Tagged: dopamine

Addiction: The Silent Killer

addiction

Before we begin, I wanted to make sure everyone knows that this is a very special and important post, above and beyond what I normally write about. The topic’s importance cannot be understated. Most of you reading this know someone or have been personally affected by addiction. If you are currently suffering from addiction, regardless of the source, I hope that you take this opportunity to learn and seek help. Life is far too short and precious. 

This week’s question comes from B, who asks, “I recently lost my boyfriend to an overdose due to an opiate addiction. In order to be at peace with what happened, I’ve been searching for information about addiction and how specifically it affects a person’s brain. How does a person develop an addiction to opiates? What changes occur in the brain after an addiction sets in?”

Well B, sadly you are not alone in experiencing this kind of tragedy. Prescription drug overdoses, for example, kill tens of thousands of people a year and leave thousands more with permanent disability, organ damage, and/or contracted infectious diseases. Likewise, more socially acceptable drugs like tobacco and alcohol bring these numbers well into the six figure range. In total, according to the NIH’s National Institute on Drug Abuse, nearly $600 billion in lost productivity and healthcare costs are associated with addiction to alcohol, tobacco, and drugs. This makes addiction not just a pressing personal matter but also a national catastrophe both in terms of the physical harm and associated healthcare costs.

Further compounding this issue, many people still do not see addiction as a disease. Instead, addicts are labeled as maladjusted, unpredictable people seconds away from committing a crime or unspeakable violence to protect their habit. They are seen as simply out of control, that the drug takes ahold of them and they are lost forever. However, this view is dangerously incorrect. By making addiction such a stigma, addicts are pushed to the darkest corners of society; instead of helping people, we may be unwittingly contributing to their injury by forcing them into the shadows out of shame or fear.

Before we get into the specifics of opiate addiction, we should first explore how the brain becomes addicted to anything in the first place. The term “addiction” is colloquially used to describe both behavioral and chemical dependency; these are not necessarily discrete elements however addiction need not be of chemical origin. One can become addicted to basically any activity because the activity itself triggers a change in the brain over time. Many people have heard of gambling and sex addiction, which fall into this category. The brain effectively associates the given activity with being a positive and gives you a sense of reward and pleasure for accomplishing it. When competitors say they are “addicted to winning,” they are not entirely off base with their word choice, since winning in competition is a very deeply rooted trigger of this neurological process. The variation then comes with how socially acceptable it is — a person who is addicted to winning basketball games gets showered in adulation, while a gambling addict is labeled socially unacceptable for doing the same.

It is in this pleasure providing activity that we find the neurological basis for addiction. We have discussed before the role of dopamine in the brain (see here for past posts), but not yet in any particular detail. As those articles have described, dopamine is an integral neurotransmitter for, among other things, the reward-pleasure centers of the brain. This system has evolved over millions of years to make us seek out things that are beneficial to survival. We like sex, caloric foods, being active, winning, and not feeling pain because all of these things allowed us to survive longer and produce more successful offspring. Unfortunately for us, this system can be easily tricked. Drugs like amphetamines and cocaine cause a large release of dopamine in the brain directly, while drugs like alcohol and heroin indirectly cause dopamine levels to increase.

To be more specific, the area of the brain in question is known as the nucleus accumbens. Dopamine producing neurons from the ventral tegmental area of the brain terminate in the nucleus accumbens, depositing dopamine into it directly. Drugs and behaviors that affect this area can do so by multiple pathways. The nucleus accumbens is directly capable of being influenced by an increase in dopamine from these dopamine producing neurons. Drugs that cause abnormal dopamine rise can cause an actual physiological change that reinforces the value of their behavior to the brain. Over time, this modulation can cause a behavioral addiction to the act of taking drugs (“drug taking behavior”). This provides the basis for not only becoming addicted to the drug itself but also the act of taking them.

Along with reinforced behavior, the body can simply become addicted to feeling pleasure and reward stimulation. This is the basis upon which one can become addicted to behaviors that do not cause an externally sourced dopamine increase. Instead, we can look at these elements as internally sourced dopamine releases. In simpler terms, the body is rewarding you for what it believes you should be doing. This system is hard wired into all of us, but some people are more susceptible to addiction than others. There is evidence that this has a genetic basis, however the specifics of this are still undefined. Still, it remains a fact that hundreds of thousands if not millions of people in the US alone are actively addicted to something. It is in our best interest as a society to more fully understand the basis for this disease so that we can better and more comprehensively treat it.

