Response to HuffPost Marc Lewis Interview on Addiction

So the Huffington Post runs a sub-blog on Addiction and Recovery and sometimes they present excellent reporting (for example, the piece on opioid addiction by Jason Cherkis who actually interviewed my boss, Dr. Mary Jeanne Kreek, for the article). But more often than not, they present quite variable reporting on addiction.  A recent interview with psychologist Marc Lewis, PhD is one such example.

Based on my own neuroscience of addiction background, I unfortunately find a number of Dr. Lewis’s claims not supported by scientific evidence and I believe the spread of such false statements can have the exact opposite of his intended effect—hurting more addicts rather than helping them. I do not claim to be the consensus voice of the addiction field but present my own arguments based on my own research and work done in the field. I also admit have not read any of Dr. Lewis’s books and am merely responding to the statements made in his interview. I include references at the end of the post.

The original interview between Carolyn Gregoire, Senior Health and Science Writer for Huffington Post and psychologist Marc Lewis, PhD

The questions (Q) by Carolyn Gregoire in the original interview are in bold, Dr. Lewis’s response (L) is italicized, and my response (S) is the un-italicized larger-size text.

Q: What’s wrong with the disease model of addiction? 

L: I know what scientists are looking at when they say addiction is a disease. I don’t dispute the findings, but I dispute the interpretation of them. They see addiction as a chronic brain disease — that’s how they define it in very explicit terms. 

My training is in emotional and personality development. I see addiction as a developmental process. So the brain changes that people talk about and have shown reliably in research can be seen as changes that are due to learning, to recurrent and deep learning experiences. But it’s not an abnormal experience and there’s nothing static or chronic about it, because people continue to change when they recover and come out of addiction. So the chronic label doesn’t make much sense.

S: The brain is a physical organ that operates under defined molecular biological principles. Drugs are physical chemical substances that perturb the molecular function of the brain. It is true that addiction is a process that can take months or even years to develop but the end result is a physical neurobiological change in how the brain functions [1, 2]. And when neuroscientists say chronic brain disease—or what my lab says A disease of the brain with behavioral manifestations—what we mean is that repeated drug use has caused a change is brain function which in turn results in a change in behavior. That doesn’t mean that this change is irreversible but, like other diseases, the first step to treatment is recognizing the underlying biological cause. Defining addiction as a chronic brain disease is not a judgment or interpretation of the development of addiction (which definitely does involve a learning and memory component [3, 4]) but is a statement asserting that drug addiction and drug cravings, compulsive drug use, and relapse are ultimately based on physical changes in the brain. It is important that we recognize this because otherwise we would not be able to treat it with effective and safe medications, in combination with other behavioral and psychological therapies.

Q: What’s problematic about the way we treat addiction, based on the disease model? 

L: Well, lots. The rehab industry is a terrible mess — you either wait on a long list for state-sponsored rehabs that are poorly run or almost entirely 12-Step, or else you pay vast amounts of money for residential rehabs that usually last for 30-90 days and people often go about five to six times. It’s very difficult to maintain your sobriety when you go home and you’re back in your lonely little apartment. 

What I emphasize is that the disease label makes it worse. You have experts saying, “You have a chronic brain disease and you need to get it treated. Why don’t you come here and spend $100,000 and we’ll help you treat it?” There’s a very strong motivation from the family, if not the individual, to go through this process, and then the treatments offered in these places are very seldom evidence-based, and the success rates are low. 

S: I strongly agree with this assessment. The rehab industry and many 12-step programs are ineffective, expensive, and rarely based on scientific evidence. The primary reason is that for decades addiction was thought of a problem of “spiritual weakness” or “lack of will power”. In reality addiction is a medical disorder based on physical neurobiological processes that make it seem like an addict has no “will power”, when in reality that addict’s brain has been hijacked to crave the drug compulsively and practically uncontrollably. However, again, I disagree that calling addiction a disease is what funnels people into rehab clinics. I believe it is the stigmatization of addiction that precludes treatment by doctors (unlike for every other disease), which in turn fuels admission into the rehab industry. Sadly, effective medications exist (such as methadone and buprenorphine for opioid addicts) that can flick a switch off in an addicts brain, satisfying their craving and allow them to live a normal live [5, 6]. Or medications such as naltrexone may be effective at reducing drinking in alcohol addicts but is not widely used [7, 8]. It is only recently that public acknowledgement of the biological basis of addiction and appropriate shifts in public policy are beginning to take place. Importantly, addiction medicine is beginning to become incorporated into medical school education and the first accredited residency programs in addiction medicine have been announced.

Q: There are lots of ways to trigger a humanistic response besides calling something a disease. So you would say that telling people who are in recovery for addiction that they have a “chronic disease” is actually doing them a disservice? 

