Brain Scans and Addiction Research: The Early Years

X-ray specs for drug effects.

The science of addiction and the technology of brain scans have both developed exponentially in the past two decades. The search for specific neurobiological markers for addiction was made possible by positron emission tomography, better known as the PET scan. Known more casually as the PET/CT scanner, the device was named the Invention of the Year in 2000 by Time Magazine. (The CT scan, for computerized tomography, uses an X-ray machine and a contrast die to measure absorption rates in different brain areas.)

The idea of a PET scan is simple: Doctors inject test subjects with radioactively tagged glucose, which passes the blood-brain barrier with ease. The more electrochemically active portions of the brain burn extra glucose for energy. So, by noting precisely where the tagged glucose has gone, and converting that information into a digital two-dimensional array, a PET scan serves as a neurobiological map of brain activity in response to specific stimuli. Functionally, PET scans are admittedly imperfect pictures of the brain, showing general areas that “light up” during the performance of a task, or in response to a drug. Technically, a PET scanner is detecting gamma rays given off when particles from the radioactive tracer collide with electrons in the brain. A variation on this approach is the SPECT scan (single photon emission tomography).

The neuroimaging techniques that followed, like nuclear magnetic resonance imaging, or MRI, provided an additional level of analysis. MRI machines look similar to PET scanners, but are essentially large magnetic field generators. They were originally known as NMRIs, for nuclear magnetic resonance imagers, but the “nuclear” part seems to have disappeared over the years. MRI scans don’t involve radioactive tracers—they track blood flow, often by means of a contrast agent. Hydrogen, a major component of water and blood, gives off identifiable energy signatures when surrounded by giant magnets. If an area of the brain is showing increased activity, it means that somewhere in that area, some brain cells are demanding more oxygen.  A rush of blood to that area supplies it, an MRI scan detects it, and a computer plots it.

 With PET and MRI scans, scientists could study the brain as a set of molecules in motion. They could create a three-dimensional picture of the brain, with the sagittal, transaxial and coronal planes all visible at once—almost a brain hologram. Addiction scientists could watch tiny areas of the brain light up with activity under the influence of specific mood-altering chemicals. Two areas of the brain were of particular interest. One was the nucleus accumbens, which was involved in the regulation of dopamine and serotonin synthesis. The other was the locus ceruleus—a tiny area of the brain saturated with cells involved in the production and release of the neurotransmitter norepinephrine.

Alcohol, cocaine, the opiates, and other drugs made the nucleus accumbens and associated regions bloom with activity on the MRI and PET scans. These early snapshots of your brain on drugs specifically showed that psychoactive drugs of abuse, the ones that altered mood and emotion, did so at the very sites in the brain known to be involved in regulating emotional states and primary drives. Without scans, scientists would not have been able to confirm the workings of the brain’s reward system in specific anatomical detail.

 As a rule, the same areas of the brain tended to light up no matter what addictive drug was under study. Whether it was a molecule of stimulation, or a molecule of sedation, sooner or later it went surging through the diffuse aggregation of mid-brain structures involved with emotion, memory, mood, sleep, and a host of specific behaviors ranging from appetite to risk-taking.

That the subjects also showed similar brain activity when they quit doing drugs was of equal interest in the beginning. Early work by Dr. Kenneth Blum at the University of Texas Health Science Center and others demonstrated that certain characteristic forms of brain activity took place in the locus ceruleus whenever abstinent addicts experienced strong cravings. The locus ceruleus helps control levels of the original “fight or flight” chemical, norepinephrine, and when an addict in withdrawal panics, the locus ceruleus lights up. Other studies of the nucleus accumbens showed abnormal firing rates in scanned addicts who were deep into an episode of craving. Drug hunger in abstinent addicts, it appeared, was not all in the head, or strictly psychological. Cravings have a biological basis, and brain scans helped to clinch the case.

Graphics credit: http://learn.genetics.utah.edu

A Few Words About Glutamate

Meet another major player in the biology of addiction.

The workhorse neurotransmitter glutamate, made from glutamine, the brain’s most abundant amino acid, has always been a tempting target for new drug development. Drugs that play off receptors for glutamate are already available, and more are in the pipeline. Drug companies have been working on new glutamate-modulating antianxiety drugs, and a glutamate-active drug called acamprosate, which works by occupying sites on glutamate (NMDA) receptors, has found limited use as a drug for alcohol withdrawal after dozens of clinical trials.

Glutamine detoxifies ammonia and combats hypoglycemia, among other things. It is also involved in carrying messages to brain regions involved with memory and learning. An excess of glutamine can cause neural damage and cell death, and it is a prime culprit in ALS, known as Lou Gehrig’s disease. In sodium salt form, as pictured---> it is monosodium glutamate, a potent food additive. About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. Drugs that boost glutamate levels in the brain can cause seizures. Glutamate does most of the damage when people have strokes.