Chemical dependency, unlike behavior based addiction, is a more complicated matter. One can only become chemically dependent on drugs, be they legal or illegal, because only drugs are capable of altering the normal physiology to the point of functional dependency. The drug alters the brain in some way that over time causes a replacement of normal function by the drug itself. For example, alcohol increases GABA receptor function (GABA reduces nerve activity) and depresses NMDA receptor sensitivity to the neurotransmitter glutamate (glutamate makes nerves more excitable). This is what is thought to cause the sedative effects. Chronic abuse of alcohol can cause these receptors to function abnormally: NMDA receptors become hypersensitive and GABA receptors become less responsive. With NMDA receptors going wild and no GABA activity to stop them, alcohol withdrawal symptoms such as the condition delirium tremens and seizures can result. Severe, untreated alcohol withdrawal can lead to death from prolonged seizures. Other drugs, such as benzodiazapines, can also cause similar withdrawal symptoms and different, non-sedative drugs, can have a variety of other withdrawal effects. In short, addiction to certain drugs isn’t just dangerous due to overdose potential but can also cause significant damage if the habit is improperly or suddenly stopped. The brain, quite literally, cannot function without them.

Specifically discussing opiates, drugs like hydrocodone (Vicodin), oxycodone (Oxycontin, Percocet), hydromorphone (Dilaudid), diacetylmorphine (heroin), and morphine are some of the most commonly prescribed drugs on the planet to treat acute and chronic severe pain. They also happen to be some of the most addictive substances available. While extremely useful in select circumstances, by and large these drugs are taken inappropriately. Many people take them to mask less than severe pain or avoid treating the underlying pathology or behavior. For example, a high school football player could either rest a sprained ankle and miss two games or take a Vicodin and play through it. For many people, these drugs are what keep them doing what they want to do when their bodies otherwise say no.

Likewise, these drugs are often over-prescribed and under-supervised. After surgery, for example, patients can be given upwards of 120 pills at a time. While the reason, to prevent unnecessary pain and suffering, is noble, ultimately it is a very sharp double edged sword. Even common pain killers like Vicodin can initiate a terrible cascade of dependency. One not need be a junkie or rebellious youth to become addicted to drugs. Sometimes something as innocuous as a broken bone or outpatient surgery can lead to a lifetime of addiction. Despite their utility in treating pain, these drugs unfortunately come at a terrible price.

Opiates can cause chemical and behavioral dependency very rapidly and this effect can grow more serious over time as the brain becomes tolerant of the drugs. Opiates operate by attaching to receptors in the brain known as opioid receptors. The body has three types of receptors (delta, kappa, and mu) and makes four of its own types of opiates, of which the well known endorphin is one (the other three are enkephalins, endomorphins, and dynorphins). Their job is to reduce the body’s response to pain signals as well as a few other functions around the body such as helping to regulate hunger and thirst. By binding to these receptors, opiate drugs take the place of these endogenous (internally sourced) opioids. However, these receptors never normally receive such a large influx of stimulation. Because of this, continuous use can cause the receptors to lose sensitivity, both reducing the value of internal opioids and forcing an ever increasing amount and strength of external opiates to keep up.

Many of the other effects, such as euphoria and sedation, are side effects related to their effect on the central nervous system, especially related to GABA receptors (the effect on which also causes the spike in dopamine that results in euphoria). Thus, opiates hit on all aspects of addiction, from dopamine release in the nucleus accumbens to opioid and GABA receptor chemical dependency. However, like with other sedative drugs, opiates can have terrible, even deadly, withdrawal symptoms as a result of their abnormal interaction with GABA.

Also, as was mentioned earlier, the dependency related to ever decreasing receptor sensitivity can cause opiate addicts to seek stronger and stronger opiates as weaker ones lose their effectiveness. This involuntary seeking behavior can and often does place them on a razor’s edge between satisfying their addiction and accidentally overdosing. Opiate overdoses are deadly serious business, often resulting in cardiopulmonary (heart and lung) emergencies such as severely depressed breathing, slowed heart rate, and low blood pressure, as well as lethargy, seizures, and loss of consciousness. If left untreated, these symptoms can become deadly in a short period of time. Sadly, it is relatively easy to overdose on opiates; so easy, in fact, that some cities around the world to distribute free overdose kits containing naloxone, a potent drug that can rapidly reverse these deadly symptoms.

In sum, we as a society must re-imagine our concept of addiction. Addiction is a very complex disease that involves multiple different areas of human behavior and biology. Clearly, the neurobiological elements involved with both the behavioral and chemical dependencies make addiction involuntary on multiple fronts. In particular, drugs, especially opiates, are tremendously difficult to leave because they take advantage of some of our most deeply seeded and essential neurobehavioral elements. Further complicating this is a genetic component of addiction that makes some much more susceptible than average. With better training, treatment, and understanding, we may be able to reclaim some of the tens of thousands of lives and billions of dollars we lose every year by pushing the problem under the rug.

