Drug-induced stress responses and addiction risk and relapse (2019)

Abstract

1. Introduction

Substance use disorders (SUDs) incur a significant burden to society in the United States and worldwide. In the United States alone, SUDs are estimated to cost $400 billion across a variety of domains, including crime, poor health outcomes, and lost productivity (US Department of Health and Human Services, 2016). There have been alarming shifts in the clinical presentation where young people are increasingly experiencing more consequences from use as demonstrated by the increases in alcohol-related liver disease (Tapper and Parikh, 2018), opioid use disorder (Martins et al., 2017), and marijuana-related vehicle crashes (Brady and Li, 2014). These trends collectively point to the importance of targeting specific mechanisms that may facilitate the transition from occasional use to chronic, problematic substance abuse.

Early life stress and cumulative adversity, including child maltreatment, are key factors that play a critical role throughout the cycle of addiction, from the development of addictive disorders, to maintenance, relapse, and recovery from SUDs (Enoch, 2011; Le Moal and Koob, 2007; Sinha, 2008, 2001). There has been limited focus on the potent effects of drug use itself on the acute stress response. Although several studies have pointed to an altered setpoint in these systems, less has focused on effects of these adaptations on cue reactivity, drug motivation, and relapse risk. For this reason, we uniquely focus on the effects of acute and chronic drug use on the biological stress pathways and their related effects on stress, reward, craving, and relapse risk. Previous work has investigated the acute effects of different drugs of abuse in animal models of acute and chronic use (Armario, 2010) and translational research on addiction course (Lijffijt et al., 2014). Thus, we focus primarily on human studies and the peripheral stress response and include central reward and motivation pathways when discussing the effects of altered peripheral stress biology on drug motivation and intake. Furthermore, this review covers the most commonly used drugs of nicotine, alcohol, cannabis, psychostimulants (i.e., cocaine and amphetamines), and opioids.

2. Acute and chronic psychoactive drug effects on peripheral stress responses

3. Drug-related adaptations in stress biology, reward, craving and relapse risk

The previous sections and Table 1 highlights the potent effects of the most common psychoactive drugs on stress biology with acute effects of stimulation for nicotine, cannabis, stimulant, and alcohol, and depressive effects of acute opioids in humans. More importantly, regular, binge and chronic use of drugs alter these stress responses, signaling significant adaptations in stress biology. As substance use escalates in frequency and intensity, adaptations in HPA axis and ANS pathways manifest as changes in basal levels, but also in phasic responses to drug, stress and challenge (see al’Absi, 2006 for review of nicotine; Ashare et al., 2012; see Blaine and Sinha, 2017 for review of alcohol; McKee et al., 2011; McRae-Clark et al., 2011). In turn, withdrawal-related basal increases in cortisol are associated with cognitive impairments (Errico et al., 2002). In turn, these cognitive impairments could perpetuate the worsening of addiction (see Bernardin et al., 2014; Besson and Forget, 2016; Spronk et al., 2013 for discussion).

This cumulative evidence begs the question of whether such adaptations in stress biology are the mere consequences of drug use, or if they also serve as interoceptive drug-related adaptations that may play a role in motivating compulsive drug use and relapse risk in chronic users. There have been decades of focus on mesolimbic striatal dopaminergic pathways as critical for the reinforcing effects of psychoactive drugs. While striatal adaptation may drive compulsive drug motivation, other positron emission tomography (PET) evidence indicates that psychoactive drug-stimulated increases in cortisol is highly correlated with dopamine release in the striatum (Booij et al., 2016; Cox et al., 2009; Wand et al., 2007) and drug-induced cortisol increases are associated with the subjective intoxication in healthy volunteers (Oswald et al., 2005). Similarly, psychological stress provocation in healthy volunteers has also been shown to increase dopamine transmission in the striatum and the PFC (Nagano-Saito et al., 2013; Pruessner et al., 2004), and cortisol responses to psychosocial stressors predict reward after amphetamine administration (Hamidovic et al., 2010). In a functional magnetic resonance imaging (fMRI), a psychological stress provocation results in robust striatal activation, specifically in the ventral striatum but not the dorsal striatum relative to non-stress cues in healthy volunteers (Sinha et al., 2016). Also, activity in the ventromedial prefrontal cortex and the rostral anterior cingulate cortex was predictive of resilient coping and low levels of alcohol use. Consistent with these findings, other fMRI studies have shown blunted stress responses in at-risk individuals is predictive of blunted central brain activity in limbic-striatal and prefrontal regions (Carroll et al., 2017; Ginty, 2013) that are critical for regulating motivated behavior and resilient coping. Other PET research has reported a loss of dopamine transmission and blunted dopamine release in drug-abusing patients is correlated with severity of addiction as well as with increases in compulsive motivation for drug and treatment failure (Martinez et al., 2011; Martinez and Narendran, 2010). Whether these blunted dopamine changes are related to blunted glucocorticoid responses to drug or stress has not been fully investigated. Nonetheless, these data highlight that drug-induced activation of stress and dopaminergic pathways are highly interactive and suggest that both may jointly play a role in psychoactive drug effects, and on compulsive drug motivation.

