Three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation

Drug addiction is a chronically relapsing disorder that is characterized by compulsion to seek and take the drug, loss of control in limiting drug intake, and emergence of a negative emotional state, reflecting a motivational withdrawal syndrome, when access to the drug is prevented.¹ Drug addiction includes three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. These three stages feed into each other to produce an addiction cycle. Each stage becomes more intense after each cycle, leading to the pathological state of addiction. These three stages reflect incentive salience/pathological habits, reward deficits/stress surfeit, and executive function deficits, respectively, which provide a powerful impetus for compulsive drug-seeking behavior that is associated with drug addiction. These domains of dysfunction correspond to neuroadaptations that reflect allostatic changes in three key neurocircuits that mediate compulsive drug seeking: basal ganglia, extended amygdala, and prefrontal cortex, respectively (Figure 1).². Allostasis in the context of addiction is the process by which the body responds to challenges to maintain apparent homeostasis through changes in brain reward and stress mechanisms.³ The allostatic state represents a chronic deviation of reward set point that is mostly observed during abstinence and not observed when the individual is actively taking drug. Thus, the allostatic view extends counteradaptive theory by stating that not only does the b-process get larger with chronic drug use but the reward set point also progressively shifts downward, thus creating an allostatic state (Figure 1 B).^3,4 This model has been proposed to explain the persistent changes in motivation in drug-dependent individuals. We propose that the relative contribution of each of these three stages to drug use and drug addiction varies both between and within individuals across time.

From positive to negative reinforcement

Another level of complexity that is added to these three stages is the fact that drug addiction includes a transition from impulsive to compulsive behaviors and from positive to negative reinforcement (Figure 2). ^5,6 Impulsivity is defined as “a predisposition toward rapid, unplanned reactions to internal or external stimuli without regard for the negative consequences of these reactions to [themselves] or others.”⁷ Compulsivity is defined as “perseverative, repetitive actions that are excessive and inappropriate.”⁸ Positive reinforcement is defined as the process by which presentation of a stimulus increases the probability of a response. Negative reinforcement is defined as the process by which removal of an aversive stimulus (or aversive state in the case of addiction) increases the probability of a response.⁹ Impulsivity often dominates at the early stages of drug addiction through repeated binge/intoxication and positive reinforcement. Individuals seek and take the drug for its initial pleasurable and reinforcing effects without regard for the potential future negative consequences of using drugs. Compulsivity dominates at later stages of drug addiction through the emergence of negative emotional states in the withdrawal/negative affect stage and anticipation of obtaining the drug in the preoccupation/anticipation stage. Such compulsivity leads to the escalation of drug intake and perseverative drug use despite adverse consequences. The transition from positive to negative reinforcement reflects a change in the underlying psychological and neurobiological mechanisms of motivation (Figure 2). Motivation can be defined as a “tendency of the whole animal to produce organized activity.”¹⁰ The neural substrates for the two sources of reinforcement that play a key role in allostatic neuroadaptations derive from two key motivational systems that are required for survival: brain reward system and brain stress system.

Within the addiction process, the concept of motivation is linked to hedonic, affective, and emotional states in the context of temporal dynamics that are elaborated by Solomon's opponent process theory of motivation.¹¹ Hedonic, affective, or emotional states, once initiated, are modulated by the central nervous system with mechanisms that reduce the intensity of hedonic feelings. This theory postulates that any motivational stimulus activates two opposing motivational processes. The a-process consists of positive or negative hedonic responses, has a fast onset and offset, correlates with the intensity, quality, and duration of the stimulus, and shows tolerance. The b-process appears after the a-process has terminated, is opposite in direction, is sluggish in onset, is slow to build up and decay, and gets larger with repeated exposure. The initial acute effect of a drug of abuse (ie, the a-process or positive hedonic response) was hypothesized to be opposed or counteracted by the b-process as homeostatic changes in brain systems. With repeated exposure to drugs, the b-process sensitizes, appears earlier after the unconditioned stimulus, lasts longer, and masks the a-process, leading to apparent tolerance.¹² Two types of biological processes have been proposed to describe the mechanisms that underlie the neuroadaptations that are associated with generation of the opponent process in drug addiction: within-system adaptation and between-system adaptation.¹³ In the within-system process, the drug elicits an opposing, neutralizing reaction within the same system in which the drug elicits its primary and unconditioned reinforcing actions. In the between-system process, neurobiological systems are recruited that are different from the ones that were initially activated by the drug.