Thank you for your question and for sharing your story, B. As always, if you want to ask a question, feel free to submit it at the link above.

Till next time,

Justin

Sources:

http://www.drugabuse.gov/related-topics/trends-statistics

http://www.drugabuse.gov/publications/science-addiction/drug-abuse-addiction

http://www.sciencedaily.com/releases/2007/10/071014163647.ht

http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_heroine.html

http://www.macalester.edu/psychology/whathap/UBNRP/Dopamine/alcoholtobac.html

http://www.guardian.co.uk/science/2013/feb/03/dopamine-the-unsexy-truth

http://www.health.harvard.edu/press_releases/drug-addiction-brain

http://www.jneurosci.org/content/22/9/3306.short

http://www.pnas.org/content/85/14/5274.short

http://www.sciencedirect.com/science/article/pii/S0028390804002199

http://www.jneurosci.org/content/12/2/483.short

http://www.sciencedirect.com/science/article/pii/016561479290060J

http://www.sciencedirect.com/science/article/pii/0091305787901924

http://www.annualreviews.org/doi/abs/10.1146/annurev.med.49.1.173

http://www.acnp.org/g4/gn401000050/ch050.html

http://www.health.harvard.edu/fhg/updates/update0405a.shtm

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715956/

http://www.uphs.upenn.edu/addiction/berman/genetic/

http://www.ncbi.nlm.nih.gov/pubmed/22204322

http://www.livestrong.com/article/68582-symptoms-opiate-overdose/

Parkinson’s Disease: Current and Future Treatments

stn_m1_2

This week’s question comes from Alex. She asks, “I saw a video on YouTube where a guy with Parkinson’s disease is able to use a machine implanted in his brain to control his shaking. Please explain this!”

The video Alex is referring to can be seen here and shows a man with the severe shaking most of us associate with Parkinson’s controlled by a device he had implanted in his brain. The effects are dramatic between when the machine is on or off; in fact, it seems that his symptoms are so severe with it off that he has moderate difficulty turning the machine back on after he had switched it off. But, before we go into detail about how that machine and other treatments for Parkinson’s work, we should first understand the disease itself and what exactly is going on in the body to cause its symptoms.

The disease itself is caused when the dopamine producing neurons in an area of the brain known as the substantia nigra begin to die. Past posts and some sources below detail the role of dopamine in the brain, so please refer back to those if you are not familiar (here). The exact reason(s) for this premature death is unknown, but evidence supports excessive oxidative stress and the inappropriate collection of certain proteins (alpha-synulcein bundles known as Lewy bodies, for the curious) in these neurons and to a lesser extent throughout the brain. In certain cases there is also a genetic cause, but for a majority of people the cause is idiopathic (without a known source).

Regardless of the reason(s) behind it, damage to the dopamine producing cells in the substantia nigra has a wide ranging effect on the body. Chief among them is parkinsonism, which is the specific name for the motor (movement) issues most visible in Parkinson’s patients. The motor issues are mainly divided into tremor, rigidity, slowness, and postural issues. Tremor is the familiar shakiness, which more often happens when not moving (resting tremor). Rigidity can come in multiple forms, but basically means the muscle is hyperactive, making it harder to move fluidly or with normal ease. Slowness is what it sounds like, preventing rapid execution of movements. Slowness is especially visible in fine motor movements, making these activities difficult since they often require multiple actions to be executed quickly and successively. Postural issues are present in more advanced stages of the disease, resulting in balance issues and frequent falls.

Beyond the motor issues, Parkinson’s can result in a whole host of issues that vary from person to person. The most common issues associated with advanced Parkinson’s are cognitive issues (ie. slowed thought, speech issues, memory issues), psychiatric issues (ie. depression, anxiety, hallucinations), and dementia. It is thought that the accumulation of the Lewy bodies mentioned earlier contribute to this loss of function. As such, these issues tend to present much later in Parkinson’s patients because it takes time for these elements to accumulate and interfere with function.

