The Consequences of Childhood Abuse Last Until Adulthood: What are the Implications for Society?

(© Derek Simon 2015)
(© Derek Simon 2015)

One of the great questions in the addiction field is why do some people become full-blown addicts while other people can use drugs occasionally without progressing to anything more serious? One part the answer definitely has to do with the drug itself. For example, heroin causes a more intensely pleasurable high than cocaine and people that try heroin are more likely to become addicted to it than cocaine. But that’s not the whole story.

I’ve written previously about how a negative, stressful environment can have long-lasting negative impacts on the development of a child’s brain (also known as early-life stress of ELS). ELS such as childhood abuse (physical or sexual) and neglect can increase the risk for a whole host of problems as an adult such as depression, bipolar disorder, PTSD, and of course drug and alcohol abuse. There’s even a risk for more physical ailments like obesity, migraines, cardiovascular disease, diabetes, and more.

Childhood abuse/neglect = psychological and physical problems as an adult.

Attitudes towards childhood development have certainly changed! Child coal miners ca. 1911 (wikipedia.org).
Attitudes towards childhood development have certainly changed! Child coal miners ca. 1911 (wikipedia.org).

This idea doesn’t sound too controversial but believe it or not, the idea that a bad or stressful situation as a child would do anything to you as an adult was laughed away as not possible. It’s only within the last decade or so that a wealth of research has supported this idea that ELS can physically change the brain and that these changes can last through the abused child’s entire life.

This recent review paper (published in the journal Neuron) is an excellent, albeit technical, summary of dozens research papers done on this subject and the underlying biology behind their findings.

Paradise lost childhood abuse review 2016 title

I especially love the quotes the author included at the beginning of the article:

Paradise lost childhood abuse review 2016 quotes

And even more recently, yet another research paper has come out that highlights how important childhood is for the development of the brain and how a stressful childhood environment can impact the function of a person as an adult.

Childhood abuse paper 2016

This most recent report, published in the journal Neuropscyhopharmacology concludes that early childhood abuse affects male and females differently. That is to say that the physical changes that occur in the brain are distinct for men and women who were abused as children.

Studies like this one are done by examining the brains of adults who were abused as kids and then comparing the activity or structure of different parts of the brain to the brains of adults who were not abused. The general technique of examining the structure or activity of the brain in a living human being is called neuroimaging and includes a range of techniques such as MRI, PET, fMRI, and others. (I’ve written about some of these techniques before. In fact, the development of better methods to image the brain is a huge are of research in the neuroscience field).

However, this study did not examine behavioral differences in the subjects, but as I said above, a great number of many other studies have looked at the psychological consequences of ELS. But this paper is really primarily interested in the gender differences in the brains of adults that have been abused as kids.

*Note: the following discussion is entirely my own and is not mentioned or alluded to by the author’s of this study at all.

This work—and the many studies that preceded it—has important implications because as a society, we have to realize that part of our personality/intelligence/character/etc. is determined by our genetics while the other part totally depends on the environment we are born into. I don’t want to extrapolate too much but the idea that childhood abuse can increase the risk of psychological problems as an adult also supports the broader notion that a great deal of a person’s success is determined by entirely random circumstances.

The_ACE_Pyramid
The Adverse Consequences Pyramid perfectly illustrates how ELS/abuse/neglect (the bottom of the pyramid) leads to much greater problems in later life. (wikimedia.org).

The science shows that a child born into a household rife with abuse will have more chance of suffering from a psychological problem (such as addiction) as an adult than someone who was born into a more stable life. The psychological problem could hurt that person’s ability to study in school or to hold down a job. And the tragic irony, of course, is that no child gets to choose the conditions under which they are born. A child, born completely without a choice of any kind over whether or not he or she will be abused, can still suffer the consequences of it (and blame for it) as an adult.

As a society, we often always blame a person’s failures as brought on by his or her own personal failings, but what if a person’s childhood plays an important role in why that person might have failed? How, as a society, do we incorporate this information into the idea of ourselves as having complete control over our minds and our destinies, when we very clearly do not? As an adult, how much of a person’s personality is really “their own problem” when research like this clearly show that ELS impacts a person well after the abuse has ended?

If the environment a child is born into has a tangible, physical effect on how the brain functions as an adult, than this problem is more than a social or an economic one: this is a matter of public health. Studies that support findings such as these provide empirical significance for public policy and public services for child care such as universal pre-K, increased availability of daycare, health insurance/medical access for children, increased and equitable funding for all public schools regardless of the economic situation of the district that school happens to be located in, etc.

