More on neuroplasticity

Neuroplasticity: how our brains re-wire.

Researchers have now shown that long-term changes affect the brain even after drug use has ceased. This concept is especially important in light of the revolutionary idea of neuroplasticity, a conception that has overtaken the field of neuroscience in recent years. The overarching concept of neuroplasticity is that our brains are constantly changing and evolving. Whereas scientists in the field once believed that we were born with all of the brain cells that we would have in our entire life, we now understand that neurons are able to regenerate, and even more importantly, that our brain circuits are able to rewire as a result of experience.  Evidence from research of the past two decades offers support for this theory. Thompson showed that patients suffering from aphasia as a result of brain injury were able to regain linguistic functioning by recruiting new areas of the brain that were not typically central to speech contribution to play a key role in language.[1] Melzack et al. showed that human perception of pain is at least partially the result of past experience that causes the brain to rewire following painful stimuli.[2]

However, evidence in favor of neuroplasticity may seem contradictory in light of the argument that drugs have a long-term effect on the brain. After all, if the brain has the ability to change so much, doesn’t this mean that it will recover from any damage that is caused by drug use? Not necessarily. While the brain is able to recover from some degree of insult, the mechanism that causes drug users to experience a euphoric event is also involved in the long-term changes that result from such abuse. According to Uys and Reissner (Glutamatergic Neuroplasticity in Cocaine Addiction, Progress in Molecular Biology and Translational Science. Vol 98. 2011) despite the fact that initially, drugs such as cocaine activate the dopaminergic pleasure system, long term use of drugs causes the brain to recruit new areas to play a role in the mechanism. The authors state:

Over time and with chronic exposure, other structures involving glutamatergic and GABAergic transmission and the brain stress systems are subsequently recruited in latter stages of addiction. For example, key glutamatergic projections are sent from the [pre-frontal cortex], amygdala, and hippocampus, and GABAergic projections are sent from medium spiny neurons of the [nucleus accumbens] core and shell to the vental pallidum and back to the [ventral tegemental area] (371).  

This statement is central to the concept of addiction. Although the individual may enjoy the first time that he or she uses a given drug and may have a strong desire to use the substance again, the real consequences of addiction usually occur as a result of chronic use. This is at least partially due to the rewiring of the pleasure circuits in the brain. However, arguing that using drugs a single time is safe, given the fact that re-wiring cannot occur on the first exposure, is naïve. Although it may take a number of times to do irreparable remodeling of neurocircuitry, it seems clear that the long term changes that occur are not worth the pleasure that may result. Uys and Reissner offer support for this claim, stating, “Long-term potentiation is observed early in the VTA, following acute exposure to drugs of abuse. This LTP lasts at least 5 days following a single drug exposure” (373).

For more on neuroplasticity, see another post.

Great book on neuroplasticity.

---

[1] Thompson, C. K. (2000). Neuroplasticity: Evidence from aphasia. J. Commun. Disord., 33, 357-366.

[2] Melzack, R., Coderre, T. J., Katz, J., & Vaccarino, A.L. (2001). Central neuroplasticity and pathological pain. Annals of the New York Academy of Sciences. 933, 157-174.

"What is the most addictive drug?"-- This and other thoughts on defining addiction

Although the consequences of using and difficulty to rehabilitate from a substance depend on many factors, including frequency and amount of time of use, the drug of choice must be considered. Drugs of abuse include, but are not limited to, marijuana, cocaine, methamphetamine, MDMA (or ecstasy), so-called “club drugs” (GHB, Ketamine, and Rophynol), LSD, phencyclidine, mescaline, heroin, opium, inhalants, anabolic steroids, and prescription drugs such as benzodiazepines and opiates pain medications. According to a 1990-1992 study from the National Comorbidity Survey, it was estimated that among 15-54 year-olds, the most commonly abused illicit drug was marijuana, with 46.3% of individuals responding affirmatively when asked if they had ever used a given substance. However, among users of any given drug, the drug with the highest percentage of dependence among individuals was heroin, with 23.1% of users dependent on the substance.