L: Well, the chronic part is really a yoke that people carry around their necks. [Proponents of the disease model] say that this is important because this is how to prevent the stigmatization of addicts, which has been a standard part of our culture since Victorian times. 

But I think that’s just bullshit. I don’t think it feels good when someone tells you that you have a chronic disease that makes you do bad things. There are ways to reduce stigmatization by recognizing the humanity involved in addiction, the fact that it happens to many people and the fact that people really do try to get better — and most of them do. There are lots of ways to trigger a humanistic response besides calling something a disease.  

S: I agree that stigma is a huge problem with the treatment of drug addiction and mental health. Admitting you are an addict or depressed or know someone who suffers from these disorders is accompanied with unnecessary shame and fear of admission of the problem. I disagree that acknowledgement of medical/neurobiological basis of these disorders (ie calling them diseases) increases stigma but in fact do humanize patients. It helps alleviates shaming–both public and self–and can help an addict to seek evidence-based, medical treatment. Acknowledging the chronic nature of the disorder is not intended to make people feel bad but is merely truthfully stating the nature of the problem in hopes that it can be properly treated; denial can be lead to false and ineffective treatments.

Q: It can be difficult to comprehend the idea that something as severe as a heroin addiction is a developmental process. Can you explain that? 

L: First of all, let’s include the whole bouquet of addictions. So there’s substances — drugs and alcohol — and there’s gambling, sex, porn and some eating disorders. The main brain changes that we see in addiction are common to all of them, so they’re not specific to taking a drug like heroin, which creates a physical dependence. We see similar brain changes in a region called the striatum, which is an area that’s very central to addiction, which is involved in attraction and motivational drive. You see that with gambling as much as you do with cocaine or heroin. So that’s the first step of the argument — it’s not drugs, per se. 

From there, it’s important to recognize that certain drugs, like opiates, create physical dependency. There’s a double whammy there. They’re hard to get off because they’re addictive, like sex or porn is, but they also make you uncomfortable when you stop taking them. People try to go off of them and get extremely uncomfortable and then they’re drawn back to it — now for physical as well as psychological reasons. 

S: It is true that all addictions involve the striatum and there are similarities between the different addictions but to say that ALL addictions affect the brain in the exact same way is an absurd simplification. Different drugs absolutely DO affect the brain differently and have differences in addiction potential and relapse potential. To say addiction to heroin is identical to addiction to alcohol is identical to gambling addiction and therefore has nothing to do with the specific drug or behavior is just plain wrong. A wealth of evidence is gathering that addictions to different drugs progress differently and effect different brain systems, despite certain changes common to all [9]. For example, even opioids such as morphine and oxycodone, whose pharmacology are probably the best understood of any drug of abuse (they interact with mu opioid receptors [10]), have different behavioral and neurobiological effects that may affect addictions to the individual drugs (see my blog post). In a paper published by the lab I work for, the Kreek lab, cocaine administration in drug naïve mice (mice that have never had cocaine in their system) results in a rapid release of dopamine [11]. In contrast, some studies show that self-administration of an opioid drug only increases dopamine in rats that have already been exposed to the drug and not naïve animals [10]. The differences in the dopamine profiles between cocaine and opioids obviously means that how these two drugs affect the brain is different and is drug-specific! These are just a few small examples demonstrating the scientific inaccuracy of lumping all addictions into one general category or making the false claim that addiction has “nothing to do with the drug” (just as reducing cancer to a single disease is entirely inaccurate and harmful for its treatment).

Q: In the case of any type of addiction, what’s going on in the brain? 

L: The main region of interest is the striatum, and the nucleus accumbens, which is a part of the striatum. That region is responsible for goal pursuit, and it’s been around since before mammals. When we are attracted to goals, that region becomes activated by cues that tell you that the goal is available, in response to a stimulus. So you feel attraction, excitement and anticipation in response to this stimulus, and then you keep going after it. The more you go after that stimulus, the more you activate the system and the more you build and then refine synaptic pathways within the system. 

The other part of the brain here that’s very important is the prefrontal cortex, which is involved in conscious, deliberate control — reflection, judgment and decision-making. Usually there’s a balance between the prefrontal cortex and the striatum, so that you don’t get carried away by your impulses. With all kinds of addictions — drugs, behavior, people — the prefrontal system becomes less involved in the behavior because the behavior is repeated so many times. It becomes automatic, like riding a bike. 

S: Dr. Lewis’s assessment is basically correct. The core of the reward circuit involves dopamine-releasing neurons of the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc; a part of the ventral striatum), which primarily drives motivated behavior and is involved in reinforcement of drug taking behavior. Conversely, the prefrontal cortex acts as a “stop” against this system and one model of addiction is the motivated-drive to seek the drug overpowers the “stop” signal from the prefrontal cortex. However, addiction is far more complex beyond just this basic system. Numerous other circuits and systems (hippocampus, amygdala, hypothalamus, just to name a few) are also involved and each individual drug or rewarding stimuli can affect these circuits in disparate ways [12].