One of our goals as a society (if indeed we believe ourselves to be a functioning society…the success of Donald Trump’s candidacy raises some serious doubts…but I digress) is the improvement of the lives of ALL of our citizens and securing the prosperity of the society for future generations. Reducing childhood poverty and abuse quite literally could help secure the future generations themselves and improve the ability of any child to grow up to become a successful and productive adult.

Public programs are essential because the unfortunate reality for many people born into poverty is that they must work all the time at low paying jobs in order to simply survive and may not be able to give their children all the advantages of a wealthier family. And this is where government and public policy step in, to correct the imbalances and unfairness inherent to the randomness of life and level the playing field for all peoples. Of course, the specific programs and policies to reduce childhood poverty and abuse would need to be evaluated empirically themselves to guarantee an important improvement in development of the brain and health of the child when he/she grows up.

And this is the real power of neuroscience and basic scientific research papers like this one. Research into how our brains operate in real-life situations reveal a side of our minds and our personalities that we never may have considered before and the huge implications this can have for society. The brain is a complex machine and just like other machines it can be broken.

Of course, we shouldn’t extrapolate too much and say that, for example, a drug addict who was abused as a child is not responsible for anything they’ve ever done in between. But is important to recognize all the mitigating factors at play in a person’s success and simply dismiss someone’s problems as “their own personal responsibility.” As a neuroscientist, I might argue that that phrase and the issues behind it are way more nuanced than the how certain politicians like to use it.

Special endnote Due to some recent shifts in my career, Dr. Simon Says Science will be expanding the content that I write about. Addiction and neuroscience will still be prominently featured but I plan to delve into a variety of other topics that I find interesting and sharing opinions that I think are important. I hope you will enjoy the changes! Thanks very much!

 

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NIH Scientists Identify a Potential New Treatment for Depression: A Metabolite of Ketamine

In a remarkable example of scientific collaboration, a new study produced by scientists at various research centers at the National Institutes of Health (NIH) have identified how ketamine works as powerful and fast-acting anti-depressant. This discovery may lead to an effective and potent new treatment for depression.

Ketamine is normally used as an anesthetic but at low doses, it has been shown to have rapid acting and long-lasting anti-depressant effects in humans. Fast relief of depression is incredibly important because most anti-depressant medications are not very effective or can take weeks (or even months in some cases) for maximal effect, which hurts the recovery of patients suffering from this crippling psychiatric disorder. However, despite its rapid action, ketamine has many side effects such as euphoria (a “high” feeling), dissociative effects (a type of hallucination involving a sense of detachment or separation from the environment and the self), and it is addictive.

If ketamine could be made safe to use without any of its other more dangerous properties, it would be a powerful anti-depressant medication.

With this goal in mind, scientists at the National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Center for Advancing Translational Sciences (NCATS), University of Maryland, and University of North Carolina-Chapel Hill sought to unravel the mystery of how ketamine works.

When ketamine enters the body it is broken down (metabolized) into many other chemical byproducts (metabolites). The team of scientists identified that it’s not ketamine itself but one of it’s metabolites, called HNK, that is responsible for ketamine’s anti-depressant action Most importantly HNK does not have any of the addictive or hallucinogenic properties of ketamine. What does this mean? This special metabolite can now be produced and can be given to patients while ketamine (and all its unwanted negative side effects) can be bypassed.

depressionOf course, many tests still need to be done in humans to confirm the effectiveness of HNK, but the study is an amazing example of how an observation can be made in the clinic, brought in the lab for detailed analysis, and then brought back to the clinic as a potential effective treatment.

But how did the scientist’s do it and how do they know that this HNK is what’s responsible for ketamine’s depression-fighting power? Keep reading below to find out.

Also, check out the NIH’s press release on the study.

The original study can be found here.

What is ketamine?

(±)-Ketamine_Structural_Formula_V1.svg
Chemical structure of ketamine (wikimedia.org).

Ketamine has traditionally been used an as anesthetic due to it’s pain relieving and consciousness-altering properties [1]. However, at doses too low to induce anesthesia, it has been shown that ketamine has the ability to relieve depression [2]. Even more remarkably, the anti-depressant effects of ketamine occur within a few hours and can last for a week with only a single dose. Most anti-depressant medications can take weeks before they start relieving the symptoms of depression (this is due to how those medications work in the brain).

However, ketamine also has unwanted psychoactive properties, which limits its usefulness in the treatment of depression. Ketamine causes an intense high or sense of euphoria as well as hallucinogenic effects such as dissociation, a bizarre sense of separation of the mind from the self and environment. Ketamine is also addictive and is an abused party drug [3].

