Brain Chemistry

The brain is a chemical powerhouse, with each of its several billion cells churning out messages in the form of molecules, stored and ready to go. Precisely released in exquisitely tiny amounts, these molecular messages control the workings of the entire body. And it is the chemical nature of brain activity that reacts and adjusts to a person's use of an addicting drug.

The basic building block of the body's nervous system is the neuron, a cell with long fibers that make contact with other neurons. In spite of the fact that most of the signaling activity of a neuron is electrical, neurons use chemical messengers to communicate with each other. This is because neurons do not actually touch each other. Instead, they use different molecules to send messages that end up causing other neurons to either stay quiet, or activate an electric current. In turn, the current in the second neuron will cause more chemical messages to flow.

The body of the neuron is pretty ordinary in size as far as cells go, but the thin fibers reaching out from each neuron make this type of cell remarkable. Most cells in the body are of such small dimensions that they show up only under a microscope. But some neurons, while still not visible to the unaided eye, have to extend several feet, in order to let the brain know, for instance, what the big toe is doing.

Chemistry Carries the Message

Each neuron, when activated, will release molecules from the business end of its output fiber, the axon, to continue a message. The molecules must cross the microscopic gap that separates the end of the axon from the next nerve cell, a space called the synapse.

Many of the molecules that are released in synapses, the so-called neurotransmitters, have already been studied in detail. While more than 20 different molecules are known to serve as neurotransmitters, scientists believe that even more await discovery. Still, it is a single molecule, dopamine, that has been identified as the neurotransmitter responsible for addictive behavior.

Dopamine. Neuroscientists have found that dopamine plays a key role in registering pleasure (allowing the person to feel pleasurable sensations), and that all drugs with addictive properties appear to affect dopamine transmission in the nervous system. The reason for all addictions, they say, lies in the particular way that dopamine is placed within, and controlled within, the brain. Dopamine serves as a key transmitter in those regions of the brain that scientists find are associated with creating pleasurable sensations. These regions include cell clusters within the middle of the brain, involved in emotions.

In these regions, dopamine is released when the neurons that make it are activated. Dopamine is immediately swept up from the narrow synaptic spaces between nerve cells after it spills from the sending neurons. The clean-up mechanism is perfectly tuned to react if more than the usual amount of dopamine is present, gearing up instantly to remove even more of it. This so-called reuptake mechanism also downshifts to low gear if less than the usual amount of dopamine is present.

In addition, receptors on the receiving neuron respond to maintain dopamine transmission. The receptor molecules for each neuro-transmitter will respond to the message, with a change of shape. Triggered by the binding of the incoming transmitter molecule, the receptor rearranges itself to fit tightly to the messenger. By altering itself, the receptor sends its own signal. In turn, the messenger adjusts a set of reactions going on inside the receiving cell. In this way, the receptor carries the message along. Perhaps the next cell, as a result, will fire off its own message more readily, or more slowly.

If a receptor for a particular transmitter is present on the next cell across a synapse, that transmitter's message will be passed along. Dopamine receptors are able to respond instantly to how much dopamine is actually in use. They will be pulled from service if a lot of dopamine is let loose. On the other hand, more receptors will be sent to the synaptic front if a dopamine shortage is sensed.

Thus the chemical balance within the nervous system is kept in tight control. The brain and nerves try to stay in a stable state so that the body runs smoothly and reacts just so to what it needs to sense. Addiction is a disturbance of the nervous system's chemistry, and actually is the result of the body's attempts to bring itself back into chemical balance.

Opiates as an Addicting Example

Morphine, heroin, and codeine are examples of addicting substances. They are known as opiates, because they are made from the opium poppy. In a person who takes one of these drugs, the brain's response to the first dose changes with repeated doses.

A dose of morphine will enter the brain through the bloodstream. There, at synapses, a receptor sees and recognizes the morphine molecule, which looks a lot like certain molecules normally present in the brain. Morphine binds to these opiate receptors, studding the surface of dopamine-making neurons. Contact with the morphine molecules in turn prods these neurons to release dopamine. Because the brain likes to stay in chemical balance, it responds to a flooding of outside substances by cutting back on certain aspects of its own chemistry. Responses to the excess dopamine must be scaled back.

Here then is the essence of addiction. Addicting drugs resemble, at the molecular level, neurotransmitters that are made by the body itself. In turn, most if not all of these substances eventually alter dopamine. But the brain and nervous system throughout the body fight to maintain the usual level of chemical activity, and the balance of dopamine.

When morphine is added, and dopamine floods receptors, the re-uptake mechanism goes into overdrive. Then, when the morphine is finally broken down by the body's metabolism, revved-up reuptake leaves the fewer receptors empty. This translates into the feelings that make the user crave more drug. The more morphine taken, the more reuptake, the fewer receptors, and the greater the interruption of dopamine transmission when the morphine is stopped.

An opiate abuser who abruptly stops taking the drug goes through a withdrawal syndrome. The symptoms of opiate withdrawal include anxiety, restlessness, yawning, flu-like symptoms including muscle and bone pain, diarrhea, wakefulness, vomiting, chills and goose bumps, and involuntary movement of the legs. All aspects of withdrawal are the physiological opposite of the initial effects of the drug: at first morphine causes sleepiness, relaxation, constipation, lessened sensation of pain, and, because of the dopamine release, euphoria (a feeling of intense well-being). It takes days to weeks to get the synapse back into metabolic balance after opiate abuse ends, depending on the dose that the user had built up to and how long the abuse had continued.