Q: What would a scientifically informed approach to addiction look like? 

L: That’s a really hard question because the fact that we know what’s happening in the brain doesn’t mean that we know what to do about it. 

A lot of recent voices have emphasized that addiction tends to be a social problem. Often addicts are isolated; they very often have difficult backgrounds in terms of childhood trauma, stress, abuse or neglect — so they’re struggling with some degree of depression or anxiety — and then they are socially isolated, they don’t know how to make friends and they don’t know how to feel good without their addiction. 

S: As I’ve stated above, a scientifically informed approach to addiction treatment already exists but is not widely used. However, one day an addict will hopefully be able to consult with a medical doctor to receive appropriate medications specific to their addiction, which will be combined with individual counseling by a psychiatrist or psychologist and a specific cognitive behavioral therapy or other psychological/behavioral therapy. The combination of medications and psychological therapy administered by trained medical professionals will be the future of evidence-based addiction medicine. Development of additional medications and/or psychological therapies for future treatment absolutely requires solid scientific evidence supporting their efficacy, which includes use of randomized control trials,  prior to widespread implementation.

But to call addiction primarily a social problem once again ignores all the basic neuroscience research that shows the powerful effects drugs have on the brain. It also ignores the prominent effect of genetics and how, due to a random role of the dice, an individual’s risk of becoming an addict can drastically increase [2, 13]. Plus the opioid epidemic that is currently sweeping the nation effects nearly every strata of society regardless of socioeconomic status, age, gender or race, and therefore cannot be explained simply by the hypothesis that addicts are people that are socially isolated. Why someone starts using drugs in the first place and how exactly they progress from a casual drug user to an addict are incredibly complex questions that scientists all over the world are attempting to answer through rigorous research. Being socially isolated or experiencing childhood trauma may certainly be factors that eschew some people towards the development of addiction but are definitely not the only ones.

Q: So what can we do about that?

L: Other than certain drugs that can reduce withdrawal symptoms, there’s nothing much medicine can offer, so we have to turn to psychology, and psychology actually offers a fair bit. There’s cognitive behavioral therapy, motivational interviewing, dialectic behavioral therapy, and now there are mindfulness-based approaches, which I think are really exciting. 

There’s been good research from Sarah Bowen in Seattle [on Mindfulness-Based Relapse Prevention] showing that mindfulness practices can have a significant impact on people, even on people who are deeply addicted to opiates. 

S: This is a completely false statement: medications for treatment of addictions exist [14]! Once again, comprehensive systematic reviews of methadone and buprenorphine, two medications used for treatment of opioid cravings, have indisputably shown that these medications are effective at keeping addicts off of heroin compared to no medication [5, 6]. Furthermore, a number of other drugs are currently being explored for treatments to alcohol and cocaine addiction [15, 16]. Some people may consider methadone or buprenorphine replacing “one drug with another” but this is naïve view of how powerfully addictive opioid drugs can be and how use of these FDA-approved medications in combination with individual psychological counseling, can lead to gradual dose reduction and amelioration of cravings. Medication-assisted addiction treatment is designed to help addicts fight their craving so that they can live a normal life. With time, dose can be reduced and cravings can become less intense.

The study Dr. Lewis cites regarding mindfulness is well designed and intriguing. However, the study did not compare mindfulness-based approaches to medication-based approaches and is therefore incomplete [17]. Nevertheless, it is an interesting approach that may be able to be combined with medication-based treatment but definitely requires more research before its efficacy can be confirmed.