A debate has been going about whether ketamine should be used for the treatment of depression and if its risks outweigh its benefits [4]. However, what if ketamine itself is not responsible for the anti-depressant function but a chemical byproduct of ketamine? This is what the scientist’s in this study reported: it’s HNK and not ketamine that are responsible for the powerful anti-depressant functions. This discovery was made in mice but how do scientists even study depression in a mouse?

 

How do scientists study depression in rodents?

mice-162163_960_720

Depression is a complex psychological state that is difficult to study but scientists have developed a number of tests to measure depressive-like behavior in rodents. While any one particular test is probably not good enough to measure depression, the combination of multiple tests—especially if similar results are found for each test—provide an accurate measurement of depression in rodents.

Some of the tests include:

Forced Swim Test

As the name reveals, in this test rodents are place in a cylinder of water in which they cannot escape are a forced to swim. Mice and rats are very good swimmers and when placed in the water will swim around for a while, searching for a way to escape. However, after a certain amount of time, the mouse will “give up” and simply stop swimming and will just float there. This “giving up” is used as a proxy for depression, similar to how people that are depressed often lack perseverance or motivation to keep trying. If you a give drug and the mice swim for much longer than without the drug, then you can make the argument that the drug had an anti-depressant effect. See this video of a Forced Swim Test.

Learned Helplessness Test

One theory of depression is that it can result from being placed in a bad situation in which we have no control over. This test models this type of scenario.

First, mice are place in chamber where they experience random foot shocks (the learning about the bad, hopeless situation). Next, they are place in a chamber that has two compartments. When a foot shock occurs, a door opens to a “safe” chamber, which gives the mouse an opportunity to escape the bad situation. One measure of depression is that some mice won’t try to escape or will fail to escape. In essence, they’ve given up at trying to escape the bad situation (learned helplessness). You can then take these “depressed” mice, and run the experiment again but this time with the anti-depressant drug you want to test and see how they do at escaping the foot shocks. Read more here.

Chronic Social Defeat Stress

Imagine you had a bully that would beat you up every day but the bully lived next door to you and would stare at you through his bedroom window? It would probably make you feel pretty crummy, wouldn’t it? Well, in essence, that’s what chronic social defeat stress test is all about [5].

A male mouse is placed in a cage with a much larger, older, and meaner male mouse that then attacks it. After the attack session, the “victim” mouse is housed in a cage where it can see and smell the bigger mouse. This induces a sense of hopelessness or depression in the “victim” mouse and it will not try to interact with a “stranger”” mouse if given a choice between the stranger and an empty cage (mice are pretty curious animals and will usually sniff around a cage with a unfamiliar mouse in it). This social avoidance is a measure of depression. In contrast, some mice will be resilient or resistant to this type of stress and will interact normally with the “stranger” mouse. Similar to above, you can test an anti-depressant drug in the “resilient” mice and the “depressed” mice.

There are a few others but these are three of the main ones used in this paper.

How did the NIH scientists figure out how Ketamine works to fight depression?

It was believed that ketamine’s anti-depressant function was due to its ability to inhibit the activity of the neurotransmitter glutamate. Specifically, ketamine inhibits a special target of glutamate called the NMDA receptor [6].

The first thing done is this paper was to study ketamine’s effects in rodent models of depression and sure enough, it was effective at relieving depression-like behavior in the mice.

Ketamine comes in two different chemical varieties or enantiomers, R-ketamine and S-ketamine. Interestingly, the R-version was more effective than the S-version (this will be more important later).

Recall that ketamine is though to work because it inhibits the NMDA receptor, but the scientists found that another drug, MK-801, that also directly inhibits the NMDA receptor, did have the same anti-depressant effects. So what is it about ketamine that makes it a useful anti-depressant then if not it’s ability to inhibit the NMDA receptor?

Ketamine is broken down into multiple different other chemical byproducts or metabolites once it enters the body. The scientists were able to isolate and measure these different metabolites from the brains of mice. For some reason one of the metabolites, (2S,6S;2R,6R)-hydroxynorketamine (HNK) was found to be three times higher in females compared to males. Ketamine was also more effective at relieving depression in female mice compared to male mice and the scientists wondered: could it be because of the difference in the levels of the ketamine metabolite HNK?

