Stimulation of the cholinergic system leads to an increase in anxiety-like behavior and depressive symptoms in normal individuals and those diagnosed with mood disorders.⁴⁰ Furthermore, preclinical evidence suggests that rats with increased sensitivity to cholinergic stimulation exhibit an increase in stress reactivity.⁴¹ Similarly, nicotine can produce an anxiogenic-like effect in female versus male mice, whereas females are less sensitive to the psychostimulant properties of nicotine, indicating that there may be sex differences in the activity of the cholinergic system which could contribute to the increased likelihood of smoking relapse in women following abstinence.⁴²

It is important to note that researchers have questioned whether smoking directly relieves stress and negative affect as anticipated by smokers, noting mixed findings in the literature.²⁰ The source of negative affect may be important—although smoking effectively reduces abstinence-induced negative affect,⁴³ its effects on environmentally induced negative affect (e.g., mood-induction procedures in laboratory settings) are less consistent.^20,43 Regarding sex differences, as previously noted, women experience greater reduction of abstinence-induced negative affect when smoking.³⁵ Sex differences in smoking-related negative affect reduction in response to environmental stressors are not well studied, highlighting an important area for further investigation, as findings may have important clinical implications for smoking cessation.

Regardless of the source, negative affect and stress are clearly related to smoking maintenance and relapse, and these relationships appear stronger for women than for men. Taken together, animal models and human studies point to stress and negative affect as critically important targets for interventions aimed at reducing smoking behavior in women.

Smoking for Nicotine Reinforcement

While negative affect may play a greater role in the smoking behavior of women, nicotine reinforcement may play a more significant role in the smoking behavior of men. It has been suggested that nicotine replacement may not be as effective in women, as women are less sensitive to the reinforcing effects of nicotine.¹⁵ Laboratory studies have identified that women, compared to men, report greater sensitivity to the negative subjective effects of nicotine (e.g., dizziness,^44,45 see also Perkins et al.⁴⁶) and less sensitivity to the reinforcing effects of nicotine (e.g., satisfying, “want more”).^46,47 Perkins and colleagues^48,49 demonstrated that men are better able than women to discriminate between doses of nicotine, indicating that men are better able to detect the interoceptive cues of nicotine. Further, women, compared to men, report greater craving relief from denicotinized tobacco than men,⁵⁰ experience less of a change in subjective effects across doses of nicotine,⁴⁸ experience less reinforcement from nicotine in the absence of visual and olfactory stimuli,⁵¹ and report greater reward and reinforcement related to verbal information about nicotine content.⁵² Such findings provide supporting evidence for the diminished role that nicotine reinforcement is thought to have in maintaining tobacco use in women and the greater role that nicotine reinforcement is thought to have in men.⁴⁹

Nicotine’s reinforcing effects are mediated by the β2 subunit of the nAChR, leading to the release of dopamine in the ventral striatum and prefrontal cortex (PFC).⁵³ In animal models, deletion of the β₂ subunit-containing nAChRs abolishes reinforcement-related behaviors, including nicotine locomotor sensitization, nicotine self-administration, and conditioned place preference.^54,55 Preclinical studies also generally support clinical findings showing differential sensitivity in female rodents in response to nicotine suggesting an underlying biological sexual dimorphism. For example, female mice respond more to the locomotor stimulating⁴² and conditioned rewarding properties of nicotine,⁵⁶ whereas male mice respond more to pharmacological properties of nicotine by titrating their consumption to available nicotine dose.⁵⁶ Currently, our group has focused on investigating mechanisms underlying these sex differences focusing on the regulatory effects of nicotine in the brain.^57–59

Cosgrove and colleagues⁵⁸ completed a large study imaging availability of the β2 subunit-containing nAChRs, which have been shown to be higher, or “upregulated” after nicotine administration or tobacco smoking. They found significantly higher numbers of nicotinic receptors in male smokers but not in female smokers when compared to same-sex nonsmokers. These findings provide a neurochemical explanation for why men generally have a preferential therapeutic response to smoking cessation medications which target nicotine receptors. Specifically, NRT may help “wean” their receptors down to nonsmoker levels over time. New technology examining dynamic changes in dopamine release during in vivo smoking has also demonstrated that males activate in response to smoking a cigarette consistently and rapidly in the ventral striatum whereas women respond faster than men in a discrete subregion of the dorsal putamen,⁶⁰ consistent with the established notion that men smoke for the reinforcing properties of nicotine, which are thought to originate in the ventral striatum.

