Brain Facts

Brain Facts

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Cocaine and the Brain: The Neurobiology of Addiction

In 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 don? 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 cocaine? 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 cocaine? 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 Alzheimer? (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 Sources
1) 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) Cocaine? Pleasurable Effects May Involve Multiple Chemical Sites , Description of cocaine? effects at the neuronal level

5) Animation of Cocaine Blocking Dopamine Reuptake

6) Brain Scans Open Window to View Cocaine? Effects on the Brain , Research on dopamine reuptake transporters

7) Psychology of Alcohol and Other Drugs: A Research Perspective. , Jung, John. Psychology of Alcohol and Other Drugs: A Research Perspective. Thousand Lakes, CA: Sage Publications, 2001.

8) Fundamental Neuroscience, Zigmond, Michael, ed. Fundamental Neuroscience. New York: Academic Press, 1999., General neurobiology textbook

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

11) Cocaine Addiction: Theory, Research, and Treatment, Platt, Gerome. Cocaine Addiction: Theory, Research, and Treatment. Cambridge, MA: Harvard University Press, 1997.

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

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