Cocaine and the Brain: The Neurobiology of Addiction
Christine FarrenkopfIn the eyes of the public, the word addict stirs up a negative image: a person of low moral character who willfully chooses to engage in questionable behavior. This image is perpetuated in the media; on a recent episode of E.R., the chief surgeon criticizes another doctor for allowing a heroin addict (who has been treated for an abscess) to exchange a dirty needle, explaining "we donât want these low-lives hanging around the hospital." The social stigma attached to addicts reflects the great gap that exists between scientific knowledge and public perception of addiction. Just as mental illness was viewed as a social problem instead of a medical issue until the last several decades, drug addiction continues to be seen as a character flaw instead of as the biological problem that it is.
As defined by the American Psychiatric Association, addiction is a "chronically relapsing disorder that is characterized by three major elements: (a) compulsion to seek and take the drug, (b) loss of control in limiting intake, and (c) emergence of a negative emotional state when access to the drug is prevented" (1) . This disorder results from the repeated use of a drug over a prolonged period of time, causing physical changes in the brain.
Perhaps the most addictive of drugs is cocaine. Cocaine acts on the mesoaccumbens dopamine (DA) pathway of the midbrain, extending from the ventral tegumental area (VTA) to the nucleus accumbens (NAc). (2) . This pathway is also known as the reward pathway as it is the area of the brain that is activated when someone has a pleasurable experience such as eating, sex, or receiving praise. (NOTE: The reward pathway was discovered through the technique of intracranial self-stimulation (ICSS) (3, p.53). An electrode was implanted in different areas of the brains of rats and was activated when the rats voluntarily pressed a lever. Stimulation in most sites in the brain was not reinforcing (ie, the rats did not regularly activate the electrode), but one site in particular was reinforcing: the reward pathway. Because of the positive effects felt when this pathway is stimulated, such behavior is reinforced.
In the DA pathway of a normal person, a transmitting neuron releases dopamine (a neurotransmitter), which then binds to dopamine receptors on the receiving neuron; an action potential is then propagated in the receiving neuron. (4) . After this has occurred, the dopamine reuptake transporters (DATs) of the transmitting cell pump the dopamine back into the cell to be used again.
Cocaine binds to the dopamine reuptake transporters, thus blocking them from functioning. (See web reference (5) . for an animation of this process.) As a result, dopamine levels increase in the synapse, and consequently, the receiving neuron is continuously stimulated. This constant firing of the neurons leads to a feeling of euphoria. In addicts, cocaine blocks between 60 and 77 percent of the DAT binding sites; in order to attain a "high," at least 47 percent of the binding sites must be blocked by cocaine. (6) .
Cocaine also acts on the reuptake transporters of serotonin and norepinephrine, and therefore, the levels of these neurotransmitters are also increased. (2) . Serotonin plays a role similar to dopamine in the DA pathway. Norepinephrine stimulates the "fight or flight" response of the sympathetic nervous system characterized by heightened heart rate, blood pressure, respiration rate, and body temperature as well as dilation of pupils and sweating; these phenomena produce an energizing feeling (7) . p.103.
At a certain point, cocaine usage ceases to be a voluntary action: this is the onset of addiction. The positive reinforcement of the sensation of euphoria eventually alters the brain so that the use of cocaine is obligatory. Animal models have been used to demonstrate such positive reinforcement (8)  p.1262-4. Lab rats were fitted with long-term intravenous catheters and were taught how to self-administer doses of cocaine by pressing a lever. The fact that the rats continued to self-administer cocaine demonstrates the desire of the rats to be under the influence of the drug. In addition, there is a correlation between the level of the dose of cocaine and the number of infusions a rat would give itself: the lower the dosage, the smaller the gap in-between self-administrations. This indicates that the rat is aware of the level of cocaine in its system and its desire to maintain that level through subsequent injections of the drug. These experiments demonstrate the "compulsion to seek and take the drug" aspect of the definition of addiction.