Binge/intoxication stage

Intense research efforts over the past three decades have been dedicated to revealing the neurochemical elements and neuronal networks that are responsible for the binge/intoxication stage (Figure 3).¹⁴ Converging evidence suggests that three main contributors to the binge/intoxication stage in the early stages of drug addiction are (i) the acute positive hedonic value of drugs,¹⁵ (ii) sensitization of incentive salience,¹⁶ and (iii) inherent poor cognitive insight.¹⁷ The later stages of drug addiction also exhibit a binge/intoxication stage that also includes tolerance and is fueled by the negative emotional states that are an important driving force to the maintenance of chronic and heavy drug use.

Intoxicating doses of drugs, including alcohol, produce the release of dopamine and endogenous opioids in the ventral striatum that correlate with the subjective effects of drugs, including feelings of being “high.”^18,19 Earlier preclinical work showed that all drugs of abuse increase dopamine release in the ventral striatum, leading to theories that suggested that this increase may be related to the hedonic value of drugs of abuse.¹⁵ Moreover, dopamine plays a key role in psychostimulant reward, but dopamine -independent reward has also been demonstrated for opioids and alcohol.^20-22 Further work established a key common role for dopamine in addiction. The dopaminergic system is important within a subcomponent of motivational systems that allows the attribution of incentive salience. Incentive salience (anchored within the construct of conditioned reinforcement) is a phenomenon by which a previously neutral stimulus acquires incentive value through pairing with a drug of abuse.¹⁶ Robust evidence indicates that dopamine plays a minor role, if any, in reward processing per se and may represent instead a reward prediction error signal.²³

The theory of sensitization of incentive salience has its origins in early work on conditioned reinforcement.²⁴ Prominent work has shown that dopamine neurons are crucial for mediating such conditioned reinforcement. Dopamine neurons in the ventral tegmental area and substantia nigra have been shown to exhibit phasic responding to a nonpredicted reward. After repeated exposure, the same neurons stop responding to a predictable reward and instead start responding to the earliest cue that predicts the future reward.^25,26 This process allows neutral cues to acquire incentive salience and thus elicit behavioral approach. One hypothesis is that the progressive sensitization of this phasic responding to cues that is associated with drug reward may contribute to maladaptive craving that is observed in individuals with substance-use disorders,^27,28 although clinical evidence for such a phenomenon is sparse.²⁹ Preclinical evidence indicates that drugs of abuse can produce a shift in the excitatory balance of dopamine neurons after acute administration,^30-38 suggesting that neuroadaptations in the dopamine incentive salience system can occur early in the addiction process. Moreover, a recent study in humans showed that the phenomenon of conditioned responding of dopamine neurons to drug-predictive cues occurred in recreational cocaine users who did not meet the criteria for cocaine-use disorders.³⁹ These results suggest that the phenomenon of sensitization of incentive salience may be important early in the addiction process but may not be a key mechanism in later stages of addiction. In contrast, there is converging evidence in the preclinical literature that the later stages of addiction may instead involve a transition from goal-directed behavior that is mediated by the ventral striatum to habit behavior that is under the control of the dorsal striatum and that is facilitated by chronic exposure to the drug.^40-49

Preclinical work has shown that the activation of dopamine D₁ but not D₂ receptors,^50,51, μ-opioid receptors (MORs),⁵² nociceptin opioid (NOP) receptors,⁵³ and α4-, β2-, and α6-containing nicotinic acetylcholine receptors (nAChRs) are required for the acute rewarding and reinforcing effects of drugs. However, these requirements are usually specific to the particular drug of abuse (D₁ for cocaine, MOR for opioids, and nAChRs for nicotine). The only exception may be NOP receptors, which have recently been shown to affect cocaine, heroin, and alcohol self-administration and drug-induced conditioned place preference.⁵³ Other neurotransmitter systems, including the serotonin 5-hydroxytryptamine (5-HT),^54,55 γ-aminobutyric acid (GABA),⁵⁵ acetylcholinergic (ACh),⁵⁵ and endocannabinoid^35,56-59 systems, are believed to contribute to the binge/intoxication stage by modulating dopamine, opioid, and nicotinic systems, although a more central role for the GABA system has been identified in the mediation of the intoxicating and reinforcing effects of alcohol.⁶⁰

