Addiction is a Reward Deficit and Stress Surfeit Disorder

Abstract

Drug addiction can be defined by a three-stage cycle - binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation - that involves allostatic changes in the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to play a role in this allostatic process. The negative emotional state that drives negative reinforcement is hypothesized to derive from dysregulation of key neurochemical elements involved in the brain reward and stress systems. Specific neurochemical elements in these structures include not only decreases in reward system function (within-system opponent processes) but also recruitment of the brain stress systems mediated by corticotropin-releasing factor (CRF) and dynorphin-κ opioid systems in the ventral striatum, extended amygdala, and frontal cortex (both between-system opponent processes). CRF antagonists block anxiety-like responses associated with withdrawal, block increases in reward thresholds produced by withdrawal from drugs of abuse, and block compulsive-like drug taking during extended access. Excessive drug taking also engages the activation of CRF in the medial prefrontal cortex, paralleled by deficits in executive function that may facilitate the transition to compulsive-like responding. Neuropeptide Y, a powerful anti-stress neurotransmitter, has a profile of action on compulsive-like responding for ethanol similar to a CRF1 antagonist. Blockade of the κ opioid system can also block dysphoric-like effects 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 system that contributes to compulsive drug seeking. The loss of reward function and recruitment of brain systems provide a powerful neurochemical basis that drives the compulsivity of addiction.

Keywords: compulsive; corticotropin-releasing factor; dynorphin; extended amygdala; opponent process; prefrontal cortex; reward; withdrawal.

Figure 1

Theoretical framework relating addiction cycle to motivation for drug seeking. The figure shows the change in the relative contribution of positive and negative reinforcement constructs during the development of substance dependence [taken with permission from Ref. (61)].

Figure 2

Neurotransmitter pathways and receptor systems implicated in the acute reinforcing effects of drugs of abuse within the medial forebrain bundle. A sagittal rodent brain section is shown. The medial forebrain bundle represents ascending and descending projections between the ventral forebrain (nucleus accumbens, olfactory tubercle, and septal area) and ventral midbrain (ventral tegmental area; not shown in figure for clarity). Cocaine and amphetamines increase dopamine levels in the nucleus accumbens and amygdala via direct actions on dopamine terminals. Opioids activate endogenous opioid receptors in the ventral tegmental area, nucleus accumbens, and amygdala. Opioids also facilitate the release of dopamine in the nucleus accumbens via actions either in the ventral tegmental area or nucleus accumbens but are also hypothesized to activate elements independent of the dopamine system. Alcohol activates GABA_A receptors or enhances GABA release in the ventral tegmental area, nucleus accumbens, and amygdala. Alcohol is also hypothesized to facilitate the release of opioid peptides in the ventral tegmental area, nucleus accumbens, and central nucleus of the amygdala. Alcohol facilitates the release of dopamine in the nucleus accumbens via an action either in the ventral tegmental area or nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the ventral tegmental area, nucleus accumbens, and amygdala either directly or indirectly via actions on interneurons. Cannabinoids activate cannabinoid CB₁ receptors in the ventral tegmental area, nucleus accumbens, and amygdala. Cannabinoids facilitate the release of dopamine in the nucleus accumbens via an unknown mechanism, either in the ventral tegmental area or nucleus accumbens. The blue arrows represent the interactions within the extended amygdala system hypothesized to play a key role in psychostimulant reinforcement. AC, anterior commissure; AMG, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; Cer, cerebellum; C-P, caudate-putamen; DMT, dorsomedial thalamus; FC, frontal cortex; Hippo, hippocampus; IF, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; MFB, medial forebrain bundle; N Acc., nucleus accumbens; OT, olfactory tract; PAG, periaqueductal gray; RPn, reticular pontine nucleus; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum; VTA, ventral tegmental area [taken with permission from Ref. (183)].

Figure 3

(A) The standard pattern of affective dynamics produced by (left) a relatively novel unconditioned stimulus (i.e., in a non-dependent state) and (right) a familiar, frequently repeated unconditioned stimulus (i.e., in a dependent state) [taken with permission from Ref. (184)]. (B) The changes in the affective stimulus (state) in an individual with repeated frequent drug use that may represent a transition to an allostatic state in the brain reward systems and, by extrapolation, a transition to addiction. Note that the apparent b-process never returns to the original homeostatic level before drug taking is reinitiated, thus creating a greater and greater allostatic state in the brain reward system. In other words, the counteradaptive opponent-process (b-process) does not balance the activational process (a-process) but in fact shows a residual hysteresis. While these changes are exaggerated and condensed over time in the present conceptualization, the hypothesis here is that even during post-detoxification, a period of “protracted abstinence,” the reward system is still bearing allostatic changes. In the non-dependent state, reward experiences are normal, and the brain stress systems are not greatly engaged. During the transition to the state known as addiction, the brain reward system is in a major underactivated state while the brain stress system is highly activated [taken with permission from Ref. (15)].