The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. Unfortunately, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. (Dissociative drugs like PCP and ketamine are glutamate antagonists.) Dextromethorphan, the compound found in cough medicines like Robitussin and Romilar, is also a weak glutamate inhibitor. In overdose, it can induce psychotic states similar to those produced by PCP and ketamine. Ely Lilly and others have looked into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

As Jason Socrates Bardi at the Scripps Research Institute writes: "Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called ‘reward centers.’ However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement.”

Glutamate receptors, then, are the “hidden” receptors that compliment dopamine and serotonin to produce the classic “buzz” of alcohol, and to varying degrees, other addictive drugs as well. Glutamate receptors in the hippocampus may also be involved in the memory of the buzz.


Writing in The Scientist in 2002, Tom Hollon made the argument that “glutamate's role in cocaine dependence is even more central than dopamine's.” Knockout mice lacking the glutamate receptor mGluR5, engineered at GlaxoSmithKline, proved indifferent to cocaine in a study published in Nature.

In an article for Neuropsychology in 2009, Peter Kalivas of the Medical University of South Carolina and coworkers further refined the notion of glutamine-related addictive triggers: "Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking," Kalivas writes. "While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic plasticity in the nucleus accumbens is critical for the expression of these behaviors."

The same year, in Nature Reviews: Neuroscience, Kalivas laid out his “glutamate homeostasis hypothesis of addiction.”

A failure of the prefrontal cortex to control drug-seeking behaviors can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

This kind of research has at least a chance of leading in the direction of additional candidates for anti-craving drugs, without which many addicts are never going to successfully treat their disease.


Graphics credit: http://cnunitedasia.en.made-in-china.com/

The Nucleus Accumbens

Final destination for addictive drugs.

The release of dopamine and serotonin in the nucleus accumbens lies at the root of active drug addiction. The pattern of neural firing that results from this surge of neurotransmitters is the “high.” It is the chemical essence of what it means to be addicted. Part of the medial forebrain bundle (MFB), which mediates punishment and reward, the nucleus accumbens is the ultimate target for the dopamine released by the ingestion of cocaine, for example.

The release of dopamine and serotonin in the nucleus accumbens appears to be the final destination of the reward pathway—the last act in the pleasure play. If you think about a drug, take a drug, or crave a drug, you are lighting up the nucleus accumbens with a surge of electrochemical activity. These are essentially the same pathways that regulate our food and water-seeking behavior. By directly or indirectly influencing the molecules of pleasure, drugs and alcohol trigger key neurochemical events that are central to our feelings of both reward and disappointment. In this sense, the reward pathway is a route to both pleasure and pain.

Alcohol, heroin, cigarettes, and other drugs caused a surge of dopamine production, which is then released onto the nucleus accumbens. The result:  Pleasure. When scientists pipe a dopamine-mimicking substance into the nucleus accumbens, targeting dopamine D2 receptors, withdrawal symptoms are blocked in morphine-addicted rats. Similarly, when scientists block dopamine receptors in the accumbens, the morphine-dependent rats exhibit withdrawal symptoms.

When you knock out large slices of the nucleus accumbens, animals no longer want the drugs. So, one cure for addiction has been discovered already—but surgically removing chunks of the midbrain just won’t do, of course.

Dopamine is more than a primary pleasure chemical—a “happy hormone,” as it has been called. Dopamine is also the key molecule involved in the memory of pleasurable acts. Dopamine is part of the reason why we remember how much we liked getting high yesterday. The nucleus accumbens (also known as the ventral striatum) seems to be involved in modulating the emotional strength of the signals originating in the hippocampus. This implicates the hippocampus in relapse, even though this area of the brain does not light up as strongly during actual episodes of craving.

The fact that we know all this is nothing short of amazing, but it is part of a larger perspective afforded by the insights of contemporary neurobiology. We know, for example, that the emotion of fear arises, in large part, through chemical changes in a peanut-sized limbic organ called the amygdala. Does this information make fear any less, shall we say, fearful? It merely locates the substrate upon which the sensation of fear is built.

Studies of the nucleus accumbens have demonstrated abnormal firing rates in scanned addicts who were deep into an episode of craving. The craving for a reward denied causes dopamine levels in the nucleus accumbens to crash dramatically, as they do when users go off drugs. Dopamine, serotonin, and norepinephrine activity soars just as dramatically when a drug user relieves withdrawal symptoms by relapsing. Drug hunger in abstinent addicts is not all in the head, or strictly psychological. Craving has a biological basis.  

Finding a way to override serotonin- and dopamine-mediated mid-brain commands is the essential key to recovery from addiction. One of the aims of a biological understanding of addiction is to tease out the mechanisms by which the reinforcing effects of addictive drugs become transformed into long-term adaptive changes in the brain.

Graphics credit: http://thebrain.mcgill.ca/

Adapted from The Chemical Carousel: What Science Tells Us About Beating Addiction by Dirk Hanson © 2008.