Withdrawal/negative affect stage

Our understanding of the neurobiology of the withdrawal/negative affect stage has dramatically increased in the past decade. This stage includes different sources of motivation to take drugs, including chronic irritability, emotional pain, malaise, dysphoria, alexithymia (inability to identify/express emotions), states of stress, and the loss of motivation for natural rewards. For example, chronic administration of all major drugs of abuse leads to stress and anxiety-like responses during acute and protracted abstinence.⁶¹

One explanation for the blunted function of the reward system during abstinence involves within-system neuroadaptations, in which the primary target of the drug rapidly adapts to neutralize the effect of the drug. Long-lasting within-system adaptations can then lead to a decrease in brain reward function when the drug is removed.¹³ For example, cocaine acutely produces dopamine and serotonin release, but decreases in dopaminergic and serotonergic transmission have been observed in the ventral striatum during cocaine withdrawal in rats.⁶² Even more compelling are studies in humans that reported lower self-reported rewarding effects of drugs and a lower striatal dopamine response after amphetamine/methylphenidate challenges in active and detoxified abusers than in controls.^63-66 Similar neuroadaptations are hypothesized to occur for other classes of drugs, including increases in MOR responsivity during opioid withdrawal,^67,68 decreases in GABAergic transmission in the ventral striatum, and increases in N-methyl-D-aspartate glutamatergic transmission in the ventral striatum.^69,70 Complex regional changes in function in key brain regions, including the ventral tegmental area, ventral striatum, interpeduncular nucleus (IPN), amygdala, and habenula, have been reported for nicotine and alcohol addiction, among other addictions.^71,72 Such within-system neuroadaptations may contribute to the withdrawal/negative affect stage by decreasing brain reward function during abstinence but may also be involved in the preoccupation/anticipation stage by providing a greater hedonic driving force to resume drug use.

Another explanation for the lower function of the reward system during abstinence involves betweensystem neuroadaptations, in which systems other than those that are involved in the positive rewarding effects of drugs are recruited or dysregulated by chronic drug use to oppose the rewarding effects of drugs of abuse.¹³ A central component of this between-system neuroadaptation is activation of the stress pathways, including the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress systems that are mediated by corticotropin-releasing factor (CRF), norepinephrine, and dynorphin.^73-75 Withdrawal from drugs of abuse acutely increases adrenocorticotropic hormone, corticosterone, and extended amygdala CRF and dynorphin during withdrawal.^76-83

Two main brain circuits probably contribute to these opponent-like processes that lower brain reward function and increase brain stress system function. Both of these circuits are heavy influenced by CRF. One circuit involves the extended amygdala, which encompasses the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), and part of the nucleus accumbens (Figure 3). The extended amygdala integrates brain arousal-stress and reward system information⁸⁴ to produce the between-system opponent process that is elaborated above. The CRF system in the extended amygdala is activated during acute withdrawal from cocaine, alcohol, opioids, Δ⁹-tetrahydrocannabinol, and nicotine.^78,85,86 Similar effects have been observed with alcohol in the lateral BNST⁸¹ Cocaine withdrawal produces anxiety-like responses that can be reversed by a CRF-receptor antagonist.^87,88 Similar results have been observed with nicotine,^86,89,90 alcohol,^79,91 and opioids.^88,92,93 Moreover, the ability of CRF receptor antagonists to block the anxiogenic-like and aversive-like motivational effects of drug withdrawal predicts the efficacy in reducing compulsive-like self-administration of cocaine,⁹⁴ nicotine,⁸⁶ and heroin⁹⁵ in rats. Although very promising, the clinical development of CRF₁-receptor antagonists for the treatment of drugand alcohol-use disorders has mostly failed.^96,97 However, these failures should be considered cautiously because the compounds that have been used have less than ideal pharmacokinetics/pharmacodynamics and physicochemical properties, and several other shortcomings in these studies may explain their negative outcomes (for details, see Spierling and Zorrilla⁹⁸).