Because the symptoms of Parkinson’s are generated largely by loss of dopamine production, the logical treatment would be to try to replace that dopamine. In fact, that is exactly what the main treatment for Parkinson’s does. Known as Levodopa, this drug is converted to dopamine in the body and can increase the concentration of available dopamine in the brain. It can have significant side effects because it can also be converted to dopamine outside the brain. This peripheral dopamine can have a whole host of effects on nerves, leading to inappropriate nerve activity. To combat this, it is usually administered alongside a drug that prevents this conversion outside the brain but allows it to occur within the brain (by not being able to cross the blood-brain barrier). Even with this concurrent drugs,  levodopa can still cause disabling side effects. Ironically, the most common are dyskinesias, or involuntary movements. Other drugs exist, but with varying degrees of effectiveness and still largely have a poor side effect profile. However, on the whole these drugs only mask the symptoms. As of now, no drug in clinical use has been shown to stop progression, though some recent compounds and genetic targets (1, 2, 3) have shown promise by a variety of mechanisms.

But, what if the symptom controlling drugs cause too many side effects, don’t last long enough, or otherwise don’t work? What if a more permanent solution is needed? Enter deep brain stimulation (DBS). As you saw in the video, deep brain stimulation can be tremendously effective in regulating the motor symptoms of Parkinson’s. DBS does this by using electrical signals to block out the errant motor signals generated in the Parkinson’s affected brain. Electrodes are placed in certain parts of the brain (specifically ventral intermediate nucleus, globus pallidus, and subthalamic nucleus) and transmit their signal directly into these areas. All of these areas are involved with some portion of motor control, though the specifics are not important in this context. Despite blocking the erroneous Parkinson’s motor signals in these areas, normal motor signals can still be processed. Think of it like a freeway where a drunk driver is swerving across the road, disrupting all of the normal traffic. Once that driver is removed from the road, traffic can resume as normal. The result of DBS is a much smoother overall motor control and significant reduction of the tremors, slowness, rigidity, and posture control issues. The drawback is that DBS involves open brain surgery and implantation of foreign bodies deep into the brain. Thus it is not considered the primary treatment for Parkinson’s patients. Hopefully in the future a similar technology can be created that involves a much less invasive procedure, allowing it to be a primary treatment option for those with progressive symptoms. Until then, drug therapy continues to be the most widely used treatment for the symptoms of Parkinson’s disease.

Hope this helps, Alex! As always, thank you for the question. If you want to submit your own, feel free to do so at the top link.

Till next time,

Justin

Sources:

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.sciencemag.org.libproxy.usc.edu/content/302/5646/819.short

http://www.psychologytoday.com/basics/dopamine

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Medications-for-Motor-Symptoms-of-PD/Carbidopa-levodopa

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm

http://www.nlm.nih.gov/medlineplus/ency/imagepages/19515.htm

http://www.mayoclinic.com/health/parkinsons-disease/DS00295

http://www.nejm.org/doi/full/10.1056/NEJMct1208070

http://www.neurology.org/content/61/7/919.abstract

http://www.ncbi.nlm.nih.gov/pubmed/11801431

http://www.ncbi.nlm.nih.gov/pubmed/22772329

http://brain.oxfordjournals.org/content/127/1/4.full.pdf

Study Drugs: Pills to Supercharge The Brain?

studying-boh

We have officially reached 1500 views! Thank you to everyone who has taken the time to read this blog so far. Truly appreciate the support.

This week’s question comes from Joe, who asks “I’ve heard of certain medications, like Adderall and Provigil, that give people a tremendous boost in focus and work ability. Provigil is especially becoming popular with the Wall Street types. How do these drugs work and are there any major negative side effects?”

I think most people have heard of stimulants becoming popular with the big city finance types, starting with cocaine in the 80’s and moving to more sophisticated pharmaceuticals like these as the years progressed. More recently, these types of drugs have become popular with otherwise normal college and even high school students looking to get more done in less time. The military has been using pills like this to keep pilots and other essential personnel awake for days at a time since the early 20th century.

Before we start, one comment: contrary to what some people may believe, no pills as of yet actually make you “smarter” or otherwise enhance your pre-existing function. What they actually do is alter your perception of reality, directly in the brain and/or by systemically suppressing signals of fatigue. The same ability is present no matter what you take, just the drugs can temporarily ease the natural feelings of fatigue that would ordinarily hold back full function.

So to answer the question generally, we can split the drugs into two basic categories. The first category, which most people are familiar with, are stimulants. Stimulants are defined as any chemical that temporarily increases physiological function. Obviously this is a very wide definition that can apply to a wide variety of things. Some drugs we encounter every day are weaker stimulants, like nicotine, than others, like caffeine. Many stimulants are illegal, like cocaine and methamphetamine. Stimulants can and often do cause addiction. Likely the strongest widely available class of stimulants are amphetamines. Adderall is actually a mix of two different types of amphetamine salts, amphetamine and dextroamphetamine. Lets explore how amphetamines work in more detail.