Most medications that are FDA approved for the treatment of tobacco dependence target the nAChR system to some extent, and significant preclinical and clinical data demonstrate that women smokers are less sensitive to the effects of nicotine in tobacco smoke, making the nAChR system a less than optimal therapeutic target for women. In order to treat female smokers effectively, medication development strategies need to target systems other than the nicotinic acetylcholine system and factors that serve to maintain smoking behavior in women, and which underlie poor treatment response. While there are a number of complex factors which facilitate poor treatment response in women, targeting negative affect and stress reactivity is a highly promising avenue for gender-sensitive medication development. Noradrenergic agents are known to attenuate stress reactivity and nicotine-related reinforcement, and targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through different gender-sensitive mechanisms.

Targeting the Noradrenergic System to Reduce Stress Reactivity, Attenuate Nicotine Reinforcement, and Improve Smoking Cessation Outcomes

Brief Overview of the Noradrenergic System

The noradrenergic system is widely known to be involved in arousal, anxiety, and, more recently, addiction,^61–63 and norepinephrine is extensively distributed throughout the brain. The noradrenergic system is comprised of two main projections: the dorsal noradrenergic bundle (DNB) has cell bodies originating in the dorsal pons (locus coeruleus; LC) and the ventral noradrenergic bundle (VNB) has cell bodies that originate in the brain stem (pons and medulla). Projections from the LC, a nucleus comprised of entirely norepinephrine containing neurons, innervate the cortices and hippocampus and projections from the brain stem innervate the hypothalamus, basal forebrain, and amygdala.^63–65

The noradrenergic receptor system is made up of three main receptor subtypes; α₁ (alpha₁), α₂ (alpha₂), and β (beta). Αlpha-1 adrenoceptors are primarily located postsynaptically⁶¹ in several brain regions, including the LC,⁶⁶ olfactory bulb, cerebral cortex, amygdala, dentate gyrus, and the thalamus,⁶⁷ and can be further subdivided into α_1a-, α_1b-, and α_1d-adrenergic receptors. Αlpha-2 adrenoceptors can be subdivided into α_2a-, α_2b-, and α_2c-adrenergic receptors and exist both presynaptically and postsynaptically⁶¹ in the amygdala, LC, and hypothalamus.⁶⁸ Beta-adrenergic receptors exist postsynaptically in brain regions previously mentioned,⁶¹ and this class of β-adrenoceptors include β₁-, β₂-, and β₃-adrenergic receptor subtypes. Antagonists at α₁ and β receptors reduce central adrenergic activity by blocking the binding of norepinephrine to postsynaptic receptors.⁶¹ Similarly, α₂ agonists stimulate inhibitory presynaptic α₂ receptors resulting in a reduction of noradrenergic firing.⁶⁹ The reduction in norepinephrine neurotransmission associated with these pharmacological agents has historically lead to their use for the treatment of hypertension, attention-deficit/hyperactivity disorder (ADHD), and more recently, substance abuse.

