A Deeper Look at the Neurocircuitry of Addiction
The discovery that addictive drugs highjack the brain’s reward system, which involves the dopaminergic neurons projecting from the ventral tegmental area of the midbrain to the nucleus accumbens in the forebrain, was major development in understanding how addiction works in the brain. The DSM-5 sticks with this simplified model, stating, “All drugs that are taken in excess have in common direct activation of the brain reward system.”
We understand the biology of addiction better than any other psychiatric disorder, and it turns out to be much more complex than a single dopaminergic tract. The simplified disease model helps combat the moral stigma our addicted patients bear, but a more detailed look tells us much more about what is going on in our patients. While it still appears that the more we know, the more we see how much we don’t know, a review of current understanding of the brain mechanisms of addiction can help us tailor interventions to individual patients’ needs at particular times in their recoveries.
Nora Volkow and her colleagues provide an excellent new review in the New England Journal of Medicine. What follows is derived from their as well as from an earlier one by George Koob and Volkow (see references below.) For heuristic purposes, they identify three stages in the process of addiction: binge and intoxication, withdrawal and negative affect, and preoccupation and anticipation, each of which has its own pathophysiology. While firm boundaries between these processes are unlikely, these stages are useful organizing concepts.
Their first stage, binge and intoxication, primarily involves the familiar dopamine reward system. Amphetamines and cocaine directly cause the release of dopamine in the nucleus accumbens, methylphenidate increases synaptic dopamine by inhibiting its reuptake, and other drugs activate dopamine release by pathways that feed into the reward system. The dopamine triggers a reward signal that promotes associative learning. Experiences of drug-induced reward (pleasure) become associated with the environmental stimuli that preceded them. With repeated exposure, the drug no longer produces the reward, but the conditioned stimuli do. Thus drug-taking environments, drug associates, and mental states before drug use come to elicit dopamine release that trigger craving, motivate drug-seeking behaviors, and lead to bingeing on the drug.
The pharmacokinetic properties of a drug preparation are strongly associated with its ability to produce this binge/intoxication cycle. Volkow and colleagues note that alcohol is the only substance for which addiction is frequently associated with oral use—though I have observed severe addiction with oral use of barbiturates and amphetamines. But in general, other drugs must be snorted, injected, or smoked to produce the rapid pulses of dopamine necessary to produce addiction.
The second stage, withdrawal and negative, affect involves both the loss of the positive reinforcing effects of pleasurable activities and the emergence of negatively reinforcing dysphoria. Over time the brain’s reward system becomes less sensitive to the effects not only of drugs, but also of natural rewards such as food, sex, and relationships. These natural pleasures of life lose their power to motivate. In addition, addictive drugs activate circuits in the extended amygdala, which comprises the central medial amygdala, the substantia innominata, the nucleus accumbens shell, and the stria terminalis. Activation of this system increases reactivity to stress and produces negative emotions. This “antireward” system, which ordinarily counterbalances the reward system to maintain homeostasis, involves stress response neurotransmitters such as corticotropin-releasing factor and dynorphin, which is an opioid peptide involved in analgesia, stress, depression, appetite, and temperature regulation, as well as addiction. Activation of the antireward system produces dysphoria, which the addict is motivated to escape by using more drugs.
It is important to note that this is a phenomenon of motivational withdrawal which is not the same as the acute physical withdrawal syndromes which occur with abrupt discontinuation of alcohol, sedative-hypnotics, and opioids. Such discontinuation syndromes involve other circuits in the brain as well as other body systems. All substances of abuse, whether or not they have an acute discontinuation syndrome, produce motivational withdrawal involving dysfunction of the reward and stress response systems.
The third stage, preoccupation and anticipation, involves down-regulation of dopamine signaling in regions of the prefrontal cortex. This leads to impairment of executive functions such as decision-making, flexibility in selecting actions, attribution of salience, and monitoring of error. This compromises the addict’s ability to follow through on what may be sincere desires to stop using. (A teacher during my residency defined the superego as that part of the personality which is soluble in alcohol. In the light of today’s neuroscience, we can now say that free will is also soluble in alcohol and other drugs.)
This summary is necessarily very far from complete—Volkow and colleagues cite research findings in much finer detail that I have covered, and there is a great deal we don’t know about addiction. I have also not addressed the genetic and developmental contributions to an individual’s vulnerability to addiction, or the various pharmacologic treatments now available or under investigation to treat addictions.
I want to close with some points about nonpharmacological treatment of addicted patients which emerge from this discussion of brain mechanisms. First, helping patients to reengage with activities that formerly provide pleasure should enhance the ability of natural, healthy rewards to compete with the motivating properties of drugs. Second, strategies to reduce patients’ stress reactivity and negative emotional states are in order—here cognitive-behavioral and other forms of psychotherapy may be effective. In addition, addicts’ executive functioning and self-regulation are compromised, teaching strategies such as avoidance and management of drug trigger situations may be effective.
Nora D. Volkow, George F. Koob, and A. Thomas McLellan. Neurobiologic Advances from the Brain Disease Model of Addiction. N Engl J Med 2016; 374:363-371.
George F. Koob and Nora D. Volkow. Neurocircuitry of Addiction. Neuropsychopharmacology Reviews 2010; 35, 217–238.