Amphetamines function by causing a large rise in the levels of dopamine and norepinephrine in the brain and prevent their reuptake, allowing these chemicals to continue to exert influence longer than normal. The specifics of this action are not important to this discussion but are described very well in this article. We have already talked about the function of norepinephrine in the brain (here), so I won’t repeat myself. Take a peek at that other article if you need a refresher.

The changes in dopamine are also tremendously important. Dopamine is a neurotransmitter in the brain responsible for a wide variety of functions. One major function is control/ heavy influence over the reward and alertness centers of the brain. So when a substance causes a major release of dopamine, one effect is you feel really good, have a very positive mood, and are very alert. MDMA, the active ingredient in the drug ecstasy, exerts its influence largely by this mechanism (it also happens to be an amphetamine). This is also where amphetamines give us the ability to remain awake. High levels of dopamine can also have an impact on higher level brain functions such as motor control, causing abnormally high motor activity and low threshold for movement. This is possibly the source of the “jitters” people get when they take dopamine releasing drugs like amphetamines. It is also the reason movement is so difficult with Parkinson’s Disease, as the dopamine producing center of the brain is damaged and dopamine levels are lower than normal.

As you might imagine, amphetamines are incredibly addictive due largely to their reward center influencing mechanism of action. They also have negative side effects such as appetite suppression that can cause longer term health effects if left unchecked. As such, their use should be limited only to those instances where their value outweighs the cost.

The second category of drugs are non-stimulants. These are drugs that seek to mimic the individual effects of the stimulant drugs without similar side effects, including addiction potential. For the treatment of ADHD, sometimes SNRIs (selection norepinephrine reputake inhibitors) are used as an alternative method to amphetamines. This seeks to produce the increase in norepinephrine found in amphetamine medication without the associated addiction potential from dopamine-related activity.

The drug you mentioned, Provigil, attempts to do a similar thing by influencing dopamine levels without a massive increase all at once. By upticking the dopamine transporters in the brain, the levels are increased more gradually and causes the desired alertness without the dose of euphoria that underlies the addictive nature of amphetamines and other stimulants. Mind you, amphetamines do a similar thing, but they also cause a massive release and prevent reuptake so it is likely that transporter alteration is the least negative of the three effects. It also has an impact on norepinephrine, serotonin, and histamine levels in various areas of the brain through its impact on neurons in the hypothalamus, though this effect is much less well understood. However, unlike amphetamines, it seems to have some potential for real cognitive enhancement. There have been basic studies that show some value to this end, and as such this drugs and future drugs like it may actually start to approach a “brain pill” rather than simply tricking your body into not being fatigued.

On the face of it, Provigil seems to work for its intended purpose and is well tolerated, however its full mechanism of action is not well understood. Based on its known mechanism of action, it is likely much less addictive than amphetamines and other stimulants. However, because it is also much less well understood it is something that should also be treated with caution and used only as indicated/prescribed.

In sum, these different types of drugs often work as marketed, but each has their own positives and negatives. You should only use these drugs under the regular care of a physician who prescribes them to you for a legitimate condition. But, should you decide to obtain them outside of that, I would advise you tread carefully. While they may seem innocent at the time and certainly useful in many contexts, you may be making a deal with the devil in the process. There are much more beneficial methods of increasing alertness (exercise, meditation, etc.) than taking a potentially dangerous pill. I would suggest trying those before jumping to a pharmaceutical solution.

Hope this helps, Joe! Thank you for the question. As always, feel free to submit questions to me directly at the link above.

Till next time, tread lightly.

Justin

Sources:

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/S0301008205000432

http://psycnet.apa.org.libproxy.usc.edu/index.cfm?fa=search.displayrecord&uid=1998-10330-005

http://journals.lww.com.libproxy.usc.edu/jonmd/Citation/1961/12000/Amphetamine_Addiction.3.aspx

http://pharmrev.aspetjournals.org.libproxy.usc.edu/content/14/1/1.short

http://www.cnsforum.com/imagebank/item/Drug_amphet_high/default.aspx

http://europepmc.org.libproxy.usc.edu/abstract/MED/10505821

http://psycnet.apa.org.libproxy.usc.edu/index.cfm?fa=search.displayrecord&uid=2004-14364-011

http://www-ncbi-nlm-nih-gov.libproxy.usc.edu/pubmed/0007701191

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/0278584688900140

http://www.medscape.org/viewarticle/739491

http://www.pnas.org/content/102/9/3495

http://www.ncbi.nlm.nih.gov/pubmed/7751968

http://www.ncbi.nlm.nih.gov/pubmed/16497598