Nicotine and the Noradrenergic System

Nicotine binds to nAChRs in the brain, and it is known that the cholinergic system interacts with the noradrenergic system. Nicotine administration or smoking can modulate the activity of the noradrenergic system and lead to an increase in peripheral sympathetic activity.^70,71 In animal models, systemic administration of nicotine increases extracellular norepinephrine levels, and this effect is mediated by the LC, the main source of noradrenergic neurons in the brain.⁷² Nicotine exerts direct effects on the LC, such that nicotine increases the firing rate of LC neurons and stimulates the release of norepinephrine.⁷³ Chronic nicotine exposure in rats can also increase the activity of tyrosine hydroxylase, a precursor for the synthesis of dopamine and norepinephrine, in brain regions innervated by the noradrenergic system but not in dopamine projection areas.⁷⁴ Both acetylcholine and norepinephrine are key neurotransmitters involved in the regulation of the amygdala-PFC pathway, which is critical to stress reactivity and emotional control.⁷⁵

In humans, smoking increases plasma levels and urinary excretion of norepinephrine and epinephrine,^71,76 and elevated baseline plasma epinephrine and norepinephrine levels seen in smokers decrease during abstinence, suggesting an increased noradrenergic activity as a result of smoking.⁷⁷ Long-term smoking has been associated with decreases in the density of the β-adrenergic receptors in blood cells and α₂-adrenergic receptor binding in the LC, and this decrease in receptor density normalizes with abstinence to nonsmoker control levels.⁷⁸ In addition, nicotine-induced increases in blood pressure and heart rate^71,76,79 are attenuated by adrenergic blockade.^80,81 In a study of nine smokers, labetalol (an α₁- and β-adrenergic blocker) attenuated nicotine-induced increases in heart rate and enhanced the decrease in symptoms associated with nicotine withdrawal after intravenous nicotine.⁸⁰ Labetalol also increased the subjective feelings of a “head rush” and “strength” of nicotine use in that study. Similarly, carvedilol (a mixed α₁- and β-adrenergic antagonist) reduced heart rate, systolic and diastolic blood pressure, and subjective ratings of “bad effects” associated with nicotine in male and female smokers but did not affect tobacco withdrawal symptoms.⁸¹ Overall, nicotine induces an increase in noradrenergic activity, and drugs that block or normalize noradrenergic activation could be used as potential pharmacotherapeutic treatments for tobacco dependence.

Noradrenergic Targets Are Effective for Smoking Cessation

Clonidine, which reduces noradrenergic activity by stimulating inhibitory presynaptic α₂ receptors, blunts LC firing in rats undergoing opiate withdrawal and attenuates opiate withdrawal syndrome in opiate dependent human subjects, providing the initial basis for α₂-adrenergic agonist treatment in drug addiction.⁶⁹ In regular smokers, clonidine has been shown to reduce tobacco craving and other tobacco withdrawal symptoms including anxiety, irritability, restlessness, and tension.⁸² A Cochrane review found that clonidine increased rates of smoking cessation by an odds ratio of 1.63,⁸³ and in studies that stratified by gender, clonidine was more effective in women than men for smoking cessation.⁸⁴ In a meta-analysis (n = 813), end-of-treatment quit rates in women were 70% for clonidine versus 18% for placebo. Men did not demonstrate an effect of medication with end of treatment quit rates of 42% for clonidine versus 43% for placebo.⁸⁵ Surprisingly, mechanisms underlying this gender difference in medication response were never pursued. Regarding stress, clonidine has been found to block stress-induced reinstatement of drug-seeking in rodents^86,87 and reduce subjective measures of stress-induced cocaine craving in nontreatment seeking cocaine users.⁸⁸ While clonidine demonstrates efficacy for smoking cessation and alleviating withdrawal symptoms associated with nicotine dependence, significant adverse events, most notably sedation, have limited its use to a second line medication for smokers who are nonresponsive to other smoking cessation treatments.⁸³