References

  1. Koob GF, Le Moal M. Addiction and the brain antireward system. Annual review of psychology. 2008;59:29-53.
  1. Kreek MJ, et al. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. The Journal of clinical investigation. 2012;122(10):3387-93.
  1. Kelley AE. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron. 2004;44(1):161-79.
  1. Tronson NC, Taylor JR. Addiction: a drug-induced disorder of memory reconsolidation. Current opinion in neurobiology. 2013;23(4):573-80.
  1. Mattick RP, et al. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. The Cochrane database of systematic reviews. 2009(3):CD002209.
  1. Mattick RP, et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. The Cochrane database of systematic reviews. 2014;2:CD002207.
  1. Anderson P, et al. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet. 2009;373(9682):2234-46.
  1. Hartung DM, et al. Extended-release naltrexone for alcohol and opioid dependence: a meta-analysis of healthcare utilization studies. Journal of substance abuse treatment. 2014;47(2):113-21.
  1. Badiani A, et al. Opiate versus psychostimulant addiction: the differences do matter. Nature reviews Neuroscience. 2011;12(11):685-700.
  1. Fields HL, Margolis EB. Understanding opioid reward. Trends in neurosciences. 2015;38(4):217-25.
  1. Zhang Y, et al. Effect of acute binge cocaine on levels of extracellular dopamine in the caudate putamen and nucleus accumbens in male C57BL/6J and 129/J mice. Brain research. 2001;923(1-2):172-7.
  1. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nature reviews Neuroscience. 2013;14(9):609-25.
  1. Kreek MJ, et al. Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nature neuroscience. 2005;8(11):1450-7.
  1. Kreek MJ, et al. Pharmacotherapy of addictions. Nature reviews Drug discovery. 2002;1(9):710-26.
  1. Addolorato G, et al. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012;37(1):163-77.
  1. Bidlack JM. Mixed kappa/mu partial opioid agonists as potential treatments for cocaine dependence. Advances in pharmacology. 2014;69:387-418.
  1. Bowen S, et al. Relative efficacy of mindfulness-based relapse prevention, standard relapse prevention, and treatment as usual for substance use disorders: a randomized clinical trial. JAMA psychiatry. 2014;71(5):547-56.

Advertisements

Personality-targeted Interventions Can Reduce Alcohol and Marijuana Use Among Adolescents

Cover-Photo-for-Conrod-post

Let me state the obvious: alcohol and marijuana are the two most widely used drugs of abuse in the United States. According to the annual National Survey on Drug Use and Health (NSDUH), (the most comprehensive survey of drug use and abuse in the United States conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA)) as of 2013, 86.8% of the population aged 18 or older have reported having consumed alcohol during their lifetime with over 16.6 million adults diagnosed with alcohol abuse disorder.

Of course, we all know the prevalence and extent of underage drinking, and the damage alcohol has on the developing brain has been heavily researched, not to mention all the significant secondary problems associated with alcohol abuse (car crashes, sexual assault on college campuses, falling off of balconies… ).

But here’s some numbers anyways: as of 2013, 8.7 million youths aged 12-20 reported past month alcohol use, a shockingly high number for an age group this is not legally allowed to drink alcohol…

Similarly, marijuana, which is still illegal in the vast majority of the US, is nearly as ubiquitous. According to the NSDUH 2013 survey, 19.8 million adults aged 18 or older reported past month marijuana use.

And with marijuana legalization in Colorado and Washington, a significant concern raised by many is that abuse of the drug among youths will dramatically increase even higher than it is now. The research supporting the damage marijuana can inflict on brain development is also significant.

But what if the risk of use of alcohol and marijuana by youths could be reduced? What if a teacher could be given the tools to not only identify certain risky personality traits in their students but also use that knowledge to help those at-risk students from trying and using drugs such as alcohol and marijuana? A series of studies coming out of the laboratory of Dr. Patricia A Conrod of King’s College London report having done exactly that.

SFN 2015 LogoI had the pleasure of seeing Dr. Conrod speak at the recent Society for Neuroscience Conference as part of a satellite meeting jointly organized by the National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA). Dr. Conrod presented a compelling story spanning over a decade of her and her colleague’s work, in which certain personality traits amongst high risk youths, can actually be used to predict drug abuse amongst those kids. Dr. Conrod argues that by identifying different risk factors in different adolescents, a specific behavioral intervention can be designed to help reduce alcohol drinking and marijuana use in these youths. And who is best to administer such an intervention? Teachers and counselors, of course: educators that spend a great deal of time interacting with students and are in the best position to help them.

The Teacher-Delivered Personality Targeted Interventions For Substance Misuse Trial, also known as the Adventure Trial, was conducted in London during 2008-2009 and the results were first published in 2010.

This ambitious study recruited 2,643 students (between 13 and 14 years old) from 21 secondary schools in London (20 of the 21 schools were state-funded schools). Importantly, this study was a cluster-randomized control trial, which means the schools were randomly assigned to two groups: one group received the intervention while the other did not. The researchers identified four personality traits in high-risk (HR) youths that increase the risk of engaging in substance abuse. The four traits are:

  1. Anxiety sensitivity,
  2. Hopelessness
  3. Impulsivity
  4. Sensation seeking.

A specific intervention based on cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET) was developed to target each of these personality traits. Teacher, mentors, counselors, and educational specialists in each school that were recruited for the study were trained in the specific interventions. In general, CBT is an approach used in psychotherapy to change negative or harmful thoughts or the patient’s relationship to these thoughts, which in turn can change the patient’s behavior. CBT has been effective in a treating a number of mental disorders such anxiety, personality disorders, and depression. MET is an approach used to augment a patient’s motivation in achieving a goal and has mostly been employed in treating alcohol abuse.