To test this, a chemically modified version of ketamine was produced that can’t be metabolized. Amazingly the ketamine that couldn’t be broken down did not have any anti-depressant effects. This finding strongly suggests that it’s really is one of the metabolites, and not ketamine itself, that’s responsible for the anti-depressant activity. The most likely candidate? The HNK compound that showed the unusual elevation in females vs males.

Similar to ketamine, HNK comes in two varieties, (2S,6S)-HNK and (2R,6R)-HNK. The scientists knew that the R-version of ketamine was more potent than the S-version so they wondered if the same was true for HNK. Sure enough, (2R,6R)-HNK was able to relieve depression in mice while the S-version did not. The scientists appeared to have identified the “magic ingredient” of ketamine’s depression-relieving power.

These experiments required a great deal of sophisticated and complex analytical chemistry. However, this is beyond my area of expertise so unfortunately cannot discuss it further.

So now the team had what they thought was the “magic ingredient” from ketamine for fighting depression. But could they support their behavior work with more detailed molecular analyses?

The next step was to look at the actual properties of neurons themselves and see if (2R,6R)-HNK changed their function in the short and long term. Using a series of sophisticated electrophysiology experiments in which the activity of individual neurons can be measured, the scientists found that glutamate signaling was indeed disrupted. However, it appeared that a different type of glutamate receptor was involved: the AMPA receptor, and not NMDA receptor. The scientists confirmed this with protein analysis; components of the AMPA receptor increased in concentration in the brain over time. These data suggest that it is alterations in glutamate-AMPA signaling that underlies the long-term effectiveness of HNK.

OK, so great! HNK reduces depression but does it still have all the other nasty side effects of ketamine? If it does, then it’s no better than ketamine itself.

For the final set of experiments, the scientists looked at the psychoactive and addictive properties of ketamine. Using a wide range of behavioral tests that I won’t go into the details of, 2R,6R)-HNK had a much lower profile of side effects than ketamine.

Finally, ketamine is an addictive substance that can and is abused illegally. A standard test of addiction in mouse models is self-administration (I’ve discussed this technique previously). Mouse readily self-administer ketamine, which indicates they want to take more and more of it, just like a human addict. However, rodent’s do not self-administer HNK! This means that HNK is not addictive like ketamine.

mental health

In conclusion, (2R,6R)-HNK appears to be extremely effective at relieving depression in humans, has less side-effects than ketamine, and is not effective. Sounds pretty good to me!

Next step: does HNK work in humans? To be continued….

Selected References

  1. Peltoniemi MA, et al. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clinical pharmacokinetics. 2016.
  1. Newport DJ, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. The American journal of psychiatry. 2015;172(10):950-66.
  1. Morgan CJ, et al. Ketamine use: a review. Addiction. 2012;107(1):27-38.
  1. Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2015;40(5):1307.
  1. Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR journal / National Research Council, Institute of Laboratory Animal Resources. 2014;55(2):221-32.
  1. Abdallah CG, et al. Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depression and anxiety. 2016.

 

Why is Addiction a Brain Disease?

I started as a contributor for the blog network addictionblog.org.

addiction blog logo copy

Read my first post, published today!

WHY IS ADDICTION A BRAIN DISEASE?

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.

Important Considerations in Optogenetics Behavioral Experiments

Image credit NSF, Inbal Goshen, Karl Deisseroth.
Image credit NSF, Inbal Goshen, Karl Deisseroth.

The third and final part of my three part guest blog series on Optogenetics has been published on the Addgene blog. Addgene is a nonprofit organization dedicated to making it easier for scientists to share plasmids and I’m thrilled to be able to contribute to their blog! This post covers the running behavioral experiments utilizing optogenetics.

Check it out!

http://blog.addgene.org/important-consideration-in-optogenetics-behavioral-experiments

 

The Materials Science of Optogenetics Experiments

(blog.addgene.org)
(blog.addgene.org)

The second part of my three part guest blog series on Optogenetics has been published on the Addgene blog. Addgene is a nonprofit organization dedicated to making it easier for scientists to share plasmids and I’m thrilled to be able to contribute to their blog! This post covers the material science aspects of running optogenetic experiments.

Check it out!

http://blog.addgene.org/the-materials-science-of-optogenetics-experiments

Optogenetics on the Addgene Blog: Part 1

(blog.addgene.org)
(blog.addgene.org)

The first part of my three part guest blog series on Optogenetics has been published on the Addgene blog. Addgene is a nonprofit organization dedicated to making it easier for scientists to share plasmids and I’m thrilled to be able to contribute to their blog!