Another factor in the reinforcement of cocaine use lies in the fact that after cocaine administration, dopamine levels fall significantly below normal, pre-consumption levels (8)  p.1272. The user therefore feels a "low," and the immediate response to alleviate this low is to take another hit of cocaine to again raise the level. Such behavior is referred to as a "binge," when a user continuously takes hits of cocaine to recover from ensuing lows (3)  p.158. This demonstrates the "loss of control in limiting intake" aspect of the definition of addiction.
Recent research has shown that reinforcement is also linked to cocaineâs ability to act on genetic material: it activates the gene that codes for the protein delta-FosB (whose levels are elevated in addicts) (9) . This protein in turn activates the gene that produces a component of glutamate receptors (GluR2), which binds the neurotransmitter glutamate. An increase in GluR2 production has been shown to increase sensitivity to cocaineâs rewarding effects.
Over a long period of usage, the brain responds to the above-normal levels of dopamine that are present during a hit. The main manifestation is a reduction in the number of dopamine receptors on the dendrites of neurons (10) .; if there are fewer receptors, then there will be less stimulation of the nerves in the DA pathway. This demonstrates how the brain of an addict is physically different from that of a normal person.
Due to this physical change in the brain, an addict will respond differently to a particular dosage of cocaine. Tolerance develops in many addicts, wherein a larger dosage is needed to attain the same high that a user initially experienced (11, p.38) . Sensitization may develop instead, wherein a user becomes more responsive to cocaine without increasing the dose (12) . The biological mechanisms behind these two phenomena are not completely understood. There is evidence that whether tolerance or sensitization develops depends at least in part on the manner in which cocaine is delivered to the body: if cocaine is taken in spaced out intervals, sensitization results; if cocaine is taken continuously through an IV or through closely spaced injections, tolerance results (13) . (14) .
Because of the altered physiological state of the brain, events that previously caused stimulation of the DA pathway (pleasurable experiences other than cocaine use) no longer do; only cocaine can induce the feeling of happiness. When an addict ceases taking cocaine, he has no source of stimulation of the DA pathway and therefore experiences severe depression, irritability, and anxiety (symptoms that are opposite of the effects of the drug) (8)  p.1271. (This is the "emergence of a negative emotional state when access to the drug is prevented" aspect of the definition of addiction.) Other factors also contribute to the negative behavior associated with withdrawal. For example, tests in lab animals have shown that levels of coricotropin releasing factor (CRF), which induces stress, rise while in withdrawal (8)  p.1273.
With repeated drug use comes a phenomenon known as place conditioning, wherein particular places and cues become associated with cocaine use (15) . Experiments using lab rats support such a conclusion (8)  p.1267. Two distinct neutral environments are set up, one of which is paired with cocaine and the other with a placebo. When the rats are allowed to freely roam between the two environments after experiencing both the cocaine and placebo, we find that they choose to spend more time in the environment where they were given cocaine. This demonstrates that the drug comes to be associated with a certain place.
The road to recovery from cocaine addiction is a long one, particularly because a patient must struggle to overcome the odds of relapse: approximately half of recovering patients succumb to relapse within a year of detoxification (16) .
The negative emotional state that results from cocaine withdrawal often causes patients to begin using the drug again. The challenge is to withstand the urge to use the drug during the time when the body "resets" the DA pathway (ie, more dopamine receptors will be activated due to the low levels of synaptic dopamine, which in turn will allow activities other than cocaine use to stimulate the reward pathway). Studies have shown that numbers of dopamine receptors will never return to pre-cocaine use levels.
Because addicts grow to associate certain places and cues with cocaine use, exposure to such stimuli may cause a relapse once an addict has "quit" (17) . If reminded of an event linked with cocaine use (such as passing by a place where one formerly used the drug or watching people smoke crack), a recovering addict will very likely feel a strong craving (10) . Such a reaction to these memory-based stimuli raises the question of how long memories are able to induce a response. Recent research has shown relapses in lab rats even after four months of abstinence (17) .