The CBT and MET interventions in this study were designed to target one of the four personality traits (for example, anxiety reduction) and were administered in two 90-minute group sessions. The specific lesson plans for these interventions were not reported in the studies but included workbooks and such activities as goal-setting exercises and CBT therapies to help students to dissect their own personal experiences through identifying and dealing with negative/harmful thoughts and how those thoughts can result in negative behaviors. Interestingly, alcohol and drug use were only a minor focus of the interventions.

The success of the interventions was determined through self-reporting. The student’s completed the Reckless Behavior Questionnaire (RBQ), which is based on a six-point scale (“never” to “daily or almost daily”) to report substance use. Obviously due to the sensitive nature of these questionnaires and need for honesty by the students, measures were taken to ensure accuracy in the self-reporting, such as strong emphasis on the anonymity and confidentiality of the reports and inclusion of several “sham” items designed to gauge accuracy of reporting over time. Surveys were completed every 6-months for 24-months (two years) which is a sufficient time frame to assess the effect of the interventions.

Most importantly, schools were blinded to which group they were placed in and teachers and students not involved in the study were not aware of the trial occurring at the school. The students involved were unaware of the real purpose and scope of the study. These factors are important to consider because it held eliminate secondary effects and helps support the direct efficacy of the interventions themselves.

The results were impressive: reduced frequency and quantity of drinking occurred in the high-risk students that received the intervention compared to the control students that did not. While HR students were overall more likely to report drinking than low-risk (LR) students, the HR students saw a significant effect of the personality-targeted interventions on drinking behavior.

Conrod et al.2013 abstract

A study of this size is incredibly complex and the statistics involved are equally complex. The author’s analyzed the data in a number of ways and published the results in several papers. A recent study modeled the data over time (the 24-months in which the surveys were collected) and used these models to predict the odds that the students would engage in risky drinking behavior. The authors reported a 29% reduction in odds of frequency of drinking by HR students receiving the interventions and a 43% reduction in odds of binge drinking  when compared to HR students not receiving the interventions.

Interestingly, the authors report a mild herd-effect in the LR students. Meaning that they believe the intervention slowed the onset of drinking in the LR students possibly due to the interactions between the HR student’s receiving the interventions and LR students. However, additional studies will need to be done in order to confirm this result.

Recall that the Reckless Behavior Questionnaire (RBQ) was utilized in this study to quantify drug-taking behavior. While the study was specifically designed to measure effects on alcohol, the RBQ also included questions about marijuana. So the authors reanalyzed their data and specifically looked at effects of the interventions on marijuana use.

Mahu et al. 2015

The found that the sensation seeking personality sub-type of HR students that received an intervention had a 75% reduction in marijuana use compared to the sensation seeking HR students that did not receive the intervention. However, unlike the findings found on alcohol use, the study was not able to detect any effect on marijuana use for the HR students in general. Nevertheless, the data suggest that the teacher/counselor administered interventions are effective at reduce marijuana use as well.

While you may be unconvinced by the modest reduction in drinking and marijuana frequency reported in these studies and may be skeptical of the long-term effect on drug use in these kids, keep in mind that the teachers and counselors that administered these interventions received only 2 or 3 days of training and the interventions themselves were very brief, only two 90-minute sessions. What I find remarkable is that such a brief, targeted program can have ANY effects at all. And most importantly, the effects well outlasted the course of the interventions for the full two-years of the follow-up interviews.

These targeted interventions have four main advantages:

  1. Administered in a real-world setting by teachers and counselors
  2. Brief (only two 90-minute group sessions)
  3. Cheap (the cost of training and materials for the group sessions)
  4. Effective!

The scope of this intervention needs to be tested on a much larger cohort of students in a larger variety of neighborhoods but it is extremely promising nonetheless. Also, it would be interesting to breakdown these data by race, socioeconomic status, and gender, all of which may impact the effectiveness of the treatments and was not considered in this analysis. Finally, how would you implement these interventions on a wide scale? I eagerly look forward to additional work on these topics.

Thanks for reading 🙂

See these other articles in Time and on King’s College for less detailed discussions of these studies.

Also see these related studies from Conrod’s group:

Castellanos-Ryan N, Conrod PJ, Vester JBK, Strain E,, Galanter M, Conrod PJ. Personality and substance misuse: evidence for a four-factor model of vulnerability. In: Vester JBK, Strain E, Galanter M, Conrod PJ, eds. Drug Abuse and Addiction in Medical Illness. Vols 1 and 2. New York, NY: Humana/Spring Press; 2012.

Conrod PJ, Pihl RO, Stewart SH, Dongier M. Validation of a system of classifying female substance abusers on the basis of personality and motivational risk factors for substance abuse. Psychol Addict Behav. 2000;14(3):243-256.

