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. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: Abstinence or withdrawal; Compulsive; Corticotropin-releasing factor; Dynorphin; Extended amygdala; Impulsive; Opponent process; Prefrontal cortex; Reward; Sensitization.

Figure 1

(A) Effect of drug availability on cocaine intake (mean ± SEM). In long-access (LgA) rats (n = 12) but not short-access (ShA) rats (n = 12), the mean total cocaine intake started to increase significantly from session 5 (p < 0.05; sessions 5 to 22 compared with session 1) and continued to increase thereafter (p < 0.05; session 5 compared with sessions 8-10, 12, 13, and 17-22). [Taken with permission from Ahmed and Koob, 1998.] (B) Effect of drug availability on total intravenous heroin self-infusions (mean ± SEM). During the escalation phase, rats had access to heroin (40 μg per infusion) for 1 h (ShA rats, n = 5-6) or 11 h per session (LgA rats, n = 5-6). Regular 1-h (ShA rats) or 11-h (LgA rats) sessions of heroin self-administration were performed 6 days a week. The dotted line indicates the mean ± SEM number of heroin self-infusions in LgA rats during the first 11-h session. *p < 0.05, different from the first session (paired t-test). [Taken with permission from Ahmed et al., 2000.] (C) Effect of extended access to intravenous methamphetamine on self-administration as a function of daily sessions in rats trained to self-administer 0.05, 0.1, and 0.2 mg/kg/infusion of intravenous methamphetamine during the 6-h session. ShA, 1-h session (each unit dose, n = 6). LgA, 6-h session (0.05 mg/kg/infusion, n = 4; 0.1 mg/kg/infusion, n = 6; 0.2 mg/kg/infusion, n = 5). *p < 0.05, **p < 0.01, compared with day 1. [Taken with permission from Kitamura et al., 2006.] (D) Nicotine intake (mean ± SEM) in rats that self-administered nicotine under a fixed-ratio (FR) 1 schedule in either 21 h (long access [LgA]) or 1 h (short access [ShA]) sessions. LgA rats increased their nicotine intake on an intermittent schedule with 24-48 h breaks between sessions, whereas LgA rats on a daily schedule did not. The left shows the total number of nicotine infusions per session when the intermittent schedule included 24 h breaks between sessions. The right shows the total number of nicotine infusions per session when the intermittent schedule included 48 h breaks between sessions. ^#p < 0.05, compared with baseline; *p < 0.05, compared with daily self-administration group. n = 10 per group. [Taken with permission from Cohen et al., 2012.] (E) Ethanol self-administration in ethanol-dependent and nondependent animals. The induction of ethanol dependence and correlation of limited ethanol self-administration before and excessive drinking after dependence induction following chronic intermittent ethanol vapor exposure is shown. ***p < 0.001, significant group × test session interaction. With all drugs, escalation is defined as a significant increase in drug intake within-subjects in extended-access groups, with no significant changes within-subjects in limited-access groups. [Taken with permission from Edwards et al., 2011.]

Figure 2

(A) Dose-response function of cocaine by rats responding under a progressive-ratio schedule. Test sessions under a progressive-ratio schedule ended when rats did not achieve reinforcement within 1 h. The data are expressed as the number of injections per session on the left axis and ratio per injection on the right axis. *p < 0.05, compared with ShA rats at each dose of cocaine. [Taken with permission from Wee et al., 2008.] (B) Responding for heroin under a progressive-ratio schedule of reinforcement in ShA and LgA rats. *p < 0.05, LgA significantly different from LgA. [Modified with permission from Barbier et al., 2013.] (C) Dose-response for methamphetamine under a progressive-ratio schedule. Test sessions under a progressive-ratio schedule ended when rats did not achieve reinforcement within 1 h. *p < 0.05, **p < 0.01, LgA significantly different from ShA [Modified from Wee et al., 2007.] (D) Breakpoints on a progressive-ratio schedule in long access (LgA) rats that self-administered nicotine with 48 h abstinence between sessions. LgA rats on an intermittent schedule reached significantly higher breakpoints than LgA rats that self-administered nicotine daily. The data are expressed as mean ± SEM. *p < 0.05. n = 9 rats per group. [Taken with permission from Cohen et al., 2012.] (E) Mean (±SEM) breakpoints for ethanol while in nondependent and ethanol-dependent states. **p < 0.01, main effect of vapor exposure on ethanol self-administration. [Taken with permission from Walker and Koob, 2007.]