Antidepressants have also shown some efficacy for the treatment of tobacco dependence. While most antidepressants antagonize nicotinic receptors (see Shytle et al.⁸⁹ for a review), it appears that antidepressants with actions on norepinephrine reuptake are particularly effective for smoking cessation. Studies of antidepressant medications for smoking cessation have found that bupropion (risk ratio [RR] = 1.69) and nortriptyline (RR = 2.03) demonstrate efficacy on par with NRT, but that serotonin reuptake inhibitors do not promote smoking cessation⁹⁰ (see also Hitsman et al.⁹¹). Bupropion’s mechanism of action on smoking cessation is unclear. There is evidence that it may increase the ability to quit through blockade of nAChR receptors⁹² but bupropion also modulates dopaminergic and noradrenergic activity. The mechanism of action for nortriptyline on smoking cessation is unknown, but it is interesting to note that nortriptyline reduces noradrenergic activity through antagonism of α1 receptors. Bupropion has not demonstrated consistent effects across genders⁹⁰ and only two studies with nortriptyline have investigated smoking cessation outcomes by gender with both demonstrating similar efficacy in women and men.^93,94 Tricyclic antidepressants have been found to block reward threshold elevations and somatic signs associated with nicotine withdrawal and to decrease nicotine self-administration in rodents.⁹⁵

Monoamine oxidase (MAO) inhibitors (MAOIs) have well-characterized antidepressant-like actions and have demonstrated clinical efficacy in treating depression (for a comprehensive review, see Shulman et al.⁹⁶). MAOs are enzymes involved in the regulation and catabolism of monoamine neurotransmitters, such as norepinephrine, dopamine, and serotonin.^97,98 Two isoenzymes of MAO are well-characterized in mammals: MAO-A and MAO-B.⁹⁷ The MAO-A subtype preferentially metabolizes norepinephrine and serotonin,⁹⁷ and MAO-A methylation has been found to be associated with nicotine dependence in women, but not men.⁹⁹ Indeed, MAOIs have been utilized as a potential pharmacotherapy for the treatment of tobacco dependence, albeit with limited efficacy. Clinical studies have found MAO-A inhibitors to be effective in reducing self-reported abstinence rates, but not abstinence rates verified by plasma cotinine levels or measures of cigarette craving.¹⁰⁰ Likewise, initial studies using MAO-B inhibitors such as selegiline, which produces inhibition of MAO-A at higher doses, exhibited efficacy in reducing self-reported craving for cigarettes¹⁰¹ and achieving biochemically verified abstinence rates,¹⁰² but subsequent studies yielded negative results with regard to the effectiveness of selegiline for tobacco dependence.^103,104 Further, a selective MAO-B inhibitor was not effective in smoking cessation as measured by end-of-treatment 4-week continuous abstinence rates,¹⁰⁵ suggesting poor efficacy of MAOIs as a treatment option for tobacco dependence.

Norepinephrine reuptake inhibitors reduce abstinence-induced subjective withdrawal symptoms and decrease self-reported smoking urges in nontreatment seeking smokers.¹⁰⁶ This same class of drugs has also been found to decrease the number of cigarettes smoked in nicotine-dependent individuals, although side effects due to treatment resulted in high drop-out rates.¹⁰⁷ High drop-out rates also lead to inconclusive findings of milnacipran, a serotonin-norepinephrine reuptake inhibitor (SNRI), in combination with the nicotine patch on smoking abstinence, but this combination did improve mood and anxiety measures in tobacco-dependent individuals with a history of major depressive disorder.¹⁰⁸ Another SNRI, venlafaxine, is not effective for smoking cessation,⁹⁰ so increasing norepinephrine and serotonin levels in combination may not be an effective strategy.

Medications targeting the noradrenergic system may be useful for the treatment of tobacco dependence. In the following sections, we discuss potential gender-sensitive mechanisms for these effects.

Targeting the Noradrenergic System to Attenuate Stress Reactivity

Stress is defined as a state of threatened homeostasis, which is counteracted by adaptive processes involving physiological and behavioral responses in an attempt to regain homeostasis.¹⁰⁹ This state of threatened homeostasis often refers to hyperarousal and the overactivation of the body’s normal processes.¹¹⁰ The array of stress responses is coordinated by the release of corticotrophin-releasing factor (CRF), and subsequent activation of the hypothalamic–pituitary–adrenal (HPA) axis and the catecholaminergic system (norepinephrine, epinephrine, and dopamine pathways) in response to stress.¹¹¹ In addition, several other neurotransmitter systems such as the serotonin and opioid system, the neuroactive steroids and inhibitory/excitatory amino acid (GABA and glutamate) system, thyroid hormones, and the immune system contribute to the adaptive response to stress (for a comprehensive review, see Tsigos and Chrousos¹¹²). Despite this generalized activation, it is the specific ability of stressors to reliably activate the CRF-HPA axis and catecholamines, including the mesocorticolimbic dopaminergic system, that has been linked to stress-induced increases in self-administration of drugs of abuse.^110,113 Relevant to this review, in nicotine-exposed animals and humans, acute stress additively increases HPA, catecholamine, and sympathetic responses.^70,114

