Digging through the roots of addiction: Understanding the causes that underlie the insidious problem of substance use disorders (SUDs).

Abstract

This issue features a selection of articles that explore mechanisms of processes that contribute to behaviors that are associated with addiction. We have identified selected articles which focus on the mechanisms underlying maladaptive consumption and affective dysregulation. In addition to the articles within this issue, we highlight the necessity of inclusive study design and acknowledgement of individual drug vulnerabilities.

This editorial’s focus on addiction is extremely timely given the recent Opioid Epidemic and resurgence of methamphetamine usage sweeping North America. The Opioid Epidemic is now claiming victims due to the illicit drug market being flooded with fentanyl and derivative compounds. Fentanyl and its adducts are particularly dangerous considering minute amounts of the drug very induce respiratory depression due to its high potency compared to heroin, oxycodone or hydrocodone (see Comer and Cahill and Karela et. al., this issue). The Opioid Epidemic has triggered national attention, in part due to the recent unprecedented decrease in overall life expectancy of US middle-aged Caucasian males (Case and Deaton, 2015). However, it is noteworthy that women transition from recreational to misuse more rapidly and exhibit higher rates of drug relapse than men, suggesting sexual dimorphism in vulnerability to addiction. As such, inclusion of both male and female subjects and use of appropriate species is important for translational studies in mental health and addiction research, which is thoroughly discussed in this issue by Lamontagne and Olmstead who focus on the “Research Domain Criteria” mandate to identify protective and vulnerability mechanisms in addiction.

Discussed herein are theories of addiction and their neural correlates: the transition from positive to negative reinforcement-mediated drug use and from increased incentive salience to habitual or compulsive taking, with the primary biological focus on striatal, habenula and cortical circuits. The negative reinforcement model suggests that drug relapse and drug seeking are driven by the need to achieve relief of negatively valanced states such as pain, depression, and/or anxiety. In other words, drug craving and taking is in part the result of a learned association with the relief of these states (Evans and Cahill, 2016). Given this premise, it is not surprising that a recent electronic record analysis of Opioid Use Disorder (OUD) that the majority of patients with OUD (between 57.8% and 81.7% depending on pain status) have a co-morbid mental health disorder, most often anxiety or depression. Koob and Schulkin in this issue have developed a framework that incorporates brainstem and extended amygdala signaling pathways that mediate negative affect associated with chronic substance use. They profile the contributions of hypodopaminergia to decreased hedonic tone, enhanced corticotropin releasing factor and noradrenergic signaling to stress, and elevated kappa opioid signaling to dysphoria. “Hyperkatefia” is appropriately described as “the pain of addiction” due to the overlapping mechanisms and association with chronic pain states. It can be argued that negative reinforcement can occur event with an initial drug taking experience. For example, negative reinforcement is achieved by pain relief following opioid use, but can also evolve from aversive opponent processes ‘kicking in’ during withdrawal states. It has recently been demonstrated that male subjects in a rodent mouse model were particularly vulnerable to kappa opioid-mediated negative affect induced by pain, suggesting that the vulnerability to addiction may be enhanced in males with ongoing pain (Liu et al., 2019). Interestingly, in this latter study, female subjects show higher endogenous kappa opioid tone regardless of pain status, perhaps in part explaining the general vulnerability of women to consume opioids to relieve negative affect in the absence of pain. Future studies may explore the contribution of additional neuropeptides in pain and addiction, considering that the brainstem and extended amygdala circuits are extensively modulated by oxytocin and vasopressin, peptides with known sex differences in expression and defined roles in emotional behavior and chronic pain (Severino et al., 2018). Several articles in this issue highlight the need to understand how negative affect contributes to pro-addiction processes, indicating that this is an imperative for researchers to address.

Also in this issue, Mathis and Kenny seek to address another core issue of addiction; how controlled drug use escalates into a compulsive behavior. They describe how the habenular complex plays a unique role in addiction as the “anti-reward system.” Mathis and Kenny describe emerging evidence that the medial and lateral habenula complex, which conducts information from limbic forebrain to limbic midbrain areas, processes aversive emotional information in order to promote or suppress adaptive addiction-related behaviors. They frame addiction as a state of globally dysregulated approach/avoidance conflict and describe how the habenular complex is poised as a node between circuits mediating affective valence of drug with circuits that mediate behavioral flexibility and habitual/compulsive behaviors. The habenular complex is able to inhibit the mesocorticolimbic dopamine circuit and in withdrawal becomes hyperactive. The authors argue that the habenular complex mediates the “opponent” anti-reward process and also the transition from acute rewarding effects as well as the aversive effects experienced during withdrawal.

In addition to the development of negative affect and increased compulsive consummatory behaviors, substance abuse and addiction is exacerbated by inhibition of executive function. Campanella et al. in this issue suggest that the study of Event Related Potentials can be used to address cognition-related components of addiction, primarily increased salience and bias toward drug-associated cues and impaired response inhibition promoting compulsive drug-taking behavior. This is conceptually aligned with the impaired response inhibition and salience attribution (iRISA) model developed by Rita Goldstein and colleagues in fMRI studies (Zilverstand et al., 2018). Additionally, Sampedro-Piquero et al. (this issue) profile SUD-induced cognitive impairment and highlight the therapeutic potential of cognitive stimulation, such as environmental enrichment, though evidence for humans is limited.

Considering all of the articles in this issue, we are left with some questions regarding the roots of addiction: Do we underestimate the motivational drive for relief of depression and anxiety? Do some drugs of abuse (such as amphetamines) blunt cognitive processing to promote habitual behaviors to create addiction more so than others (i.e. opioids and alcohol)? Is the environmental and genetic vulnerability to addiction a sum of decreased aversive responses during intoxication and a sensitivity to aversive responses during withdrawal? We stress the need for research that targets biological and environmental underpinnings that promote an individual’s susceptibility to disordered use of a specific substance with the expectation of diversity and not homogeneity of generative mechanisms and circuitry.