Figure 3

(A) Relationship between elevation in ICSS reward thresholds and cocaine intake escalation. (Left) Percent change from baseline response latencies (3 h and 17-22 h after each self-administration session; first data point indicates 1 h before the first session). (Right) Percent change from baseline ICSS thresholds. *p < 0.05, compared with drug-naive and/or ShA rats (tests for simple main effects). [Taken with permission from Ahmed et al., 2002.]. (B) Unlimited daily access to heroin escalated heroin intake and decreased the excitability of brain reward systems. (Left) Heroin intake (± SEM; 20 μg per infusion) in rats during limited (1 h) or unlimited (23 h) self-administration sessions. ***p < 0.001, main effect of access (1 or 23 h). (Right) Percent change from baseline ICSS thresholds (± SEM) in 23 h rats. Reward thresholds, assessed immediately after each daily 23 h self-administration session, became progressively more elevated as exposure to self-administered heroin increased across sessions. *p < 0.05, main effect of heroin on reward thresholds. [Taken with permission from Kenny et al., 2006.]. (C) Escalation in methamphetamine self-administration and ICSS in rats. Rats were daily allowed to receive ICSS in the lateral hypothalamus 1 h before and 3 h after intravenous methamphetamine self-administration with either 1- or 6-h access. (Left) Methamphetamine self-administration during the first hour of each session. (Right) ICSS measured 1 h before and 3 h after methamphetamine self-administration. *p < 0.05, **p < 0.01, ***p < 0.001, compared with session 1. ^#p < 0.05, compared with LgA 3 h after. [Taken with permission from Jang et al., 2013.]

Figure 4

(A) The effect of the CRF₁ receptor antagonist MPZP on operant self-administration of alcohol in dependent and nondependent rats. Testing was conducted when dependent animals were in acute withdrawal (6-8 h after removal from vapors). Dependent rats self-administered significantly more than nondependent animals, and MPZP dose-dependently reduced alcohol self-administration only in dependent animals. The data are expressed as mean + SEM lever presses for alcohol. [Taken with permission from Richardson et al., 2008.] (B) Abstinence-induced escalation of nicotine intake is blocked by a CRF₁ receptor antagonist. Effect of MPZP (s.c., −1 h) on nicotine self-administration during the active period in rats given extended access to nicotine. *p < 0.05, compared with baseline; ^#p < 0.05, compared with after-abstinence vehicle treatment; n = 8). The data are expressed as mean + SEM lever presses for nicotine. [Taken with permission from George et al., 2007.] (C) MPZP reduces cocaine intake in ShA and LgA rats. The data are expressed as mean + SEM cocaine intake (mg/kg). *p < 0.05, **p < 0.01, compared with vehicle. [Taken with permission from Specio et al., 2008.]

Figure 5

Neurocircuitry framework for the between-systems neuroadaptations hypothesized to mediate the transition to dependence in addiction. (Top) The hypothesis outlined here is that excessive activation of elements of the brain reward system (dopamine and opioid peptides via μ opioid receptors) in turn activates dynorphin in the ventral striatum, which in turn suppresses dopamine release to contribute to the negative emotional (dysphoric-like) effects of drug withdrawal. (Bottom) The hypothesis outlined here is that activation of elements of the brain stress systems in the extended amygdala during withdrawal (CRF, norepinephrine, and dynorphin) sensitize via feed-forward mechanisms and also contribute to the negative emotional (anxiety-like) effects of drug withdrawal.

Figure 6

The progression of compulsive drug use over time mediates recruitment of brain stress systems. The schematic illustrates the shift in underlying motivational mechanisms. As the addictive process progresses over time, the initial positively reinforcing, pleasurable drug effects are augmented by negatively reinforcing relief from a negative emotional state. The data summarized in the present treatise suggest that the neuroadaptations that encompass the recruitment of extrahypothalamic CRF and dynorphin brain stress systems are key to this shift. Initial use is characterized by activation of the hypothalamic-pituitary-adrenal axis to drive the binge/intoxication stage. Impulsive use is characterized by prefrontal cortex dysfunction with activation of corticotropin-releasing factor (CRF), γ-aminobutyric acid (GABA), and possibly dynorphin in the prefrontal cortex and subsequent disinhibition of the nucleus accumbens and extended amygdala that in turn drive increases in dynorphin in the nucleus accumbens and CRF in the extended amygdala. Compulsive use involves a pronounced activation of CRF in the extended amygdala, dynorphin-induced decreases in dopamine in the nucleus accumbens, and a pronounced loss of executive control in the prefrontal cortex, all leading to the spiralling distress and loss of control associated with full-blown dependence mediated by negative reinforcement.