Addiction as a stress surfeit disorder

Abstract

Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction.

Hypocretin Receptor 2 Antagonism Dose-Dependently Reduces Escalated Heroin Self-Administration in Rats

“…The escalation of heroin intake observed in LgA animals contrasts with the lower, more stable intake levels observed in ShA animals (Ahmed et al, 2000b;Barbier et al, 2013;Greenwell et al, 2009a, b;Schlosburg et al, 2013;Vendruscolo et al, 2011;Walker et al, 2000). It is hypothesized that escalated heroin taking is mediated, in part, by the dysregulation of brain reward and stress systems (eg, HCRT, dynorphin, substance P and corticotropin-releasing factor; CRF) particularly within subregions of the extended amygdala via negative reinforcement mechanisms (for review, see Koob et al, 2014) Effects of acute heroin withdrawal on Hcrtr2 mRNA expression levels in reward/stress-related brain regions of heroin-naive, short access (ShA) and long access (LgA) to heroin rats. Bars indicated the mean percentage change ( þ SEM) from control (ie, naive) values of Hcrtr2 mRNA expression.…”

“…Heroin has been argued to be the second most harmful psychoactive drug, behind only alcohol (Nutt et al, 2010). Opioid addiction is characterized by patterns of excessive/repetitive drug seeking and taking, including a preoccupation with obtaining the drug, a loss of control over drug intake, and the development of somatic and/or affective withdrawal symptoms (Koob et al, 2014). Treatment options to date are mainly based on substitution therapy with the use of long-lasting opioid agonists such as methadone (Camí et al, 1985;Kleber et al, 1987).…”

“…In rats, short access (1 h per day; ShA) to heroin produces stable levels of drug intake, whereas long access (6-23 h per day; LgA) to heroin self-administration can lead to escalated self-administration, which reproduces several key symptoms of heroin dependence reminiscent of the human condition (Ahmed et al, 2000a;Barbier et al, 2013;Vendruscolo et al, 2011). It has long been hypothesized that during limited access conditions, drug intake is mainly driven by the positive reinforcing properties of heroin, whereas during extended access, negative reinforcement mechanisms predominate, in which brain stress systems are recruited and the drug is taken to alleviate negative affective states associated with drug withdrawal (for review, Koob et al, 2014).…”

“…These receptors have different affinities for HCRT peptides such that HCRT-1 binds to both receptors, whereas HCRT-2 binds selectively to HCRT-R2. Importantly, HCRT neuronal projections include reciprocal connections to the extended amygdala and other basal forebrain regions (Baldo et al, 2003;Peyron et al, 1998) implicated in negative reinforcement (for review, Koob et al, 2014). To date, HCRT-R1 has been shown to mediate the positive reinforcement of drug seeking of all major drug classes, including psychostimulants, nicotine, alcohol, and opioids.…”

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…Kappa opioid receptors (KORs) are located presynaptically on DA terminals and suppress DA release in the NAc (Werling et al, 1988;Svingos et al, 2001;Ebner et al, 2010). Previous data suggest that exposure to chronic stress, such as repeated withdrawal from chronic intermittent ethanol (CIE) exposure, leads to prolonged activation of KORs (Walker and Koob, 2008), possibly contributing to reduced DA function, which is positively correlated with negative affect (see Koob et al, 2014 for a review). Elevations in intra-cranial self-stimulation (ICSS) thresholds are associated with anhedonia, and a recent study showed that prolonged activation of KORs resulted in significantly elevated ICSS thresholds (Chartoff et al, 2016).…”