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Neuroscience Breakthroughs Since Graduate School - Part 2: Addiction

Updated: Dec 30, 2022

Addiction inevitably involves loss, including executive functions, health, pleasure from everyday life, productivity, and often relationships. There has been a paradigm shift to a more complete model of addiction that combines negative and positive reinforcement. Although many factors contribute to substance use disorders, stress and deficient dopamine receptors may be crucial. Abused drugs cause direct and indirect dopamine release at the nucleus accumbens. While dopamine begins the reward cascade, addiction involves diverse neurotransmitters. Craving is one of the most dangerous threats to sobriety. Craving emerges from a complex network of subcortical and cortical projections. The loss of brain volume due to apoptosis contributes to hypofrontality, impairing an addict's ability to resist craving and causing relapse. Neurofeedback is an evidence-based treatment for substance use disorder. The Scott-Kaiser modification of the Peniston Protocol plus rehabilitation for substance use disorder has achieved a rating of probably efficacious, comparable to accepted medical treatments. This second installment focuses on the neuroscience of addiction and the efficacy of neurofeedback interventions.

Alcohol is cunning, baffling, and powerful (The Big Book of Alcoholics Anonymous).

A Paradigm Shift

The view before 1969 was that addiction is fueled by drug dependence. This negative reinforcement model proposed that addicts ingest their next dose to avoid or escape unpleasant withdrawal effects.

Young addict

Negative reinforcement strengthens the behavior it follows. For example, an addict's "coke runs" can increase the likelihood of drug use by forestalling a cocaine "crash." This is different from punishment, which weakens the behavior by following it with an aversive consequence. Graphic © Suzanne Tucker/


A tragedy of addiction is that punishing outcomes like arrests, job loss, and overdoses often cannot overcome drug craving.

The negative reinforcement model was incomplete because addicts crave drugs after completely withdrawing from them. Graphic © Jan H Andersen/

Addict heating a drug

For example, Vietnam war veterans who had become addicted to high-purity heroin during their service suddenly relapsed after years of sobriety while back in the US. Graphic © Combatcamerauk/

US soldiers in Vietnam

A more complete model of addiction emerged when researchers demonstrated that nonhuman animals will self-administer virtually all the addictive drugs abused by humans. Graphic © Jagodka/

Rat with long tail

The revolutionary new view was that a drug’s reinforcing properties are due to its actions at specialized receptors. If you breed animals without the necessary receptor, they won’t self-administer the drug.

These studies showed that animals will:

1. inject abused drugs without physical dependence

2. prefer the place where they received the drug

3. expend considerable effort to obtain more of the drug

4. still work for the drug if it produces aversive consequences like shock

5. relapse after withdrawal when exposed to stressors, drug cues, and the original drug

Cocaine powder

Which other species does this resemble? Graphic © s_bukley/

The Circuitry of Addiction

Dopamine encodes information about stimulus salience (relevance), including rewards and threats. The prefrontal cortex (PFC) evaluates craving-related information in response to drug-related cues. Networked structures include the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and nucleus accumbens (NAC).

The hippocampus (HPC), insula, central nucleus of the amygdala, and the bed nucleus of the stria terminalis (BNST) consider affective states, context, and stress when processing craving-related information.

Dorsolateral prefrontal cortex (DLPFC) activation increases craving by amplifying the response to drug-related cues through its connection with the OFC, ACC, and NAC. The ventromedial prefrontal cortex (vmPFC) exercises emotional control and inhibits actions. Conditioning and the loss of brain volume interfere progressively cripple these functions.

George and Koob (2013) summarized critical addiction neurocircuitry in the graphic below © PNAS.

Craving is what makes addiction to drugs so difficult to overcome. The intense craving that follows a cue that has been previously associated with the drug, combined with a stressful state or a dysphoric state, represents an unstoppable force that leads to drug intake and relapse for most addicted individuals (George & Koob, 2013).

The Helplessness of Craving

A description of the physiological mechanisms mediating craving cannot convey a drug user's experience of profound helplessness. Their loss of control is intense and pervasive. When they relapse, addicts feel like a stranger in their brain is making disastrous decisions they cannot prevent. They feel helpless, terrified, hopeless, and ashamed.

