Neurobiologic Advances from the Brain Disease Model of Addiction
Stages of Addiction
Figure 1.Stages of the Addiction Cycle.
For heuristic purposes, we have divided addiction into three recurring stages: binge and intoxication, withdrawal and negative affect, and preoccupation and anticipation (or craving).10 Each stage is associated with the activation of specific neurobiologic circuits and the consequential clinical and behavioral characteristics (Figure 1).
BINGE AND INTOXICATION
All known addictive drugs activate reward regions in the brain by causing sharp increases in the release of dopamine.11-13 At the receptor level, these increases elicit a reward signal that triggers associative learning or conditioning. In this type of Pavlovian learning, repeated experiences of reward become associated with the environmental stimuli that precede them. With repeated exposure to the same reward, dopamine cells stop firing in response to the reward itself and instead fire in an anticipatory response to the conditioned stimuli (referred to as “cues”) that in a sense predict the delivery of the reward.14 This process involves the same molecular mechanisms that strengthen synaptic connections during learning and memory formation (Box 2). In this way, environmental stimuli that are repeatedly paired with drug use — including environments in which a drug has been taken, persons with whom it has been taken, and the mental state of a person before it was taken — may all come to elicit conditioned, fast surges of dopamine release that trigger craving for the drug20 (see Box 2 for the mechanisms involved), motivate drug-seeking behaviors, and lead to heavy “binge” use of the drug.21-23 These conditioned responses become deeply ingrained and can trigger strong cravings for a drug long after use has stopped (e.g., owing to incarceration or treatment) and even in the face of sanctions against its use.
As is true with other types of motivational learning, the greater the motivational attribute associated with a reward (e.g., a drug), the greater the effort a person is willing to exert and the greater the negative consequences he or she will be willing to endure in order to obtain it.24,25 However, whereas dopamine cells stop firing after repeated consumption of a “natural reward” (e.g., food or sex) satiating the drive to further pursue it, addictive drugs circumvent natural satiation and continue to directly increase dopamine levels,11,26 a factor that helps to explain why compulsive behaviors are more likely to emerge when people use drugs than when they pursue a natural reward (Box 2).
WITHDRAWAL AND NEGATIVE AFFECT
An important result of the conditioned physiologic processes involved in drug addiction is that ordinary, healthful rewards lose their former motivational power. In a person with addiction, the reward and motivational systems become reoriented through conditioning to focus on the more potent release of dopamine produced by the drug and its cues. The landscape of the person with addiction becomes restricted to one of cues and triggers for drug use. However, this is only one of the ways in which addiction changes motivation and behavior.
For many years it was believed that over time persons with addiction would become more sensitive to the rewarding effects of drugs and that this increased sensitivity would be reflected in higher levels of dopamine in the circuits of their brains that process reward (including the nucleus accumbens and the dorsal striatum) than the levels in persons who never had a drug addiction. Although this theory seemed to make sense, research has shown that it is incorrect. In fact, clinical and preclinical studies have shown that drug consumption triggers much smaller increases in dopamine levels in the presence of addiction (in both animals and humans) than in its absence (i.e., in persons who have never used drugs).22,23,27,28 This attenuated release of dopamine renders the brain’s reward system much less sensitive to stimulation by both drug-related and non–drug-related rewards.29-31 As a result, persons with addiction no longer experience the same degree of euphoria from a drug as they did when they first started using it. It is for this same reason that persons with addiction often become less motivated by everyday stimuli (e.g., relationships and activities) that they had previously found to be motivating and rewarding. Again, it is important to note that these changes become deeply ingrained and cannot be immediately reversed through the simple termination of drug use (e.g., detoxification).
In addition to resetting the brain’s reward system, repeated exposure to the dopamine-enhancing effects of most drugs leads to adaptations in the circuitry of the extended amygdala in the basal forebrain; these adaptations result in increases in a person’s reactivity to stress and lead to the emergence of negative emotions.32,33 This “antireward” system is fueled by the neurotransmitters involved in the stress response, such as corticotropin-releasing factor and dynorphin, which ordinarily help to maintain homeostasis. However, in the addicted brain, the antireward system becomes overactive, giving rise to the highly dysphoric phase of drug addiction that ensues when the direct effects of the drug wear off or the drug is withdrawn34 and to the decreased reactivity of dopamine cells in the brain’s reward circuitry.35 Thus, in addition to the direct and conditioned pull toward the “rewards” of drug use, there is a correspondingly intense motivational push to escape the discomfort associated with the aftereffects of use. As a result of these changes, the person with addiction transitions from taking drugs simply to feel pleasure, or to “get high,” to taking them to obtain transient relief from dysphoria (Figure 1).
Persons with addiction frequently cannot understand why they continue to take the drug when it no longer seems pleasurable. Many state that they continue to take the drug to escape the distress they feel when they are not intoxicated. Unfortunately, although the short-acting effects of increased dopamine levels triggered by drug administration temporarily relieve this distress, the result of repeated bingeing is to deepen the dysphoria during withdrawal, thus producing a vicious cycle.
PREOCCUPATION AND ANTICIPATION
The changes that occur in the reward and emotional circuits of the brain are accompanied by changes in the function of the prefrontal cortical regions, which are involved in executive processes. Specifically, the down-regulation of dopamine signaling that dulls the reward circuits’ sensitivity to pleasure also occurs in prefrontal brain regions and their associated circuits, seriously impairing executive processes, among which are the capacities for self-regulation, decision making, flexibility in the selection and initiation of action, attribution of salience (the assignment of relative value), and the monitoring of error.36 The modulation of the reward and emotional circuits of prefrontal regions is further disrupted by neuroplastic changes in glutamatergic signaling.37 In persons with addiction, the impaired signaling of dopamine and glutamate in the prefrontal regions of the brain weakens their ability to resist strong urges or to follow through on decisions to stop taking the drug. These effects explain why persons with addiction can be sincere in their desire and intention to stop using a drug and yet simultaneously impulsive and unable to follow through on their resolve. Thus, altered signaling in prefrontal regulatory circuits, paired with changes in the circuitry involved in reward and emotional response, creates an imbalance that is crucial to both the gradual development of compulsive behavior in the addicted disease state and the associated inability to voluntarily reduce drug-taking behavior, despite the potentially catastrophic consequences.
Biologic and Social Factors Involved in Addiction
Only a minority of people who use drugs ultimately become addicted — just as not everyone is equally at risk for the development of other chronic diseases. Susceptibility differs because people differ in their vulnerability to various genetic, environmental, and developmental factors. Many genetic, environmental, and social factors contribute to the determination of a person’s unique susceptibility to using drugs initially, sustaining drug use, and undergoing the progressive changes in the brain that characterize addiction.38,39 Factors that increase vulnerability to addiction include family history (presumably through heritability and child-rearing practices), early exposure to drug use (adolescence is among the periods of greatest vulnerability to addiction), exposure to high-risk environments (typically, socially stressful environments with poor familial and social supports and restricted behavioral alternatives and environments in which there is easy access to drugs and permissive normative attitudes toward drug taking), and certain mental illnesses (e.g., mood disorders, attention deficit–hyperactivity disorder, psychoses, and anxiety disorders).40,41
It is estimated that the most severe phenotypic characteristics of addiction will develop in approximately 10% of persons exposed to addictive drugs.42 Thus, although long-term exposure to drugs is a necessary condition for the development of addiction, it is by no means sufficient. Yet for those in whom there is progress to addiction, the neurobiologic changes are distinct and profound.