Check it out!

http://blog.addgene.org/a-primer-on-optogenetics-introduction-and-opsin-delivery

The Genetic Link Between Creativity and Psychiatric Disease

(www.wikipedia.org)
(www.wikipedia.org)

The biological sciences are in a golden era: the number of advanced technological tools available coupled with innovations in experimental design has led to an unprecedented and accelerating surge in knowledge (at least as far as the number of papers published is concerned). For the first time in history, we are beginning to ask questions in biology that were previously unanswerable.

No field demonstrates this better than genetics, the study of DNA and our genes. With the advent of high-throughput DNA sequencing, genetic information can be acquired literally from thousands of individuals and even more remarkably, can be analyzed in a meaningful way. Genomics, or the study of the complete set of an organism’s DNA or its genome, directly applies these advances to probe answers to questions that are literally thousands of years old.

A recent study, a collaborative effort from scientists in Iceland, the Netherlands, Sweden, the UK, and the US, is an example of power of genomics and to answer these elusive questions.

Power eet al. Nat. Neursci. 2015. Title

The scientists posed an intriguing question: if you are at risk for a psychiatric disorder, are you more likely to be creative? Is there a link between madness and creativity?

Self-portrait with bandaged ear. Vincent van Gogh, 1889. (wikipedia.org)
Self-portrait with bandaged ear. Vincent van Gogh, 1889. (wikipedia.org)

Aristotle himself once said, “no great genius was without a mixture of insanity” and indeed, the “mad genius” archetype has long pervaded our collective consciousness. But Vincent Van Gogh cutting off his own ear or Beethoven’s erratic fits of rage are compelling stories but can hardly be considered empirical, scientific evidence.

But numerous studies have provided some evidence that suggests a correlation between psychiatric disorders and creativity but never before has an analysis of this magnitude been performed.

Genome-wide association studies (GWAS) take advantage of not only the plethora of human DNA sequencing data but also the computational power to compare it all. Quite literally, the DNA of thousands of individuals is lined up and, using advance computer algorithms, is compared. This comparison helps to reveal if specific changes in DNA, or genetic variants, are more common in individuals with a certain trait. This analysis is especially useful in identifying genetic variants that may be responsible for highly complex diseases that may not be caused by only a single gene or single genetic variant, but are polygenic, or caused by many different genetic variants. Psychiatric diseases are polygenic, thus GWAS is useful in revealing important genetic information about them.

This video features Francis Collins, the former head of the Human Genome Project and current director of the National Institutes of Health (NIH), explaining GWAS studies. The video is 5 years old but the concept is still the same (there’s not many GWAS videos meant for a lay audience).

The authors used data from two huge analyses that previously performed GWAS on individuals with either bipolar disorder or schizophrenia compared to normal controls. Using these prior studies, the author’s generated a polygenic risk score for bipolar disorder and for schizophrenia. This means that based on these enormous data sets, they were able to identify genetic variants that would predict if a normal individual is more likely to develop bipolar disorder or schizophrenia. The author’s then tested their polygenic risk scores on 86,292 individuals from the general population of Iceland and success! The polygenic risk scores did associate with the occurrence of bipolar disorder or schizophrenia.

Next, the scientists tested for an association between the polygenic risk scores and creativity. Of course, creativity is a difficult thing to define scientifically. The authors explain, “a creative person is most often considered one who take novel approaches requiring cognitive processes that are different from prevailing modes of thought.” Translation: they define creativity as someone who often thinks outside the box.

In order to measure creativity, the authors defined creative individuals as “belonging to the national artistic societies of actors, dancers, musicians, and visual artists, and writers.”

The scientists found that the polygenic risk scores for bipolar disorder and schizophrenia each separately associated with creativity while five other types of professions were not associated with the risk scores. An individual at risk for bipolar disorder or schizophrenia is more likely to be in creative profession than someone in a non-creative profession.

 The authors then compared a number of other analyses to see if this effect was due to other factors such as number of years in school or having a university degree but this did not alter the associations with being in a creative field.

Finally, the same type of analysis was done with two other data sets: 18,452 individuals from the Netherlands and 8,893 individuals from Sweden. Creativity was assessed slightly differently. Once again creative profession was used but also data from a Creative Achievement Questionnaire (CAQ), which reported achievements in the creative fields described above, was available for a subset of the individuals.

Once again, the polygenic risk scores associated with being in a creative profession to a similar degree as the Icelandic data set; a similar association was found with the CAQ score.

The authors conclude that the risk for a psychiatric disorder is associated with creativity, which provides concrete scientific evidence for Aristotle’s observation all those years ago.