A Two-Stage Cue Reactivity Model

Hayashi et al. (2013) proposed a two-stage model of cue reactivity. The medial orbitofrontal cortex (mOFC) determines a drug's subjective value based on self-reported craving. The DLPFC combines drug availability and cues in the context of time to adjust the mOFC estimation of drug value.

Multiple structures are responsible for craving, the intense motivation to acquire and ingest a drug. The dorsolateral prefrontal cortex (DLPFC) anticipates the effects of drug ingestion and estimates drug availability in the individual's situation. The DLPFC communicates its conclusions to the anterior cingulate cortex, orbitofrontal cortex, and nucleus accumbens. The anterior cingulate cortex (ACC) determines stimulus value by comparing the value and cost of acting on the stimulus. The orbitofrontal cortex (OFC) evaluates the drug's subjective value. Finally, the nucleus accumbens (NAC) promotes action in response to craving, communicating with the globus pallidus (GP) of the basal ganglia and the thalamus (Thal).

The vmPFC can inhibit action and regulate emotion through its connections with the NAC and central nucleus of the amygdala (CeA), which mediates emotional states. Action inhibition and emotional control progressively weaken as experimental drug use transitions to substance use disorder.

Neurotransmitters Involved in Addiction

Although many factors contribute to developing substance use disorders, stress and deficient dopamine receptors (e.g., low density or hypofunctional) may be crucial.


Stress contributes to developing an addiction and relapse (Haass-Koffler & Bartlett, 2012). Stress can precipitate mood disorders like depression in vulnerable individuals directly and indirectly through insomnia. Clinicians must treat two disorders when patients abuse drugs to manage their symptoms. Stress from everyday life and drug withdrawal can trigger drug craving and relapse. Graphic © El Nariz/

Stressed woman

A Reward Deficiency Hypothesis

Before abusing drugs, addicts may require more powerful stimuli (e.g., drugs) to achieve normal enjoyment. In contrast, non-addicts may find drugs too intense to be enjoyable.

After chronic drug use, addicts experience a further weakening of their frontal lobe response to primary reinforcers (e.g., food) and drugs, which become less pleasurable (Advokat et al., 2019).

Chronic drug abuse downregulates dopamine receptors and dopamine production: The 'high' is blunted (Volkow et al., 2010).

Diminished positive reinforcement motivates addicts to engage in more frequent, intense, novel, and risky behaviors.

How Abused Drugs Affect Reward Circuitry

Abused drugs directly or indirectly increase dopamine release at the midbrain ventral tegmental area (VTA), which projects upwards to the forebrain nucleus accumbens, amygdala, hippocampus, and prefrontal cortex. This circuit, called the mesolimbocortical pathway, is also activated by natural rewards (e.g., food and intimacy) and participates in non-drug addictions like pathological gambling (Nestler, 2005; Zhang et al., 2018). Graphic © Fernando Da Cunha/Science Photo Library.

Mesolimbocortical pathway

Modified artist's caption. Illustration of the reward pathway in the human brain. This pathway is initiated when a pleasurable stimulus, such as food, sex, or drugs, is experienced. The stimulus (upper orange arrow) triggers the release of dopamine (blue arrows) by the ventral tegmental area (VTA, dark blue sphere). Dopamine travels to several different areas of the brain that, in turn, release dopamine (red arrows). These areas include the nucleus accumbens (red sphere), which initiates motor outputs (lower orange arrow) to sustain the pleasurable stimulus, the prefrontal cortex (pink), which shifts focus and planning toward the pleasurable stimulus, and the amygdala, which is involved in conditioned learning and emotions. Descending prefrontal cortex glutamate projections (green arrows) to the nucleus accumbens and VTA produce craving.

Addicts experience pleasure when VTA axons release large dopamine pulses to bind to the nucleus accumbens, increasing its firing rate. The amygdala classifies drug-related stimuli as salient and creates emotional memories of previous drug use. The hippocampus helps create declarative memories of their use. Finally, the PFC integrates information regarding drug availability, stimulus value, and subjective value (salience). The PFC plans how to obtain and ingest drugs, associates drug cues with craving, reinforces drug use, and inhibits action and regulates emotion (Advokat et al., 2019; George & Koob, 2013; Volkow et al., 2019).


Craving emerges from a complex network of subcortical and cortical projections. These include the medial hypothalamus (MH) to the medial prefrontal cortex (mPFC) and the DLPFC, the insula to the ACC, OFC, and habenula,