Conrod PJ, Stewart SH, Comeau N, Maclean AM. Efficacy of cognitive behavioral interventions targeting personality risk factors for youth alcohol misuse. J Clin Child Adolesc Psychol. 2006;35(4):550-563.

Conrod PJ, Castellanos-Ryan N, Strang J. Brief, personality-targeted coping skills interventions and survival as a non-drug user over a 2-year period during adolescence. Arch Gen Psychiatry. 2010;67(1):85-93.

O’Leary-Barrett M, Mackie CJ, Castellanos-Ryan N, Al-Khudhairy N, Conrod PJ. Personality-targeted interventions delay uptake of drinking and decrease risk of alcohol-related problems when delivered by teachers. J AmAcad Child Adol Psychiatry. 2010;49(9):954-963.

The Scientist’s Toolbox: Techniques in Addiction Research, Part 1

Lab Mice IMG_4102
(Image © Derek Simon 2015)

One of the most important questions that every scientist learns to ask is “How do you know that…?” As scientists, we are trained to be skeptical. When we consider a bit of research done by a colleague, before we are inclined to believe the data,  we need to be sure that they conducted the right experiments and that those experiments were done correctly. This doesn’t mean that scientists are stubborn or closed-minded. The reality is quite the opposite. Scientists are ready to incorporate new ideas and new results but first we need to know that the data are real. That’s what being a skeptic is all about: reserving judgment until you know all the facts.

The question “How do you know that..?” is one of the intellectual tools we use when considering whether or not data are real or not. This question has two parts: 1) how do you measure the thing that you interested in and 2) how do you know the effect you are seeing is actually based on what you think it is? What type of comparisons do you need to make in order to test the effect you’re interested in?

The first point of the question relies on special tools, equipment/technology, and experimental setups that are used to take measurements. For example, if you want to know how much a mouse likes taking a drug, then you need a way to measure how much drug it takes and how often it takes the drug (more on this in a bit). Today, I’ll go over a few of the tools that we use in addiction research.

The second part is more important (and more difficult to explain) but is really at the heart of the scientific method. It is all about experimental design and making sure you make the proper comparisons and analyses. I won’t discuss these details any more right now but will save this discussion for a future post.

Instead, let’s take a look at a few of the tools a scientist studying drug addiction has in his/her toolbox.

Locomotor Activity Test

The psychostimulants amphetamine and cocaine act in very similar ways and have very similar effects on the brain. We know that stimulants sort of “amp you up” or make you feel like you have more energy. Think of how you feel after drinking too much coffee. And what do you do when you have more energy? You tend to move around more (maybe you feel a little twitchy/antsy after too much of that coffee…). The same thing happens to mice and rats.

Locomotor Activity Test Chamber with a mouse. Image from UC-Davis Mind Institute (http://www.ucdmc.ucdavis.edu/mindinstitute/).
Locomotor Activity Test Chamber with a mouse. Image from UC-Davis Mind Institute (http://www.ucdmc.ucdavis.edu/mindinstitute/).

We can measure the amount of movement using a locomotor activity test. This test uses a special piece of equipment that uses light beams and a light-sensitive detector. Whenever the animal moves around the test box, the light beams are broken and the detector records that information. One way to analyze the data is by simply plotting beam-breaks (photo-cell counts are the same thing) that occur over the time of the test period. This way you have a measure of how much the animal moves around in a certain amount of time (more beam-breaks/time unit equals greater movement). A more sophisticated analysis of this same data can actually give you information on where in the box the animal spends its time. Does is just pace back and forth in a small area of the box or does it explore the entire chamber? This type of exploratory behavior data is valuable information and can be useful to other fields that may or may not study drug addiction. The general test for this exploratory behavioral analysis, regardless of speed of the movement caused by drugs, is the open field test.

 

Multiple test boxes with a computer that collects the data. Image from Douglas Mental Health Institute (http://www.douglas.qc.ca/page/neurophenotyping-motor-function).
Multiple test boxes with a computer that collects the data. Image from Douglas Mental Health Institute (http://www.douglas.qc.ca/page/neurophenotyping-motor-function).

An interesting phenomenon has been identified with psychostimulants. If you give an animal an injection of cocaine it will move around more compared to regular animals. But if you give it another dose of cocaine the next day it will move around even more than it did on the first day. This is called locomotor sensitization and is an important property of psychostimulants like amphetamine and cocaine.

The graphs below are real data that I took from a figure from one of our lab’s papers so you can see what locomotor sensitization looks like.

Cocaine-induced locomotor sensitization. Unterwald EM et al. J. Pharmacol. Expt. Ther. 1994.
Cocaine-induced locomotor sensitization. (Unterwald EM et al. J. Pharmacol. Expt. Ther. 1994.)