However, future analyses will have to broaden the definition of creativity beyond just narrowly defined “creative” professions. For example, the design of scientific experiments involves a great deal of creativity but is not considered a creative profession and is therefore not included in these analyses, and a similar argument could be made with other professions. Also, no information about which genetic variants are involved or what their function is was discussed.

Nevertheless, this exciting data is an example of the power that huge genomic data sets can have in answering fascinating questions about the genetic basis of human behavior and complex traits.

For further discussion, read the News and Views article, a scientific discussion of the paper, which talks about potential evolutionary mechanisms to explain these associations.

The Formation of New Memories in the Human Brain

Image of the structure of the mouse Hippocampus (Image courtesy of www.gensat.org).
Image of the structure of the mouse Hippocampus (Image courtesy of http://www.gensat.org).

How are new memories created?

This is a fascinating question in neuroscience and at the very core of what makes us human. After all, our entire concept of ourselves is defined by our memories and without them, are we even ourselves? This is a pretty lofty philosophical discussion… but today we’re only interested in the neuroscience of memory.

In specific, what happens to individual neurons in the human brain when a new memory is created and recalled?

Researchers at the University of California-Los Angeles performed a study in humans that has shed some light on this important question. Published recently in the journal Neuron, the novelty of the study involved recording how many times a neuron would fire during a specially designed memory test. In other words, the scientists were able to monitor what happened to individual neurons in a human being as a new memory was being created!

Title Ison et al. 2015

This article is open access (able to downloaded and distributed for free). The article can be found here or download the pdf.

Before I go into what the researchers found, let’s see how it was done.

The subjects in the study were patients being treated for epilepsy. As part of their clinical diagnosis, they had been implanted with an electrode, a tool used to measure neuronal activity or in other words, the electrode measures how often a neuron fires. The fact these patients already had an electrode inserted into the brain for clinical reasons made it convenient for the researchers to conduct this study.

Left Temporal Lobe (www.wikipedia.org)
Left Temporal Lobe (www.wikipedia.org)

The brain region in which the electrode was implanted is called the medial temporal lobe (MTL). The image to the right is of the left human temporal lobe. The medial region of the temporal lobe is located more towards the center of the brain.

Human Hippocampus (www.wikipedia.org)
Human Hippocampus (www.wikipedia.org)

One specific region of the MTL, the hippocampus, is believed to be the primary brain region where memories are “stored”. Specifically, previous studies in animals and humans have suggested that the MTL and hippocampus are very important to encoding episodic memory. Episodic memory involves memories about specific events or places. In this study, the example of episodic memory being used is remembering seeing a person at a particular place. Another example: the game Simon™ can be considered a test of your brain’s ability to rapidly create and recall short-term episodic memories!

Simon game memory

*Note: Episodic memory is considered one of the main bifurcations of declarative memory, or memories that can be consciously recalled. The other type of declarative memory is semantic memory, which are memories of non-physical/tangible things, like facts.

To test the episodic memory of remembering a person at a particular place, images were presented to the patients while the neurons were being recorded. There were 5 different tasks (all completed within 25-30min). See Figure 1 below from the paper.

Figure 1: Experimental Design
Figure 1: Experimental Design

First, a pre-screening was done in which the patients was shown many random images of people and places. The activity of multiple neurons was recorded and the data was quickly analyzed then 3-8 pairs of images were compiled. In each pair, 1 image was “preferred” or “P” image, meaning the neurons being recorded fired when the “P” image was shown. The second image was “non-preferred” or “NP” image, meaning the neurons did not respond to it when it was shown.

The first task is the “Screening” test. Each “P” and “NP” image was shown individually and the neurons response to each was recorded. As you would expect, the neuron would fire heavily to the “P” image and not very much to the “NP” image.

The second task was the “learning task” in which a composite image of each of the “P” and “NP” image pairs was made. The person in the “P” image was digitally extracted and placed in front of the landmark in the “NP” image. After the composite images were shown, the individual images were shown again.

For example, in one image pair for one patient, the “P” image was a member of the patient’s family while the “NP” image was the Eiffel Tower (for this example, see Figure 2). The composite image in the “learning” task was the family member in front of the Eiffel Tower. Another example of a “P” image was Clint Eastwood and the “NP” image was the Hollywood sign. The composite image would therefore be Clint Eastwood in front of the Hollywood sign. (However, in some image pairs the “P” image was a place and “NP” image was a person).

