Remarkable scientific progress over the past five decades has helped us develop knowledge of how drugs of abuse induce pleasure, reinforce use, and lead to the compulsive self-administration we call addiction. We now know that addiction is largely a brain disease. This progress was driven by interdisciplinary research that blended neuroanatomy, molecular biology, pharmacology, and neuroimaging. I am a contributor to this research, as are Eric Nestler, Nora Volkow, Herbert Kleber, George Aghajanian, Jean-Lud Cadet, George Koob, Ken Blum, Mary Jeanne Kreek, and others who have pieced together clues to construct the neurobiological infrastructure of addiction.
The Locus Coeruleus
In the 1970s, when Kleber, Aghajanian, and I were at Yale, we made key discoveries linking the pontine locus coeruleus (LC) and noradrenergic hyperactivity directly to opioid withdrawal. My studies in the 70s demonstrated that chronic opioid use suppresses LC activity, and withdrawal from opioids results in rebound noradrenergic overdrive. These changes, which manifest as anxiety, restlessness, and other opioid-withdrawal symptoms, could be reversed by opioids, and, for the first time, non-opioids like clonidine. In 1978, we proved opioid dependence is not just psychological but has discrete neuroanatomical and neurochemical causes.
In the 1980s, Karl Verebey and I presented our findings that smoking cocaine was as addictive as injecting the drug. By 1984, Charles Dackis and I challenged decades of thought and reoriented addiction to craving and wanting rather than withdrawal by showing that cocaine was addictive, even without a withdrawal syndrome, through dopamine. We suggested that cocaine addiction resulted in dopamine depletion. Nora Volkow, now director of the National Institute of Drug Abuse (NIDA), subsequently revolutionized the field using positron emission tomography (PET) and functional MRI (fMRI) to visualize how drugs alter human brain function. She highlighted hypofrontality—decreased activity in the prefrontal cortex (PFC)—as a key driver of impaired judgment, impulsivity, and compulsive drug use. This provided a basis for understanding addiction as a disease of decision-making and self-regulation, not just craving/pleasure.
Neuroscientist Ken Blum is best known for his work on reward deficiency syndrome in drug-using people. I asked him how he made his dopamine gene discovery. He said that in 1987 he called Professor Ernest Nobel, asking if he would like to find the first alcoholism gene. “While almost laughing at me, he listened to my plan. We used tissue from a brain bank that housed people who died from cirrhosis of the liver, compared to so-called controls who died from gunshots.”
Blum and fellow researchers published their findings in JAMA in 1990 to great controversy. “However, to my surprise, the DRD2 gene and associated polymorphisms over the past three-and-one-half decades stood the test of time and are now considered a top risk gene for all reward deficiency behavior.”
Addiction and Brain Changes
Volkow described the common neuroanatomy of drug reinforcement, centering on the mesolimbic dopamine system. Using PET imaging, she demonstrated decreased D2 receptor availability and impaired prefrontal activity in addicted individuals. Her work highlighted the roles of the orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) in causing poor impulse control and craving, further validating the brain disease addiction model.
Cadet’s NIDA research showed that chronic stimulant use leads to neurodegeneration and oxidative stress, particularly affecting dopaminergic neurons. These changes impair motor function, cognition, mood, and behavior. My work, with work from Cadet and others, emphasized the importance of prevention, especially since addiction can cause lasting, potentially irreversible brain changes.
Addiction-Altering Gene Expression
Eric Nestler’s lab at Mount Sinai in New York conducted research demonstrating how drugs of abuse influence and alter gene expression within the locus coeruleus and nucleus accumbens (NAc). This research advanced our understanding of how drugs of abuse cause loss of control and addiction. Throughout his career, he has brilliantly connected cellular changes to behavioral outcomes, providing direct evidence that cellular adaptations cause behavioral symptoms of opiate withdrawal.
Nestler’s research showed how repeated cocaine exposure alters gene expression, learning, and synaptic plasticity within the brain’s dopamine reward circuitry, specifically the dopamine-rich nucleus accumbens.
Nestler’s 2025 research provides strong evidence of a molecular explanation for the persistent risk of relapse, uncovering how addictive drugs hijack the brain’s reward system by reprogramming genes.
Systems Neuroscience
Modern models recognize addiction as a systems-level disorder. All drugs of abuse converge on the mesolimbic dopamine system, but via different mechanisms. Cocaine blocks dopamine reuptake, while opioids inhibit GABA neurons, disinhibiting dopamine release. Cannabis activates CB1 receptors.
Glutamate, a neurochemical, emerged as a key mediator of craving and relapse. While dopamine governs initial reward, glutamate regulates long-term plasticity and drug-cue associations.
The endocannabinoid system (ECS), particularly some CB1 receptors, modulates dopamine and glutamate signaling. Drugs like cannabis directly activate the ECS, but even nicotine and alcohol influence it indirectly. Most recently, intravenous cannabinoids were shown to reduce alcohol craving.
Ozempic, Wegovy, and Other GLP-1RAs
GLP-1 receptor agonists (GLP-1RAs) like semaglutide (Ozempic, Wegovy) and liraglutide (Saxenda, Victoza) were developed to treat Type 2 diabetes by targeting glucose homeostasis and satiety via the gut-brain axis. There is growing evidence that these drugs also modulate central reward systems, notably dopaminergic pathways.
This dampening of dopamine release blunts the impact of highly palatable foods, alcohol, and possibly drugs like cocaine or opioids. GLP-1Rs seem to reduce pathologic reward-seeking without suppressing mood or motivation.
Different Drugs Vary in Actions
Cannabis, alcohol, opioids, and other drugs act indirectly by modulating inhibitory control over dopamine neurons. In contrast, stimulants like cocaine and amphetamines act more directly on the dopamine system, producing faster, larger, more sustained increases in dopamine.
Volkow pointed out that repeated exposures to drug combinations lead to faster addiction due to more intense conditioning. For example, a speedball (a combined stimulant/depressant) is a powerful trigger. Speedballs provide maximal dopamine release.
Addiction neuroanatomy can explain polysubstance abuse and why A.A. and 12-step programs consider all drugs of abuse similarly.
Summary
Neurobiological research findings over the past 50 years moved addiction from being perceived as a moral failing to being understood as a drug-induced chronic brain disease. We thought we proved this in 1978 when we showed that withdrawal is driven by neurotransmitter dysregulation, laying the groundwork for modern neurobiological models of addictions. But, of course, not everyone realizes this even today.
Addiction causes significant changes in motivational, emotional, and decision-making brain circuits. Rather than family, friends, work, food, water, and sex, the motivational hierarchy is upended and replaced with finding and using drugs. It’s also important to know that recovery is not a straight line. Many attempts to quit may be necessary. Recovery requires time, often aided by medication, exercise, behavioral therapy, treating comorbidities, and a healthy diet.
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