There is no well-established treatment plan for cocaine addiction, but the most effective measures are to combine a medicine with drug counseling. Drugs such as vigabatrin are being developed that seek to reduce the pleasure of a cocaine hit (this drug stops cocaine from increasing dopamine levels in the DA pathway and prevents subjects from developing place/cue associations in baboons) (18) . Anti-depressants are often prescribed to alleviate the negative behavior of withdrawal. New research is concentrating on neutralizing cocaine in the bloodstream so that it is unable to affect the DA pathway (18) . While medications are an important part of the recovery process, counseling also plays a seminal role as the patient must learn to resist the urge to use cocaine. Group and individual therapy sessions aid patients in coming to terms with their problem and building up self-confidence (19) . Cocaine-specific skills training (CST) teaches patients to identify the places and cues that cause them to feel cravings; they then seek to avoid or adjust their reactions to such stimuli (20) .
Viewing cocaine addiction as a chronically relapsing disease of the brain is a new concept for much of the public. Such scientific evidence forces people to re-evaluate their views of addicts (in particular the stereotypes associated with them) as it demonstrates that an addict must be recognized as someone with an altered brain state, just as someone with a mental illness or Alzheimerâs (15) . Addicts cannot be cured through incarceration; instead, the process of recovery requires both counseling and medication. In fact, the lasting biological effects of cocaine addiction are so far-reaching that rehabilitators often comment that there is no way to "cure" someone of cocaine addiction - - one can only learn how to live with it.
WWW Sources1) The Neuroscience of Addiction, Research article on mechanisms of addiction
2) Addiction to Cocaine and Amphetamine , Research article on mechanisms of cocaine addiction
3) Addiction: From Biology to Public Policy Goldstein, Avram, M.D. Addiction: From Biology to Public Policy. New York: W.H. Freeman and Company, 1994., In-depth discussion of biological aspects (in addition to social aspects) of addiction, appropriate for undergrads
4) Cocaineâs Pleasurable Effects May Involve Multiple Chemical Sites , Description of cocaineâs effects at the neuronal level
6) Brain Scans Open Window to View Cocaineâs Effects on the Brain , Research on dopamine reuptake transporters
9) Scientists Identify Brain Chemicals Involved in "Switching On" Cocaine Addiction, , How cocaine affects our genes
10) How It All Starts Inside Your Brain , Article on biological mechanisms of addiction, appropriate for the layman
12) National Institute on Drug Abuse Research Report: Cocaine Abuse and Addiction , Good source of all aspects of cocaine and addiction
13) Addiction, Dopamine, and the Molecular Mechanisms of Memory , Research article on addiction
14) Addiction Becomes a Brain Disease , Scientific research on mechanisms of addiction
15) Addiction is a Brain Disease, and It Matters , Written by the director of the Nation Institute on Drug Abuse on addiction
16) Treatment: New Ways to Stay Clean , general article on drug treatment
17) Study Sheds Light on Cocaine Relapse , short article on cue-induced relapse
18) Seeking Ways to Crack Cocaine Addiction , Article discusses medications being developed to help overcome cocaine addiction
19) Combining Drug Counseling Methods Proves Effective in Treating Cocaine Addiction , Information on drug counseling
20) Coping Skills Help Patients Recognize and Resist the Urge to Use Cocaine , Information on therapy for cue-induced relapse
01/01/2006, from a Reader on the Web
A recent family member just arrived home after spending 30 days at Hazelden, which teaches the addict and the family that Cocaine addiction is a disease and not a question of will power. As a result, I began my research online and saw your article. You seem to state the same thing but I disagree with your conclusion, as I disagree with Hazelden's philosophy. Your paper did not prove that addiction is a biological disease, it only explains what happens when someone becomes addicted to cocain in a scientific manner. A disease is an illness that people don't have a control over, an illness that people don't invite into their lives. Your papers states that addiction becomes a disease after a period and intensity of use. How can that be an illnesss when you cause the condition? You are causing the problem. If a football atheletes perpetually hurts his back from the sport and has permanent back pain, is that a disease or a chronic pain? Your paper also states that to cure the addiction, an addict must resist the temptation and go through counseling and rebuild self esteem. That is will power, determination and control. How can you conclude that addiction is a disease then? I truly would appreciate a response back. I have an issue with this claim. I feel that to give an addict such reasonings is to tell them that they are not in control and that if relapse or death happens, it is the fault of the disease. That is misguidance in my view. An addict should be held responsible for his or her action and recognize their weaknesses and failures so that they can truly work on their problem. Thank you.