It’s a little hard to read but there are two groups of animals: one that receives cocaine injections (the top line) and the other that receives saline injections (the bottom line). Saline is a saltwater solution that is a standard control solution that has no biological effects. Each data point represents an average of several animals from each group. The baseline graph shows the locomotor activity before injections (no differences). As you can see, at day 1 the cocaine animals are already moving more than the saline group. This increase in movement continues over the 14 days of the experiment, evidence of locomotor sensitization.

This video shows an analysis of locomotor activity using video tracking software instead of light-beam breaks.

Self-Administration

Locomotor activity is all good and well but not all drugs of abuse cause locomotor sensitization. More directly related to addiction in humans, how do we even know if the animal likes the drug or wants to take the drug? Humans addicts crave the drug and compulsively use it, meaning the desire to do the of the drug overpowers the addict’s self-control. Is there a way we can study this type of drug-taking behavior in animals? The answer is yes!

Self-administration is a very versatile and powerful technique used throughout the addiction field. This technique allows the animal to control whenever it takes the drug and however much it wants. We can study many different aspect of drug taking using self-administration.

A diagram for a typical self-administration chamber. Image from Med Associates (http://www.med-associates.com/).
A diagram for a typical self-administration chamber. Image from Med Associates (http://www.med-associates.com/).

 

The basic idea is is simple: The rodent (mouse or rat) is placed in a chamber and presented with two levers. If the mouse the presses one lever (the active lever) it receives a dose of drug but if it presses the other lever (inactive lever) it does not. The self-administration sessions are run for a set period of time and the number of presses is recorded for each lever. Over the course of several days the animal steadily increases the amount of lever presses, thus the amount of drug it takes. Meaning the animal learns how to take drug and then takes more and more of it. Just like a human addict would do!

Alternatively, the mouse can poke its nose at a special hole that acts just like the active lever. I’ll use “lever press” and “nose poke” interchangeably because they essentially mean the same thing.

Here’s a little cartoon I found on YouTube of a rat that is self-administering nicotine.

 

Here’s another video that shows a real mouse self-administering a natural reward (meaning not a drug of abuse but food in this case).

 

There are several important variations to this basic idea that help scientists to not only make the experiments easier to control and data better/easier to analyze, but allow different aspects of drug taking to be studied.

For example if you are studying alcohol addiction, then when the mouse presses the lever a spout may appear that allows the animal to drink the alcohol (the inactive lever produces a bottle of water only). This is perfect for testing alcohol self-administration because both humans and mice drink alcohol. But what if you want to study heroin or cocaine self-administration? Humans (nor mice) drink or eat these drugs. So how does the drug get delivered to the mouse when it presses the lever?

The answer is intravenous self-administration. In this version, a small surgery is performed where a small tube (a cathether) is threaded into the jugular vein of the animal. This tube is fixed to the mouse back and attached to another tube that is part of the self-administration apparatus. This time when the mouse hits the lever, a dose of drug is pumped directly into its vein! See the diagram and videos above for more details.

Intravenous self-administration has several advantages.

  • As explained above, it allows us to deliver drugs to animals that won’t take them orally.
  • It allows the drug to act immediately on the animal because the drug is being delivered directly into the bloodstream.
  • It allows us to control the dose of the drug. When the mouse hits the lever (or nose pokes) it receives a fixed amount of drug that the scientist decides on ahead of time. That way we know how much total drug the mouse takes during a single self-administration session.
  • There is no variability in whether the animal is receiving the full dose or not. For example, if the lever press results in a food pellet, there is no guarantee the animal will eat the whole thing. But if you set the self-administration apparatus to deliver 0.5mg of heroin every time the lever is pressed, then there is no doubt if the full 0.5mg dose is delivered to mouse ever time.

Warning: not for the squeamish! This video shows you how to do the catheter implantation surgery on a mouse that will be used for intravenous self-administration!

Finally, best of all, self-ad can be used to address many different types of questions related to different stages in the addiction cycle. Here I briefly describe some of the more common experimental questions and applications that self-ad can help to address.

