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 Drug for Head Lice and Heartworm Shows Promise Against Alcohol Abuse

Unlikely candidate helps alcohol-dependent mice cut back on the sauce.

Say what you will about glutamate-gated chloride channels in the parasitic nematode Haemonchus contortus—but the one thing you probably wouldn’t say about the cellular channels in parasitic worms is that a drug capable of activating them may prove useful in the treatment of alcoholism and other addictions.

When scientists go looking for drugs to use against addiction, they do not typically begin with a class of drugs that includes a medication for use against head lice and ticks. But that is exactly where the trail led Daryl Davies, co-director of the Alcohol and Brain Research Laboratory at the University of Southern California. Davies and his group were interested in a set of molecules in the brain known as P2X receptors. A subtype of these receptors, involved in ion channel gating, cease to function in the presence of ethanol. The researchers found that if you keep flooding the receptor with alcohol, these ion gates shut down permanently—an example of how alcohol abuse can change the brain.

Another compound that works on the same ion gate is ivermectin, an anti-parasitic medicine used around the world in humans and animals. As it turns out, ivermectin blocks the effect that alcohol has on P2X receptor subtypes. In recent research, the USC team demonstrated that alcohol-dependent mice drank half as much when they were also given ivermectin. This “newly identified alcohol pocket” is a mystery at present. But ivermectin does appear to work primarily on glutamate systems. (See previous post). For now, the researchers can’t say for certain why ivermectin makes mice drink less, but suspect it has something to do with how the brain signals that it’s time to stop drinking. Davies has speculated that a drug like ivermectin could be of use in treatment programs other than “abstinence-based models.” As Suzanne Wu reports in USC Trojan magazine, the team is now at work on other drugs based on ivermectin’s molecular structure. “If there was already a drug that was 95 percent effective, I might not be studying ivermectin,” Davies told the magazine. “I might not even be in the alcohol field. The funding for alcoholism research hasn’t caught up with the magnitude of the consequences of not finding a cure.”

Photo credit: http://www.usapetexpress.com

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/

Further

The Economic Cost of Heavy Drinking

Some food, or rather, some drink for thought.

A recently released study conducted for the CDC Foundation estimates that the economic costs of excessive drinking in American totaled $223.5 billion in 2006.  Binge drinking accounted for 76.4%, or $170.7 billion of the total costs, according to the report. Binge drinking is defined as 4 or more drinks for women and 5 or more drinks for men within a two-hour period.

The report estimates that the per capita cost of excessive drinking was approximately $746 for every man, woman, and child in the United States in 2006. 

Here is a breakdown of the cost of excessive drinking:

·         72.2% ($161.3 billion) - Lost productivity
·         11% ($24.6 billion) - Healthcare
·         9.4% ($21.0 billion) - Criminal Justice
·         7.5% ($16.7 billion) - Other costs (e.g., property damage)

(The study was conducted for the CDC Foundation, a nonprofit enterprise that creates programs with the Centers for Disease Control for fighting threats to health. The study analyzed 2006 costs obtained from national databases.)

Graphics Credit: http://cdc.gov

Are You Okay?

A variety of drinking tests: the good, the bad, and the silly.

Here’s a short, no-nonsense questionnaire that uses your weekly drinking habits to produce an at-a-glance comparison of how your intake stacks up against others your age and sex. For example, your result might say: “Only 4% of the adult male population drinks more than you say you drink.” Which is food for thought, at least. Join Together (sponsored by The Partnership at DrugFree.org and Boston University School of Public Health) provides this service.

Here is the Mayo Clinic alcohol use self-assessment test, which says with refreshing frankness: “This assessment can’t diagnose you with an alcohol use or abuse problem, but it can help you evaluate your drinking and understand whether you may benefit from seeking help.” Tends to be a bit stern on the drinks-per-day end of things, but otherwise it’s quite straightforward.

Then there is the venerable Michigan MAST Test, first offered in 1971, and revised regularly every since. It’s showing its age a bit as a clinical tool, but here is a link to the 22-question self-administered version: TEST

Iondesign’s Drink-O-Meter is a whimsical test that makes a sober point: “Why not take our test to calculate the state of your kidneys, wallet, and quantity of alcohol you have consumed over the years?” Why not? Well, maybe because you can’t HANDLE the truth: Test results give an estimate of the total number of drinks you have consumed, an estimate of how much money you’ve spent—and an estimate of the number of Ferraris you could have bought instead.

And finally, we have the amazing and ever-popular CAGE Test, so called for the system of naming and memorizing the questions. The CAGE test takes less than a minute, requires only paper and pencil, and can be graded by test takers themselves. It goes like this:

1. Have you ever felt the need to (C)ut down on your drinking?

2. Have you ever felt (A)nnoyed by someone criticizing your drinking?

3. Have you ever felt (G)uilty about your drinking?

4. Have you ever felt the need for a drink at the beginning of the day—an “(E)ye opener?

People who answer “yes” to two or more of these questions should seriously consider whether they are drinking in an alcoholic or abusive manner. Unfortunately, the CAGE test is considered to be an accurate diagnostic tool primarily in the case of adult white males.

Photo Credit: http://tokyotek.com

A 12 Days of Christmas Blog Meme

Wrapping it up.

From DrugMonkey’s blog: “The rules for this blog meme are quite simple. Post the link and first sentence from the first blog entry for each month of the past year.” (Credit to Janet Stemwedel and John Lynch for the idea.)

Here are the 12 first lines from 2011 here at Addiction Inbox. Click month for full story:

January: Films popular in Europe feature more drinking episodes per movie than their equally popular American counterparts, according to a report by the European Centre for Monitoring Alcohol Marketing (EUCAM).

February: The Director of the Office of National Drug Control Policy issued a warning about the new synthetic stimulants now being clandestinely marketed as bath salts or insecticide.

March: The U.S. Drug Enforcement Administration (DEA) exercised its emergency scheduling authority yesterday to outlaw the use of “fake pot” products.

April: In the first published examination of thirdhand smoke pollution and exposure, researchers at San Diego State University discovered that non-smokers who move into homes purchased from smokers encounter significantly elevated nicotine levels in the air and dust of their new homes two months or more after moving in.

May: What would it be like to have written a drug memoir and an autobiography before you turned 30? Would it seem like the end or the beginning? Are there any worlds left to conquer?

June: The song is not about cigarette addiction, but it could be.

July: Readers may remember the dark day of January 1, 2008, when the U.S. set an all-time record: One out of every 100 adults was behind bars. That’s more than 2.3 million people

August: The cost of addiction treatment is a legitimate medical expense, as long as you are talking about drug and alcohol addiction, which the IRS recognizes as a genuine medical disease.

September: The DSM-V, when it debuts it 2012, is set to replace the category of “Substance-Related Disorders” with a new category entitled "Addiction and Related Disorders." 

October: It’s official: The Obama administration has thrown off the gloves, repudiating Attorney General Eric Holder’s vow of two years ago that the federal government was not interested in prosecuting “state-legal” cannabis activity.

November: They first turned up in Europe and the U.K.; those neon-colored foil packets labeled “Spice,” sold in small stores and novelty shops, next to the 2 oz. power drinks and the caffeine pills.

December: After years of tightening regulation and dramatic declines in the number of adult smokers, Big Tobacco is targeting teenagers like never before.

Photo Credit: http://simplemom.net