so, is cocaine addiction,in the same category as,someone with ms or me, thats what i would think you were trying to say, these are also diseases, but people with these diseases didnt choose to have them, a cocaine addict made their choice on their first lesson of taking the drug.enough said ... Wendy Pearce, 18 February 2006
Serendip you do not understand what the word addiction means. Your example about back pain makes no sense. No one wakes up or is born intrinsically addicted to alcohol, porn, or cocaine. You have to experience a thing to become addicted. If you want to blame someone for that initial experience than that is a different story from telling someone it is their fault they are "addicted" Addiction is a biological and frequently psychological state, the brain transmitter chemistry has changed such that a person is completely driven to get the 'high' created by that drug. There is no matter of "willpower," their brain is telling them without the drug they will die. Addicts do not have control over that urge, it has become a chemical force of nature in their brain. Relapse itself even cannot always be considered willpower since the 'once addict' still has that wiring in their brain to tell them to get high. It is a very powerful force and not one that is easily overcome, and really only something that an addict can truly understand. Fortuntalely there is help for addicts beyond willpower, like using methadone maintenance to wean someone from the need for cocaine, but the road is long and hard regardless ... Reader on the web, 2 April 2006
Hi, just read your page, very interesting and very helpful. I have lived with an addict who injects cocaine. I have seen what has happened to a once lovely person and the effects his addiction has had on us innocent bystanders. He did this to himself, we didn't ask for him to inflict the misery on to us too. It is a self inflicted addiction not disease. My father is an alcoholic! His behaviour patterns are similar to my ex-husbands but neither has a disease. Addiction is not disease in the sense that my non-smoking healthy living grandfather, who died of lung cancer had. I am still very bitter towards my ex I must admit and so my empathy for addiction is low so maybe I am not looking objectively at your page, but addicts not only abuse themselves but those who love them. The Hep C he contracted using shared needles is a disease! ... Karon, 3 April 2006
I am responding to someone's response to the article on cocaine addiction. S/he states: "A disease is an illness that people don't have a control over, an illness that people don't invite into their lives," and then suggests that since becoming addicted has to do with choices the addict makes, it isn't really a disease; that treating it as if it were a disease somehow prevents the addict from being "held responsible for his or her action" -- that addicts must "recognize their weaknesses and failures so that they can truly work on their problem." Cocaine and the Brain: The Neurobiology of Ad... Reality is more complex than yes-no, black-white, or a disease-personal weakness dichotomy. Addiction is a coping mechanism, with, as both the article and responder point out, a scientific, biochemical neurological basis. And with the notable exception of crack babies, few addicts are born addicted. But addiction is a disease nonetheless, a social disease. Unfortunately, for some who survive the trauma of dysfunctional childhoods with repeated physical and emotional abuse, a drug induced 'feel good' may be the only joy they have ever known. Physiological and psychological addiction take over, and it will take community support, counseling, drug therapy and yes, individual will power, to break free. But the abused child who grows up to be a drug addict doesn't invite or choose the abuse. The disease model is closer to the truth of the cause of addiction -- a toxic social environment with multiple dysfunctional experiences. And like any other disease, some people are naturally more or less susceptible to addiction -- not everyone who grows up under socially adverse conditions becomes an addict, and some who seemingly have had ideal environments do get hooked. But just because the etiology is not bacterial or viral or genetic is no reason to circumscribe the paradigm of addiction to 'bad choices' or 'not enough will power'. The problem won't get solved without looking at the whole picture of causation, and the disease model holds the promise of bringing light, without heat, to this war zone ... Judy Brody, 14 April 2006
I am a cocaine addict. My choice is rock cocaine. I have been clean for a week and a half, and it is hard. Hard to sleep, i dream of smoking it. I get shaky and want it so much. I am not in any treatment plan or on any anti-depressant drugs. I have no job at the moment and no money. That is the only reason i am clean. I try to think of other ways to get high and can't. I am so uncomfortable in my own skin. I think of ways to kill myself and came close. I know the affects and that it is a serious thing, but i want it. I just don't care any more. I have been going through some serious withdrawl and i know if given the chance i will do it again. I do wish i would have never started. I don't know why i am typing this, i guess because i have no one to talk to. I am in pain and there isn't anything i can do ... Laura, 10 May 2006
I have been using for about half a year; my use escalated when I realized it helped me - or so I thought - stay sharp and alert on the job. I deejay overnights at an easy listening radio station.