A person who steadily uses morphine develops tolerance to the drug. This means that more and more drug is needed to produce the same effect of the original dose. A tolerant morphine user can take massive doses that would kill a first-time user. The usual dose of morphine prescribed for medical purposes is 5 to 20 milligrams. However, cancer patients as well as street addicts may take several hundred milligrams a day. In extreme cases, thousands of grams a day of morphine may be taken.

Another Example: Cocaine

Cocaine, a drug that is rapidly addicting, also causes a person to feel pleasure because of its action on dopamine. In the case of cocaine, the reuptake mechanism itself is directly affected. Cocaine molecules bind especially well to the uptake molecules that normally sweep released dopamine back into the neuron that let it out. Cocaine essentially blocks the reuptake process by occupying the reuptake sites. As a result, dopamine stays in the synapses. Increased impulses spread out from the reward circuit when cocaine is present. But the reaction of the reuptake mechanism to too much dopamine is to boost the number of reuptake molecules. Once the cocaine is gone, the synapses are so empty of dopamine that the user feels an immediate and intense craving for more drug.

Morphine and its drug relatives act to increase the release of dopamine. Cocaine makes more dopamine stay in the synapse. The end result on the reward system from both these drugs is the same, an increase in dopamine. Other addicting substances, such as alcohol and nicotine, also act to increase dopamine transmission through the reward circuitry, although in a less direct way.

Addiction and Other Brain Chemicals

Despite the current emphasis on dopamine, neuroscientists realize that it is not just dopamine that is involved in addiction. Some drugs that end up as addicting have actions that are clearly caused by changes in another major transmitter system, the adrenergic system. This set of nerve cells use the transmitters adrenaline and noradrenaline (also called epinephrine and norepinephrine).

The adrenergic system is the same system that you feel going into action when you are under stress. A person who faces immediate danger experiences the so-called fight-or-flight response: racing heart, butterflies in the stomach, and trembling muscles readied for action. These responses occur because adrenaline is released from the adrenal gland sitting on top of the kidneys. Adrenaline is also squirted out by nerves.

Opiates dampen the signals coming from a tiny group of adrenergic cells in the upper brain stem. When an opiate abuser stops taking the drug after constant use, he or she feels anxiety. This anxiety may be triggered by the adrenergic system. A new approach to treating addicts in withdrawal involves adding a drug called clonidine, which calms the anxiety produced by the adrenergic system in an addict trying to quit.

Progress in Addiction Research

People have known for centuries that opium and more refined chemicals made from the sap of the unripe poppy seed pod can soothe pain and induce sleep. But only in the 1970s did scientists stumble on the fact that opium, morphine, codeine, heroin, and all manmade opiate drugs closely mimic the molecular structure of a set of natural neurotransmitters. These neuroscientists had identified the brain's own morphine, calling it endorphin.

Even caffeine, the active ingredient in coffee, cola drinks, and chocolate, mimics a natural neurotransmitter within the brain called adenosine. Caffeine's ability to boost alertness and change the rates of contraction of some smooth muscles comes from its actions at adenosine receptors.

Scientists have identified the purpose of the brain's own opioids. Say an animal has been injured. Because of the actions of brain opiates, the animal does not yet notice the sensation of pain. This allows the injured animal to escape the source of the injury. Once the animal is away from danger, the injury itself then needs to be noted so that the animal can hide and heal—in other words, it is then necessary for the animal to feel its pain. So the body's own opiates are crafted by evolution to work in an emergency, but to then fade away and allow pain to assert itself. The poppy makes its own molecules, morphine and codeine, most likely to counter insects. These substances just happen to fit in the receptors that have evolved in animals for their own needs.

Similarly, caffeine, and its chemical relatives in tea (theophylline) and chocolate (theobromine), were probably meant to affect insects chewing on the plants, but also turn out to affect people who eat or drink the foods and beverages brewed from the seeds and leaves. When people chew the leaves of the coca plant, from which cocaine is made, the cocaine serves up its effect to the dopamine reuptake system, though the plant is merely equipped to defend against chewing bugs with far simpler nervous systems.

Beyond the Surface Receptors

Many brain researchers now study second messengers, which guide the reactions that take place within neurons after transmitters bind to the surface receptors. When morphine binds to its opiate receptors, these altered receptors in turn activate an enzyme inside the nerve cell that governs the firing of the cell. Repeated activation of this enzyme, adenylate cyclase, eventually leads to a weakened response that will require more drug, simply to maintain the enzyme's normal function.

Just as response to transmitter is adjusted in addiction, so too are the activities of the second messengers. New drugs may soon be invented to treat addiction inside the neuron by targeting the second messenger systems within it.

The Future of Research

Drug addiction is the brain's response to the interruption of its normal chemical balance. By coincidence, drugs that people have taken from plants and purified and copied through chemistry are able to mimic the basic means by which one nerve cell communicates with another. By understanding the intricate workings of the brain's chemistry, scientists hope to find ways to interrupt an addict's self-destructive impulses, which in fact arise from the impulses within the brain.

see also Brain Structures; Cocaine; Heroin; Imaging Techniques: Visualizing the Living Brain; Research; Tolerance and Physical Dependence.