Figure 4

(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 5–22 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 Ref. (74)]. (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 Ref. (73)]. (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 mg/kg/infusion of intravenous methamphetamine during the 6 h session. ShA, 1 h session (n = 6). LgA, 6 h session (0.05 mg/kg/infusion, n = 4). **p < 0.01, compared with day 1 [taken with permission from Ref. (75)]. (D) Nicotine intake (mean ± SEM) in rats that self-administered nicotine under a fixed-ratio (FR) 1 schedule in either 21 h (LgA) or 1 h (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 Ref. (185)]. (E) Ethanol self-administration in ethanol-dependent and non-dependent 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 Ref. (186)].

Figure 5

(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 Ref. (84)]. (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 Ref. (187)]. (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 Ref. (188)]. (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 Ref. (185)]. (E) Mean (±SEM) breakpoints for ethanol while in non-dependent and ethanol-dependent states. **p < 0.01, main effect of vapor exposure on ethanol self-administration [taken with permission from Ref. (85)].

Figure 6

(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 Ref. (97)]. (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 Ref. (99)]. (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 Ref. (98)].

Figure 7

(A) The left panel shows the effect of ethanol withdrawal on absolute extracellular dopamine concentrations in the nucleus accumbens in ethanol-withdrawn rats. The middle and right panels show the spontaneous activity of antidromically identified ventral tegmental area-nucleus accumbens dopamine neurons in control (middle) and ethanol-withdrawn (right) rats [taken with permission from Ref. (102)]. (B) The left panel shows individual firing rates of antidromically identified ventral tegmental area-nucleus accumbens dopamine neurons recorded from morphine-withdrawn and control rats. Each circle represents the mean firing of at least a 5-min recording. Horizontal lines indicate the mean activity. The middle and right panels show the spontaneous activity of a selected number (4) or antidromically identified ventral tegmental area-nucleus accumbens dopamine neurons in control (middle) and morphine-withdrawn (right) rats. Each panel represents the neuronal activity of a single cell. Recordings in both cases were obtained 24 h after the last morphine and saline administration, respectively [taken with permission from Ref. (103)]. (C) Firing rates of dopamine cells in the ventral tegmental area following 1–10 days of withdrawal from chronic nicotine treatment (6 mg/kg/day for 12 days). The data are expressed as mean ± SEM. The number of dopamine cells recorded is given in parentheses. *p < 0.01, compared with control group [taken with permission from Ref. (189)]. (D) Profile of dialysate serotonin and dopamine concentrations during a 12-h extended-access cocaine self-administration session. The mean ± SEM presession baseline dialysate concentrations of serotonin and dopamine were 0.98 ± 0.1 nM and 5.3 ± 0.5 nM, respectively (n = 7) [taken with permission from Ref. (104)].

Figure 8

Effects of CRF₁ antagonist on compulsive-like responding for drugs of abuse in rats with extended access to drug (A). The effect of the CRF₁ receptor antagonist MPZP on operant self-administration of alcohol in dependent and non-dependent 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 non-dependent 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 Ref. (190)]. (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 Ref. 77)]. (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 Ref. (146)].

Figure 9

Diagram of the hypothetical “within-system” and “between-system” changes that lead to the “darkness within.” (Top) Circuitry for drug reward with major contributions from mesolimbic dopamine and opioid peptides that converge on the nucleus accumbens. During the binge/intoxication stage of the addiction cycle, the reward circuitry is excessively engaged, Middle. Such excessive activation of the reward system triggers “within-system” neurobiological adaptations during the withdrawal/negative affect stage, including activation of cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB), downregulation of dopamine D₂ receptors, and decreased firing of ventral tegmental area (VTA) dopaminergic neurons, Bottom. As dependence progresses and the withdrawal/negative affect stage is repeated, two major “between-system” neuroadaptations occur. One is activation of dynorphin feedback that further decreases dopaminergic activity. The other is recruitment of extrahypothalamic norepinephrine (NE)-corticotropin-releasing factor (CRF) systems in the extended amygdala. Facilitation of the brain stress system in the prefrontal cortex is hypothesized to exacerbate the between-system neuroadaptations while contributing to the persistence of the dark side into the preoccupation/anticipation stage of the addiction cycle [taken with permission from Ref. (191)].