The excessive release of dopamine and opioid peptides produces subsequent activation of the dynorphin system in the basal ganglia and extended amygdala, which has been hypothesized to feed back to decrease dopamine release and contribute to the dysphoric syndrome that is associated with cocaine dependence.⁹⁹ Dynorphins produce aversive dysphoric-like effects in animals and humans and have been hypothesized to mediate negative emotional states^100,101 and depressionlike, aversive responses to stress and dysphoric-like responses during withdrawal from drugs of abuse. Recent evidence suggests that the dynorphin/κ-opioid system in the extended amygdala also mediates compulsive-like responding for methamphetamine, heroin, and alcohol with extended access and dependence.¹⁰¹

Another system is the habenula-to-IPN pathway. The habenula plays a key role in encoding aversive states,^102,103 in part by decreasing dopamine neuron firing in the ventral tegmental area after failure to receive an expected reward.^102,103 This hypothesis is consistent with the finding that nAChRs in the habenula-IPN appear to modulate aversive responses to nicotine¹⁰⁴ and nicotine withdrawal.^105,106 We recently reported that the habenula-IPN pathway is also under the influence of the CRF system.^90,106 Activation of this pathway during nicotine withdrawal was potentiated by CRF-producing neurons in the ventral tegmental area that project to the IPN. The downregulation of CRF messenger RNA in the ventral tegmental area and CRF₁-receptor blockade in the IPN prevented emergence of the negative emotional states associated with withdrawal and reduced excessive nicotine intake after abstinence.^90,106

In addition to these subcortical circuits that involve the brain reward and stress systems, the insular cortex is an important cortical region for emotional aspects of the withdrawal/negative affect stage. Cravings for food, cocaine, and nicotine have been shown to activate the insular cortex,^107-109 and tobacco smokers with damage to the insular cortex were able to stop smoking easily with little, if any, withdrawal symptoms, craving, or relapse.¹¹⁰ The insula is hypothesized to integrate autonomic, visceral, and emotional information¹¹¹ during withdrawal and abstinence to produce the motivation to obtain the drug within a negative reinforcement framework (ie, obtain relief from negative emotional states associated with withdrawal). Supporting this hypothesis, imaging studies have reported differential activation of the insula during craving, possibly reflecting interoceptive cues. Such activation during craving also could be driven by the activation of cortical CRF systems when considering the substantial level of CRF neurons and CKF₁ receptors in the insula.^112,113 Finally, reactivity of the insular cortex has been suggested to serve as a biomarker to help predict relapse.¹¹⁴

Preoccupation/anticipation stage

Intoxicating doses of drugs, particularly alcohol, marijuana, and opioids, and high doses of psychostimulants are associated with cognitive impairments, including poor working memory, inattention, impulsivity, and delay discounting¹¹⁵ (for review, see Oscar-Berman and Ilutner¹¹⁶). Such cognitive impairment significantly contributes to relapse and the escalation of drug intake and results from drug-induced dysfunction of the dorsolateral, ventrolateral, and lateral prefrontal cortex and orbitofrontal cortex (Figure 3).,^115,117-120 For example, working-memory impairments have been associated with higher levels of alcohol, methamphetamine, and cocaine use in both humans and rats.^121-125

Craving is a key part of the preoccupation/anticipation stage. Large interindividual variability has been observed in the intensity of craving and the source of craving. In humans, cue-induced craving activates the dorsolateral prefrontal cortex, anterior cingulate gyrus, and medial orbitofrontal cortex.^126-130 Cues that are associated with cocaine craving also increase doparnine release in the ventral striatum, prefrontal cortex, and amygdala and endogenous opioid peptide release in the frontal cortex and anterior cingulate.^131-134 Such activation of the reward/salience systems during acute craving episodes is further potentiated because of a decrease in the inhibitory function of the prefrontal cortex (orbitofrontal cortex, ventromedial cortex, and anterior cingulate cortex) in humans with substance-use disorders.^19,135,136 Indeed, substance-use disorder is associated with chronic executive dysfunction, including impairments in decision making, self-regulation, inhibitor control, attention, and working memory,¹¹⁷ that may be caused by increases in GABAergic and CRF activity in the prefrontal cortex.^123,137 Another key neurotransmitter system that is associated with impairments in behavioral inhibition is the dopaminergic system. Brain imaging has consistently shown lower dopamine D₂ receptor availability in the striatum and prefrontal cortex after protracted abstinence in humans, nonhuman primates, and rodents.¹³⁸ Preclinical models have shown that lower D₂ receptor availability is associated with greater motivation for cocaine¹³⁹ and cognitive deficits.¹⁴⁰ Decreases in striatal dopamine, combined with increases in GABA and CRF signaling in the prefrontal cortex, may lead to an overactive ”Go“ system that drives craving and habits and a hypoactive ”Stop“ system that normally inhibits impulsive behavior and negative emotional states through the activation of specific corticostriatal loops.^141-144