  • Initial use and escalation of use. How much will the animal take when it is first exposed to the drug? Will the animal reach a ceiling in the amount of drug it will take in a single session?
  • Maintenance of drug taking. One cool variation is you can make it more difficult for the animal to get the same dose of drug. This is called a progressive ratio self-administration. For example, the animal may need to press the lever 5 times before it receives a dose. You can keep increasing the number of presses during each session to see how hard the animal will work for a dose. One way this experiment can be interpreted is how badly does the animal want the drug? Some animals will press the lever many, many times just to get a small dose. This type of behavior is similar to the intense cravings that human addicts can experience.
  • Extinction and Relapse. You can run a special type of experiment where you run a self-administration experiment like normal and then change it so that the active lever no longer gives the animal a dose of drug. Eventually, the animal presses the lever less and less as it learns that it will no longer get the drug. This is called extinction of self-administration. This is like being in a rehab clinic where you are prevented from taking the drug. However, after the extinction sessions, if the scientist gives the animal another does of drug this will causes animal to start pressing the lever at high rates again. This a called reinstatement of self-administration and is model of relapse. What other types of conditions or factors can cause reinstatement (relapse behavior)? This situation is just like an abstinent cocaine addict who may not be craving cocaine but if he/she takes even a single hit, this can be sufficient for that person to sink back into full-blown addiction.

Let’s take a look at some real data. The graph below is from a paper from our group that looks at oxycodone self-administration in mice.

Oxycodone self-administration by adult and adolescent mice. (Zhang Y et al. Neuropsychopharmacol. 2009.)
Oxycodone self-administration by adult and adolescent mice. (Zhang Y et al. Neuropsychopharmacol. 2009.)

 

This study is interested in comparing oxycodone self-administration between adult mice and adolescent mice. As you can see, the number of nose pokes at the active hole (remember, same thing as a lever presses) increases during the course of the experiment (don’t worry about FR1 vs FR3) while the inactive hole is ignored, because it does not result in drug administration. Note that the nose pokes are plotted over the time of the administration sessions (2 hours) and that 9 sessions are run (one every day).

Microdialysis

The types of experiments I’ve described so far are great ways of studies addictive behaviors but they don’t really tell you about what’s going on in the brain. These behavior experiments are useful in themselves but they are much more powerful if they can be combined with another type of experiment that gives you a window into what’s changing in the brain at the same time as the behaviors.

In my post Synapse to it, I described how neurotransmitters are released by the pre-synaptic neurons into the synaptic cleft so that they can act on receptors located on the post-synaptic neuron. Using microdialysis, you can sample the fluid that exists in the synaptic cleft and actually measure the amount of neurotransmitters being released!

This is an extremely difficult and very technically complicated technique and I will only go into the basics about it. First, the microdialysis probe is surgically placed into a region of the brain that you are interested in studying.

The microdialysis probe itself is like a very thin piece of tubing that allows the experimenter to flow fluid into it one side(inlet) and collect the fluid that flows out of the other side (outlet). At the tip of the probe (the part that’s actually inside the brain) is a special type of material that allows fluid from inside the brain to flow into the tubing (a semi-permeable membrane).

Schematic of a microdialysis probe. Image from Wikipedia.
Schematic of a microdialysis probe. Image from Wikipedia.

After the surgery, you run your behavioral experiment, and while you are doing that you start flowing fluid into the brain. The fluid that the microdialysis probe flows in is of a similar consistency to the fluid that exists naturally in the brain. As the fluid inside the probe moves through the tubing, it causes fluids in the brain to enter into the probe and through the tubing where it can be collected when it flows out of the tubing.

Let’s say you give an animal a drug that causes a neurotransmitter to be released in the brain region you are interested in. Then some of those released neurotransmitters will enter the microdialysis probe because some of the fluid that enters the probe is from the synaptic cleft.

You keep collecting fluid at different time points during your experiment. When the experiment is over, then you can use chemistry to determine what neurotransmitters are in the fluid you collected. Best of all, you can determine how much of those neurotransmitters you have! How you do actually use chemistry to do this is a very technical part of the procedure and is not important to this discussion.

And all that work gives you a nice graph of the neurotransmitters that are released at different times during your experiment.

Now for some real data. Below are figures from a paper that our lab produced that uses microdialysis to study release of the neurotransmitter dopamine.

Evidence of probe placement in the Caudate  Putamen. (Zhang Y et al. Brain Res. 2001.)
Evidence of probe placement in the caudate putamen. (Zhang Y et al. Brain Res. 2001.)

 

Cocaine-induced increase in DA. (Zhang Y et al. Brain Res. 2001.)
Cocaine-induced increase in DA. (Zhang Y et al. Brain Res. 2001.)

 

In this study, the effect of cocaine on dopamine release in a region of the brain called the caudate putamen is being studied. The first image shows you that the microdialysis probe was placed in the right area of the brain (the white line that pierces through the dark area is the tract in the caudate putamen). The graph shows that injection of cocaine (the arrows) causes an increase in dopamine release in this brain region. Interestingly, the dopamine levels have returned to normal by the end of the experiment. Note: C57Bl/6J is the strain of mouse used in this study.

These are just three of the techniques that are used in addiction research. But we scientists have very big toolboxes! I’ll to explain some more in a later post.

Feel free to contact me or comment if you have questions!

Thanks for reading 🙂