The PFC-amygdala axis is critical for the regulation of emotions and stress reactivity, and noradrenergic projections play a role in the regulation of PFC and amygdala activity. Exposure to even mild uncontrollable stress markedly impairs PFC-dependent cognitive function.¹¹⁵ In response to psychological stress, amygdala projections activate noradrenergic neurons in the LC and the dopaminergic neurons in the ventral tegmental area (VTA) resulting in increased release of norepinephrine and dopamine throughout the forebrain. High levels of norepinephrine and dopamine release in the PFC markedly impair PFC-mediated cognitive functions, while high levels of catecholamine release in subcortical structures such as the amygdala and nucleus accumbens strengthen affective associations and habitual responses,¹¹⁶ such as those underlying substance use.

Preclinical research demonstrates that exposure to acute stress induces relapse to drug-seeking in both nondependent and drug-dependent laboratory animals, particularly in reinstatement paradigms, a phenomenon mediated by brain stress circuits including noradrenergic pathways.^87,117 Reinstatement paradigms use stress to elicit responding for a drug following extinction and are used to model relapse and craving. Footshock stress has been shown to effectively reinstate nicotine-seeking behaviors in rats.¹¹⁸ Acute challenge with yohimbine, an α₂-adrenergic antagonist and pharmacological stressor that provokes the norepinephrine system by transiently increasing noradrenergic firing, has demonstrated robust reinstatement of drug-seeking behavior following extinction.¹¹⁹ Conversely, agents that blunt or normalize noradrenergic signaling can block stress-induced reinstatement to drug-seeking. Zislis et al.¹²⁰ demonstrated that clonidine attenuated footshock-induced reinstatement of nicotine-seeking behavior. Consistent with this finding, Yamada and Bruijnzeel¹²¹ demonstrated that stimulation of α₂-adrenergic receptors with clonidine or dexmedetomidine infused into the central nucleus of the amygdala attenuated stress-induced reinstatement of nicotine seeking. Likewise, α₁-adrenergic antagonists have been found to block reinstatement of nicotine-seeking by a nicotine prime or a nicotine cue.¹²²

Clinical research also indicates that stress exposure induces craving and relapse to drug taking. Human laboratory studies suggest that stress-induced craving states are associated with increases in cardiovascular activity and dysregulated HPA axis function.^123,124 In smokers, stress precipitated smoking lapse and increased HPA axis reactivity, and tobacco craving. Moreover, increased cortisol, adrenocorticotropic hormone (ACTH), and tobacco craving were associated with increased smoking lapse following stress.¹²⁴ In a subsequent study, these stress-related effects on smoking were eliminated in subjects treated with guanfacine, an α_2a-adrenergic agonist.¹²⁵ Specifically, guanfacine attenuated the effect of stress on smoking lapse, ad-lib smoking, tobacco craving, and normalized cortisol responding. Consistent with these findings, noradrenergic targets have shown efficacy in attenuating stress reactivity in other drug addicted populations.