Findings from several well-controlled laboratory studies in treatment-seeking or non-treatment seeking and acutely abstinent drug-abusing patients have shown a blunted stress cortisol and ANS axis response to stress and drug cue provocations along with higher basal cortisol and HR along with disrupted HRV responses (Table 2; see Sinha, 2008 and Milivojevic and Sinha, 2018 for review). Such responses are predictive of higher relapse risk after treatment and co-occur with greater drug craving during stress and drug cue provocation (Ashare et al., 2012; McKee et al., 2011; Milivojevic and Sinha, 2018; Sinha, 2011; Sinha et al., 2006). Blunted cortisol arousal to stress cues is also predictive of increased alcohol motivation to drink alcohol in binge, heavy drinkers (Blaine et al., 2018). Thus, these studies consistently link adaptations and changes in peripheral and central stress responses to compulsive drug motivation and relapse risk, thereby suggesting a need to target these pathways as both markers of addiction risk and severity but also in treatment development (Milivojevic and Sinha, 2018).

On the basis of the review presented in previous sections, we present a heuristic model to illustrate the drug-stress motivation cycle in Fig. 2. The findings presented earlier suggest a feed-forward cascade of effects of drugs on stress biology. Our stress biology is wired to help us to adapt to life’s struggles but, in the face of increasing drug use and abuse, this critical biological process is handicapped and blunted. Consequently, heavy and chronic drug users are more vulnerable to negative affect, distress and poor stress coping. Furthermore, with blunted or more “tolerant” stress responses to drug use, greater levels of drug use are needed to maintain allostasis, thereby driving a cycle of increased drug use and stress disruption that further drive greater compulsive drug motivation and relapse risk.

4. Factors affecting drug effects on stress responses

5. Conclusions and future directions

Intake of psychoactive drugs has significant acute effects on the peripheral stress pathways. These effects parallel drug-related effects on central stress and reward pathways to alter acute drug-related subjective, neuroendocrine, and physiological states. Regular, high levels of drug use alter stress and reward responses both in tonic and phasic responding and recent findings suggest that such alterations are significantly associated with the tolerance, withdrawal and intoxication effects of drugs as well as in predicting current drug use and future relapse. This review suggests that addictive substances, although varying in neurobiological targets of action, are similar in having a significant and potent effect on stress pathways, to affect stress responses, craving, and drug intake.

However, it should be noted that there are limits to what can be concluded from the current literature and important areas for future research. Most studies discussed here have focused entirely on either naïve participants/light users or chronic/dependent users; only a few have compared across different types of users. For those that have compared across substances, chronic use is generally associated with a blunting of the drug-induced activation of the stress systems (Holdstock et al., 2000; King et al., 2006; Stormark et al., 1998; Thayer et al., 2006); however, this has not been fully elucidated in many drugs. More research comparing light users to heavy users is necessary to understand the neuroadaptations that occur to drug administration fully. Additionally, most studies compare stress reactivity in chronic substance users to healthy controls are cross-sectional. Thus, it cannot be determined if the stress dysregulation of heavy users is caused by chronic exposure to substances or predisposes them to future drug use. It is probably, and indeed very likely, that the effect is synergistic. Individuals with a disrupted stress response, due to early trauma or family history, are more likely to abuse drugs, which in turn further dysregulates their stress response. Thus, longitudinal research, such as the massive undertaking that is the Adolescent Brain Cognitive Development (ABCD) study, is vital for determining if drug use results in adaptations to the stress response system or exacerbates pre-existing stress dysregulation. Chaplin and colleagues in this special issue address these temporal associations in an excellent overview of the developmental aspects of the link between substance use and stress response dysregulation.

Substance-related adaptations to the stress system may occur along a continuum. By artificially focusing on one end of the spectrum or the other, we may not be capturing the full spectrum of neuroadaptations in the stress response to addictive substances. Animal models to some extent can address this continuum but, such as seen in opiates (Armario, 2010), the stress system response to drug intake may differ between animals and humans. A future review should synthesize findings across species. Finally, certain individual differences, some of which have been noted above, may hasten or slow down the progression along this continuum.

Despite the gaps in the literature, these findings collectively suggest that dysregulation of the stress responses may serve as potential markers for prevention efforts and a target for the development of therapeutic interventions (Greenwald, 2018; Milivojevic and Sinha, 2018). Prevention efforts that target individuals with certain risk factors known to impact the stress system (e.g., early life adversity, genetic, family history) may reduce the likelihood that these individuals will develop a substance use disorder. Concerning treatment efforts for individuals with addictive disorders, the extant treatments are modestly effective at best. There is preliminary evidence that pharmacological interventions that target the adrenergic system may reduce craving evoked by both drugs and stress (Fox and Sinha, 2014; Fox et al., 2012; Lê et al., 2011; Milivojevic and Sinha, 2018). Behavioral treatments that address the management of stress-related craving could enhance the efficacy of existing treatments. Thus, identifying specific biomarkers related to dysregulated stress responses might allow us to identify novel treatment approaches targeting normalizing of the stress response to improve addiction treatment efforts.

Funding

This work was supported by grants from the National Institutes of Health grant numbers, R01-AA013892, R01-AA020504, PL1-DA024859, and T32-DA007238.

References