The third task was “assessing learning”. The image of just the person in the composite image was shown and the patient had to pick out the correct landmark he/she was paired with. For example, the picture of the family member was shown and the patient would have to pick out the Eiffel Tower image.

The fourth task was the “recall” task. The landmark image was shown and the patient had to remember and say the person it was paired with. For example, the Eiffel Tower was shown and the patient had to say the family member’s name.

Finally, the fifth task was a “re-screening” in which each individual image was shown again so the neuron’s activity could be compared to the Task 1, pre-learning.

The activity of multiple neurons were recorded for each image for each of the tasks. The data was then analyzed in number of different ways and the activity of different neurons was reported.

And what was found?

Figure 2: Response of Neruons in the Hippocampus from One Patient
Figure 2: Response of Neurons in the Hippocampus from a Patient

Let’s go back to the family member/Eiffel tower example. The researchers were able to show that a neuron in the hippocampus responded heavily to the picture of the family member (“P” image) but not to the Eiffel Tower (“NP” image). After showing the composite image, the neuron now responded to the Eiffel Tower too in addition to the family member! (The neuron also fired a comparable amount to the individual family member image as the composite image).

As you can see in Figure 2, each little red or blue line indicates when a neuron fired. For example, in Task 1 you can clearly see more firing (more lines) to the “P” image than the “NP” image. You can see that after Task 2, the neuron responds to either the “P” or “NP” image (especially obvious in the Task 5). The middle graph indicates the firing rate of the neurons to the “NP” image and it clearly shows increased firing rate of the neuron after learning (AL) compared to before learning (BL). It may look small, but the scientists calculated a 230% increase in firing rate of the neuron to “NP” image after the learning/memory task took place!

What does this mean? It means that a new episodic memory has been created and a single neuron is now firing in a new pattern in order to help encode the new memory!

This was confirmed the other way around too. In another patient, the “P” neuron was the White House and the “NP” image was beach volleyball player Kerry Walsh. The neuron that was being recorded fired a lot when the image of the White House was shown but not so much for the Kerri Walsh image. Then the composite image was shown and the learning/recall tasks were performed. The neuron was shown to fire to both the White House image AND the Kerry Walsh image! The neuron was responding to the new association memory that was created!

Keep in mind these are just two examples. The scientists actually recorded from ~600 neurons in several different brain regions besides the hippocampus but they only used about 50 of them that responded to visual presentation of the “P” image, either a person or a landmark (the identification of visually responsive neurons was crucial part of the experiment). Remarkably, when the firing rates of all these neurons was averaged before and after the memory/learning tasks, a similar finding to the above examples was found: the neuron now responded to the “NP” image after the composite was shown!

Many other statistical analyses of the data was done to prove this was not just a fluke of one or two neurons but was consistent observation amongst all the neurons studied but I won’t go into those details now.

But what’s going on here? Are the neurons that respond to the “P” stimulus now directly responding to the “NP” image or is more indirect, some other neuron is responding to the “NP” which in turn signals to the “P” neuron to increase in firing? The authors performed some interesting analyses that both of these mechanisms may apply but for different neurons.

Finally, were all the recorded neurons that were engaged in encoding the new episodic memory located in the hippocampus? The answer is no. Responsive neurons were identified in several brain regions besides the hippocampus including the entorhinal cortex and the amygdala. But most of the responsive cells were located within the parahippocampal cortex, a region of the cortex that surrounds the hippocampus, thus not surprising it is very involved in encoding a new memory.

In conclusion, the scientists were able to observe for the first time the creation of a new memory in the human brain at the level of a single neuron. This is an important development but such a detailed analysis has never before been done in humans and, most importantly, in real time. Meaning, the experiment was able to observe the actual inception of a new memory at the neuronal level.

However, one major limitation is that the activity of these neurons were not studied in the long term so it’s unknown if the rapid change in activity is a short-term response to the association of the two images or if it really represents a long-term memory. The authors acknowledge this limitation but the problem is really in the difficulty of doing such studies in humans. It’s not really ethical to leave an electrode in someone’s brain just so that you can test them every week!

But what does all of this mean? The authors do suggest that the work may help to resolve a debate that has been going in on the psychology field since the 40s. Do associations form gradually or rapidly? These results strongly suggest new neurons rapidly respond to encode the new memory formation.

But how will these results shape the neuroscience of memory? The answer is I don’t know and no one does. Thus is the rich tapestry of neuroscience, another thread weaved by the continuing work of scientists all over the world  in order to understand what it is that makes us human: our brains.