Importantly, α₂-adrenergic agonists stimulate presynaptic inhibitory autoreceptors and consequently inhibit norepinephrine release, and this action has been found to improve attention, working memory, and inhibitory control in non-human primates.¹²⁶ Specifically, guanfacine reduces excitatory postsynaptic neurotransmission in the medial PFC and bed nucleus of the stria terminalis in rats,¹²⁷ brain areas associated with stress exposure. Provocation of the noradrenergic system elicits a stress response in humans and animals and has been found to increase distractibility and impulsiveness in rodents. Animal studies have also shown α₂-adrenergic agonists to have anxiolytic-like actions on stress-related behavior associated with mesolimbic prefrontal dopamine turnover,¹²⁸ and improvement of connectivity in the PFC during periods of stress.¹²⁶ Furthermore, several studies have shown that guanfacine is associated with significant improvement in attention, hyperactivity/impulsivity, and frontal executive functioning tasks in children with ADHD and tic disorders^129,130 as well as in adults with ADHD.¹³¹ Interestingly, our group has recently shown that guanfacine relative to placebo increases prefrontal activation to incongruent stimuli in a Stroop task during functional magnetic resonance imaging sessions in brain areas relevant to attention to inhibitory control.¹²⁵ These data suggest that effects of α₂-adrenergic agonists on PFC function may underlie decreases in stress-induced relapse to smoking.

Our research group has also found that guanfacine appears to preferentially act through gender-sensitive systems for smoking cessation. We have found that guanfacine significantly and equally reduced the number of cigarettes per day following a quit attempt for both men and women over a 4-week proof-of-concept treatment period. However, when examining mechanisms for these treatment effects, guanfacine decreased smoking lapse, reduced cigarettes smoked, and reduced tobacco craving following stress in women but not men.¹³² Consistent gender findings have been found in cocaine users, where α₂-adrenergic agonist treatment decreased cocaine and alcohol craving, anxiety, and negative mood following stress imagery in cocaine-dependent women but not men.¹³³

Overall, preclinical and clinical findings indicate that women are generally more likely to smoke cigarettes to alleviate negative affect and reduce stress compared to men. Moreover, women are less likely to succeed in a quit attempt because of perceived stress and anxiety associated with quitting smoking. Medications targeting the noradrenergic system, specifically a reduction in noradrenergic signaling, have been found to reduce stress-induced relapse in animal models and attenuate stress-induced craving in humans. Our preliminary data suggest that these treatment effects appear to be more pronounced in women compared to men, supporting gender-sensitive therapeutic development targeting the relationship between stress and smoking.

Targeting the Noradrenergic System to Attenuate Nicotine Reinforcement

Drugs such as nicotine stimulate dopamine neurons in the mesolimbic pathway, a critical brain pathway underlying the rewarding effects of drugs of abuse. In particular, nicotine stimulates the VTA of the brain which leads to dopamine release in the ventral striatum, also called the nucleus accumbens, and this is critically tied to the pleasurable effects experienced from the drug. As previously mentioned, the primary reinforcing effects of nicotine are mediated by nAChRs containing the β₂ subunit,⁵³ which are necessary for nicotine to stimulate dopamine release in the ventral striatum and PFC. The mesolimbic dopamine system is modulated by norepinephrine,^63,65,134 and noradrenergic neurons provide excitatory input to mesolimbic dopamine neurons.⁶³ Burst firing of VTA dopamine neurons is increased by stimulation of the noradrenergic cell bodies in the LC, however, attenuating norepinephrine signaling with noradrenergic agents eliminates and normalizes the firing of VTA neurons.^135,136

Consistent with the notion that the noradrenergic system modulates the mesolimbic dopamine system, there is extensive evidence that noradrenergic transmission is involved in reinforcement and the rewarding properties of drugs of abuse.⁶³ The administration of amphetamine has been shown to increase the release and prevent the uptake of catecholamines in adrenergic neurons,¹³⁷ and amphetamine-induced dopamine release in the nucleus accumbens is abolished in α_1b-adrenergic receptor knockout mice and in dopamine beta-hydroxylase (DBH) knockout mice lacking norepinephrine.^138,139 High rates of intracranial self-stimulation (ICSS) are obtained in the medial forebrain bundle (MFB) of the lateral hypothalamus, an area that coincides with major rostral projections of noradrenergic fibers,¹⁴⁰ as well as in the LC and throughout the DNB and VNB pathways,¹⁴¹ and drugs of abuse exert mechanistic actions that summate with rewarding stimulation of the MFB.¹⁴² Conversely, compounds that deplete brain norepinephrine disrupt ICSS.¹⁴³