Implications for personalized medicine

Our thesis is that there are considerable individual differences in the patterns of drug use and the psychological mechanisms that drive drug use. Drug use may be driven by the binge/intoxication stage for some individuals and by the withdrawal/negative affect stage for others. With psychostimulants and even alcohol, binge-like patterns can predominate in some individuals. Such individuals may escalate their drug intake in a binge-like pattern for various reasons, including peer pressure, sensation seeking, externalizing disorders, and drug-induced cognitive impairment (eg, decision making, monitoring, renegade attention, and transcendence failure) with little, if any, initial negative emotional symptoms. Other individuals may quickly develop a pattern of chronic and heavy use that is caused by either conscious or unconscious attempts to self-medicate existing negative emotional states. Such individuals often have preexisting conditions that generate powerful negative emotional states, such as posttraumatic stress disorders, sexual abuse, major depressive disorder, or anxiety disorder, and will use drugs to obtain relief from these negative emotional states. However, chronic high-dose binge-like patterns of drug intake can cause the development of negative emotional states and ultimately drive self-medication of a state that is created by the drug itself. Ultimately, both the binge/intoxication stage and withdrawal/negative affect stage will contribute to a pathological state of compulsive drug seeking and taking. One intriguing area of research is the identification of genetic, biological, and psychological subpopulations of humans with substance-use disorder within the framework of the three stages of addiction to better understand the drug addiction process and potentially predict treatment efficacy. Our thesis is that addiction treatments may benefit from the development of medications that specifically target each phase of the addiction process to personalize treatment and obtain better treatment outcome and compliance. In the past decade, notable advances have been made, and there is clear clinical evidence in humans that some treatments (eg, naltrexone) may be better suited for the treatment of the binge/intoxication stage, whereas others (eg, acamprosate) may be more appropriate for the preoccupation/anticipation stage. However, to date, these findings have had little impact in real life for the treatment of substance-use disorders because of the limited number of available medications and limited number of patients who receive appropriate treatment.

There are individual differences in executive function, prefrontal cortex function, brain stress system function, and dopamine reward signaling, and the genetics of negative emotional states may help identify subgroups of patients with substance-use disorder that may help predict treatment outcome. Attempts are being made to identify genetic markers, including single-nucleotide polymorphisms (SNPs), that may predict the vulnerability to substance-use disorders and responsiveness to treatment. Several research groups have identified gene variants in the metabolic enzymes and receptors that are directly modulated by drugs of abuse, such as MOR, nAChRs, cytochrome p450, and alcohol dehydrogenase. Such findings are very encouraging and suggest that some of these gene variants may predict the response to specific treatments.^145-149 Several SNPs that are associated with the CRF system have also been associated with excessive alcohol use. An association was found between SNPs that are related to the CRF₁ receptor gene (Crhr1) and binge drinking in adolescents and alcohol-dependent adults.^150-152 Another important genetic association has been found between alcohol dependence and SNPs that are related to the gene that encodes neuropeptide Y (NPY). NPY is an anxiolytic peptide that is involved in emotional regulation and stress coping and is known to antagonize the effects of CRF on addiction-like behaviors. Studies have linked SNPs of the Y₂, receptor gene (NPY2R) and alcohol dependence, alcohol withdrawal symptoms, comorbid alcohol and cocaine dependence, and cocaine dependence.¹⁵³ The G1258A polymorphism of the NPY gene has been linked to alcohol dependence.¹⁵⁴ The rsl6147 SNP of the NPY promoter gene was linked to tobacco addiction.¹⁵⁵ Should a medication become available that modulates CRF or NPY, such genetic analysis may reveal that subpopulations of subjects who carry specific SNPs might be more responsive than others.