Before being able to pin down addiction, as defined for a given illicit drug, it is important to define addiction. While individuals disagree about the exact meaning of “addiction” the DSM-IV-TR defines substance abuse, which is the precursor to any form of addiction, as:

A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period:

1.     Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions or expulsions from school; neglect of children or household)

2.     Recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use)

3.     Recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct

4.     Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights)

B. The symptoms have never met the criteria for Substance

             Dependence for this class of substance.

Individual drug addictions, referred to by the DSM, as “dependence” are similar among various substance types despite small differences for a given drug. An example is seen in classification of opioid dependency:

            1. A strong desire or sense of compulsion to take the drug;

2. Difficulties in controlling drug-taking behavior in terms of its onset, termination, or levels of use;

3. A physiological withdrawal state when drug use is stopped or reduced, as evidenced by: the characteristic withdrawal syndrome for the substance; or use of the same (or a closely related) substance with the intention of relieving or avoiding withdrawal symptoms;

4. Evidence of tolerance, such that increased doses of the drug are required in order to achieve effects originally produced by lower doses;

5. Progressive neglect of alternative pleasures or interests because of drug use, increased amount of time necessary to obtain or take the drug or to recover from its effects;

6. Persisting with drug use despite clear evidence of overtly harmful consequences, such as harm to the liver, depressive mood states or impairment of cognitive functioning.

The DSM’s sixth point is important, especially for researchers who study drug addiction. Individuals who have a drug addiction are usually aware that their lifestyle choices have negative effects; however, their choice to use the drug despite such consequences is one of the primary characteristics of an addiction. What leads people to continue to intake substances that causes obvious self-harm?

How do rats become addicted to cocaine?

Cocaine

You guessed it: Cocaine.

The title says it all. Sure, people might do cocaine for a variety of reasons, such as availability, curiosity, or for social acceptance within a group of peers that uses the substance. In my post from Wednesday, I discussed the effects of cocaine on the brain, and the changes that occur as a result of using the drug. Today I want to discuss how rats in a lab "do" cocaine, since it's clear they can't do this:

So here is the deal. If you know anything about or operant conditioning, then you will follow what I am about to describe. If you are not familiar with operant conditioning, here is a good link for a refresher course on behaviorism. Operant Conditioning

First, rats are not given food for approximately one day, so that they will be hungry when first placed in the operant box for what we call "food training." Here is a picture of the operant box:

A lever is extended out from both sides, but only one side actually does anything. Here, we are saying that is the right side. So, the rat is curious and moving about in the cage, and presses the lever on the right side. A light comes on above the lever, a tone sounds, and most importantly, he is rewarded by a pellet of food that is released for him. He thinks to himself how cool that was, and tries it again on the left side. No such luck. Tries the right side again, and sure enough: a pellet of food is released following the tone and light paired cue.

The rat spends 15 hours in the operant box, which is enough time (for most rats) to put two and two together, thus realizing that pressing the right lever results in a reward.

Okay, so he realizes that the right lever equates to a reward. What does this have to do with drug administration? I'm getting there.

The rat has a catheter on its back, which looks like a backpack. Here is a similar, but not exact design:

[I'm getting a little ahead of myself, but as an FYI, in many cases, the rat also has a cannula on its brain, so that after it is killed, the investigator is able to examine the brain histology.]

The rat has a catheter that is hooked up to an infusion pump that is filled with cocaine.

It is similar to the above picture, but that the levers are still present, and the rat only receives an infusion of cocaine when he presses the right lever. Once again, a light and a tone are cues that come on as the infusion of cocaine is being delivered. 

Most of the rats end up liking the infusion, and thus, continue to press the lever and receive more cocaine. I should note that there are certain precautionary measures that are placed to keep the rat from overdosing on the cocaine. For example, after receiving one infusion, the rat has to wait 30 seconds before it is able to get another "hit." Even if the rat presses the lever during this "time out" period, there will be no drug administered. Also, after receiving a certain amount of infusions per session the rat is cut off. As my mentor Kate says, "The party's over." This keeps them from having a cocaine hangover, and thus generating a negative response to the drug. Having an aversive effect to cocaine would hinder the animal in its later cocaine sessions, and as a result, he would not be very enticed to try the drug at a later time.