Morphine and Oxycodone Affect the Brain Differently

(Neurons. Image from Ana Milosevic, Rockefeller University)
(Neurons. Image from Ana Milosevic, Rockefeller University)

Why are some drugs of abuse more addictive than others?

 This is a central question to the addiction field yet it remains largely a mystery. All drugs of abuse have a similar effect on the brain: they all result in increased amounts of the neurotransmitter dopamine (DA) in an important brain region called the mesolimbic pathway (also known as the reward pathway). One of the core components of this pathway is the ventral tegmental area (VTA), which contains many neurons that make and release DA. VTA neurons communicate with neurons in the nucleus accumbens (NAc). This means that the axons of VTA neurons project to and synapse on NAc neurons. When VTA neurons are stimulated, they release DA onto the NAc, and this is a core component of how the brain perceives that something is pleasurable or “feels good.” Many types of pleasurable stimuli (food, sex, drugs, etc.) cause DA to be released from the VTA onto the NAc (See the yellow box in the diagram below). In fact, all drugs of abuse cause this release of DA from VTA neurons onto NAc neurons.

*Important note: many other brain regions are involved in how the brain perceives the pleasurable feelings of drugs besides the VTA and NAc, but these regions represent the core of the pathway.

"Dopamineseratonin". Licensed under Public Domain via Wikipedia.
“Dopamineseratonin”. Licensed under Public Domain via Wikipedia.

Check out these videos for a more detailed discussion of the mesolimbic pathway.

But if all drugs of abuse cause DA release, then why do different drugs make you feel differently? This is a very complicated question but one component of the answer is that different drugs have different mechanisms and dynamics of DA release.

For the opioid drugs like heroin, morphine, and oxycodone, they are able to bind to a special molecule called the Mu Opioid Receptor (MOPR). This action on the MOPR results in an indirect activation of DA neurons in the VTA and a release of DA in the NAc. While all opioid drugs reduce the feeling of pain and induce a pleasurable feeling, they have slightly different properties at the MOPR.

The different properties of the opioids may be a reason why some are more abused than others. For example, a number of studies have suggested that oxycodone may have greater abuse potential than morphine. This means that oxycodone is more likely to be abused morphine.

But do the different properties of morphine and oxycodone on the MOPR affect DA release and is this important to why oxycodone is more likely to be abused than morphine?

Vander Weele et al. 2015 titleThis is the question that scientists at the University of Michigan sought to address. Using several different sophisticated techniques, the scientists looked at differences in DA release in the NAc caused by morphine and oxycodone, two common opioid drugs.

Rats were injected with either morphine or oxycodone and then DA release was measured using either fast-scan cyclic voltammetry or microdialysis. I’ve discussed microdialysis in a previous post but in brief, it involves drawing fluid from a particular brain region at different time points in an experiment and then measuring the neurotransmitters present (using advanced chemistry tools that I won’t explain here).

Voltammetry is a more technically complicated technique. In brief, it uses electrodes to measure sensitive voltage changes. Since a molecule has specific electrochemical properties, these voltage changes can be related back to a specific molecule, such as the neurotransmitter DA as in this study. Voltammetry may even allow greater temporal resolution (easier to detect very precise changes at very short time frames, like seconds), which may make it more accurate than microdialysis (which can only measure neurotransmitter release on the scale of minutes).

Because each technology has its own limitations and potential problems, the authors used both of these techniques to show that they are observing the same changes regardless of the technology being used. Showing the same observation multiple times but in different ways is a common practice in scientific papers: it increases your confidence that your experiment is actually working and what you are observing is real and not just some random fluke.

The authors administered a single dose of either morphine or oxycodone to rats and then measured the DA release in the NAc as described above. What they found were very different patterns!

Morphine resulted in a rapid increase in DA (less than 30 seconds) but by 60 seconds had returned to normal. In contrast, oxycodone took longer to rise (about 20-30 sec before a significant increase was detected) but remained high for the entire 2 minutes that it was measured. The difference in DA release caused by morphine and oxycodone is striking!

Many other changes were observed such as differences in DA release in different sub-regions of the NAc, different effects on phasic release of DA (DA is often released in bursts), and differences in the other neurotransmitters such as GABA (morphine caused an increase in GABA release too while oxycodone did not). I won’t discuss these details here but check out the paper for more details.

Of course, do these differences in DA release explain why oxycodone is more often abused than morphine? Unfortunately no, there are many other factors (for example, oxycodone is more widely available than morphine) to consider. Nevertheless, this is some intriguing neuroscientific evidence that adds one more piece to the addiction puzzle.