With regard to the noradrenergic system’s involvement in the reinforcing properties of drugs of abuse, depletion of norepinephrine¹⁴⁴ and neurochemical lesions of noradrenergic neurons¹⁴⁵ can suppress voluntary ethanol self-administration in rats. Similarly, DBH knockout mice that cannot synthesize norepinephrine exhibit a reduced preference for ethanol.¹⁴⁶ Noradrenergic agents that block norepinephrine signaling decrease nicotine self-administration and reduce nicotine-evoked dopamine release in the nucleus accumbens in rodents.^122,147 Similarly, agents that decrease norepinephrine release also reduce conditioned place preference to nicotine¹⁴⁸ and attenuate nicotine withdrawal-induced deficits in brain reward thresholds.¹⁴⁹

Very few studies have examined clinical outcomes for gender-sensitive treatments targeting nicotine reinforcement. Preliminary findings from our group demonstrate that guanfacine reduces smoking-related reinforcement in men but not women in an ad-lib smoking session, and that reductions in smoking-related reinforcement are associated with an increased ability to resist smoking in men, but not women.¹²⁵ These findings are consistent with studies showing that α₂-adrenergic agonists modulate dopamine neurotransmission in the PFC. For example, guanfacine and clonidine attenuated phencyclidine (PCP)-induced dopamine release in the rat PFC,¹⁵⁰ and clonidine decreased extracellular dopamine in the rabbit caudate nucleus.¹⁵¹

The noradrenergic system plays a key role in mediating drug-motivated behaviors in rodents and in humans, and the reduction of noradrenergic signaling is able to block the reinforcing properties of nicotine, as well as other drugs of abuse. While extensive preclinical literature exists on noradrenergic contributions to nicotine reinforcement, research in clinical populations have been limited. Preliminary data in humans suggests that noradrenergic treatment approaches are able to target gender-sensitive mechanisms underlying tobacco dependence in men smoking for nicotine reinforcement.

Conclusions

Converging lines of preclinical and clinical evidence indicate that gender-sensitive approaches to medication development are needed to address the critical health disparities in cessation rates and exacerbated health risks that female smokers face. Most FDA-approved medications for smoking cessation target the nicotinic/cholinergic system to some extent (nicotine derivatives, nicotinic partial agonists, or compounds with known affinity for nAChRs) and may not directly target factors which maintain smoking behavior in women. The considerable body of data suggesting that women are generally more likely to smoke to regulate negative affect and stress, while men are generally more likely to smoke for the reinforcing properties of nicotine, suggests an important direction in the development of smoking cessation treatments. Substantial preclinical evidence demonstrates that noradrenergic transmission is involved in stress-induced relapse and nicotine-related reinforcement, yet there is a surprising lack of clinical investigations translating these findings to humans. Early work with clonidine demonstrated efficacy for smoking cessation with preferential treatment outcomes for women, which have never been pursued, and recent preliminary evidence suggests that noradrenergic agents, in particular guanfacine, may improve the poorer treatment outcomes seen in women. We hypothesize that smoking activates different brain systems modulated by noradrenergic activity in women (PFC-amygdala axis) and in men (mesolimbic dopamine system), and noradrenergic compounds can preferentially target these gender-sensitive systems. Continued work will determine whether the noradrenergic system holds promise for the identification of new neurobiological targets and the repurposing of existing targets for gender-sensitive therapeutic development.

Funding

This work was funded by National Institutes of Health P50DA033945 (Office of Research on Women’s Health [ORWH], National Institute of Drug Abuse [NIDA], FDA Office of Women’s Health to SAM); MH077681 (National Institute of Mental Health to MRP and YSM); K02DA031750 (NIDA to KPC); K12DA031050 (ORWH, NIDA, National Institute of Alcohol Abuse and Alcoholism [NIAAA] to CMM and PHS); T32AA015496 (NIAAA to TLV).

Declaration of Interests

None declared.