I am scared and confused-- I came out to some members of my family when my use started getting out of control.
I curse the day I ever started using. I would like someone - anyone who is dealing with the same problem - to email me; perhaps (in addition to NA meetings) we could help each other deal with this.
My friends who don't use aren't talking to me much anymore.
Please help; I hope I can return the favor ... Ben, 29 May 2006
I think that your article made a lot of sense. I am trying to figure out how to deal with my fiance/ father of my child's addiction to cocaine. I have been with him for 3 yrs and I have recently found out that he had had a previous problem with it and was using it again. In fact, you broke down the process of cocaine addiction so well that I feel the need to leave him. I can't deal with the lifetime resposibility of having a cocaine addict with a permanently altered brain state as a partner. He will never be the same ... Krystle, 31 May 2006
I agree with the comments the last writer shared. I have a thiry year old son who feels smoking pot is OK. After all it's not crack/cocaine or heroin. Well he graduated to the former. I never really thought it was that powerful addiction unless you were using it. I don't agree that is really biological if you conciously choose to smoke it. I do believe it's a lot about self esteem and caring about yourself. My son was in a terrible auto accident in January and almost died. He was the passenger in the car of someone who had smoked crack the whole weekend prior to the accident. For six weeks I sat by his bedside praying he wouldn't die. Then he miraculously lives and ends up on my doorstep telling me he has been on a crack run for the past two months.
What to do? ... Reader on the web, 4 June 2006
In most academic institutions, my premise is akin to intellectual suicide. Society and science today probably finds my stance as laughable, yet the men and women upon whom this country (America) was founded would not be blind to the wisdom. Drug addiction, as well as alcohol and pornography addiction, are simply attributable to our human nature. The bible calls it "sin," yet we can't have that today, now can we? The Old Testament called it "idolatry" and today we call it "addiction." Christ died for us all and gave us a means whereby we can gain strength and the power to overcome. For us to think we might escape the claws of coccaine on our own is folly. A loving God really does care. (1 Corinthians 10:13): "No temptation has seized you except what is common to man. And God is faithful; He will not let you be tempted beyond what you can bear. But when you are tempted, He will also provide a way out so that you can stand up under it." I know this may sound like the crazy talk of a religious zealot, yet God is real... and He really does want us to go to Him for help. Coccaine and all ... Frank Zedar, 10 June 2006
I would like to respond to the reader that stated Cocaine addiction is not a disease because the individual's chosen actions brought it about. If this were true, then most Diabetes, heart disease and Cancer are also NOT disease, as lifestyle factors (smoking, lack of exercise, etc) predispose an individual to these illnesses.
It is already a crime to obtain, own and use cocaine. Adding more blame on the addict may make you feel justified, but it does nothing to resolve this problem. Every addict also has blameless family and friends who are victimized. To search actively for this brain altering disease's treatment should be a priority; leave the blame game to the courts ... Bonnie Clancy, 27 September 2006
The mayor of Bridgeport, John Fabrizi, was exposed as a Coacine addict when the FBI was conducting an investigation on corruption in Bridgeport, and inadvertingly revealed the info on Fabrizi which the Feds didn't intend to divulge at that point in time. The mayor says he is off Cocaine and cured and is taking treatments or something to that effect. Connecticut Post, the leading newspaper in the area, conducted a series of interviews and tests on the mayor, which the mayor agreed to and reported that the mayor had no signs of being on Cocaine.
I knew a drug addict who was addicted to drugs and his wife threatened to leave him unless he went for rehabilatation. He went and kept getting high marks for recovering from drug addiction, but he confided to me that he was still on drugs and was able to fool all the experts. Is this possible?
Is it possible that a mayor of a city of some 200,000 people or the largest city in Connecticut can govern and make decision coherently. Can the mayor properly govern? Could he have fooled Conn. Post the same way the above mentioned addict fooled his wife and even his doctors? ... George Mougios, 24 November 2006
i found the aricle interesting and learned a lot about what the drug can to do the bis handrain as a recovering alcoholic sober for six years i can appriciate the info as i live with and am married to what was a closet coke addict, just since christmas of this year did things get really out of control, our kids and myself are homeless and struggling to make it while he is working a great job and staying out every time there is a dime in hiack... s hand i am at wits end i love him to death but need to know what kind of meds would work for himif any he really needs an out as do i and the kids we want our family back, thanks ... Judi Lamb, 8 June 2007
I found your article extremely in depth. Comprehenable. It is unfortunate that in with all the information that we have that addiction is still so widely misunderstood. Choice comes into a drug addicts life maybe one or two times. Much in the same way unprotected sex comes into an HIV carriers life once or twice. Even Diabetes and many forms of Cancer are avoidable, yet once people have succumbed, it somehow seems easier for people to acknowledge the repercussions of aquireing mentioned diseases as just that. Agreed in almost all cases, the addict did at one time have a choice. Once this disease gets into the brain, it is like any other disease. If left untreated it will change your life immeasurably and more than likely kill you ... Warren, 17 October 2007
The response from [a] previous reader is INCORRECT. A disease or illness is not always unprovoked, look at the obese person who became diabetic or the smoker who has lung cancer ... Kristin, 22 July 2007
In response to the reader comment From 1/1/06.......... Since June, 2006, I have fallen prey to what I feel to be the beginning of cocain addiction. I Was baffled by the craving and submission aspect of this drug and my struggle with my lack of power over it. that is, untill I read your article on the subject. After reviewing the article and one readers comments, I have to thank you sincerely. in my younger years,( I am 44) I partook from time to time(once every year or two) with friends and relatives on special occasionsand never craved afterwards. i believed that i wasn't capable of becoming addicted because it really wasn't important to me at any other time. Until March 2006, it had been some 15 years between usage. last summer with what I believe to be wonderful, nice caring successful people, we all kinda got into it together. And I of course believed I was above the possibility of becoming addicted. Then around January 2007, I decided that I was over my phase and was going to quit. Two weeks later, told myself that it was under control and that every now and then was still ok. But I descovered after every shameful morning after, I would say that this was the last time, and a few weeks later, was unable to say no. This went on until June. then one night one of my close friends that was my party buddie and I started talking and we both realized that we both had the same concearns and decided to quit together. and we did. for 103 days. And we did it twice more since then. and now I can finally admit that I am an addict. My stuggles continue, but i try to accumulate more and more Successes, days. We now call each other when we have the cravings, and are going to continue fighting the monkey.Ther are still moments of discouragement, but the successes are greater and adding up. I am weak, but i'm going to win. I believe the statement to be correct that at a certain point, when you cannot control your mind, the addiction has become a disease. i also believe this is not true for everyone. I call it two types of addiction, voluntary and chemical. My fiance who struggled with alcohal all her life passed away two years ago. and after watching for four years, I can honestly say that she had a disease, no control over it whatsorver. thanks for having a place for information. were not all bad people. Learning day by day ... Jon Meadows, 3 November 2007
My 24 y.o. daughter died of cocaine intoxification Octtober 21, 2006. She had been diagnosed with having bipolar disease by her child and adolescent psychiatrist. She had had this psychiatrist for the last eight years. Previously, she was a heroin addidct and used methodone. When she tapered off of the methodone, she immediately went to cocaine. I either was in denial, or clueless to how affected by drugs she was. I sent her to therapy constantly, as well as to as many rehabs as I could afford. I feel I could have done more, and will never forgive myself for not doing more to help her. I miss her so much. I will never get over this or forgive myself. Please help me ... Shelly Crawford, 12 December 2007