The chemicals responsible

The CREB protein, a transcription factor activated by cyclic adenosine monophosphate (cAMP) immediately after a high, triggers genes that produce proteins such as dynorphin, which cuts off dopamine release and temporarily inhibits the reward circuit. In chronic drug users, a sustained activation of CREB leaves the user feeling depressed and dissatisfied, and unable to find pleasure in previously enjoyable activities, often leading to a return to the drug for an additional "fix". It also leads to a short term tolerance of the substance, necessitating that a greater amount be taken in order to reach the same high.

Another transcription factor, known as delta FosB, is thought to activate genes that, counter to the effects of CREB, actually increase the user's sensitivity to the effects of the substance. Delta FosB slowly builds up with each exposure to the drug and remains activated for weeks after the last exposure—long after the effects of CREB have faded. The hypersensitivity that it causes is thought to be responsible for the intense cravings associated with drug addiction, and is often extended to even the peripheral cues of drug use, such as related behaviors or the sight of drug paraphernalia. There is some evidence that delta FosB even causes structural changes within the nuclear accumbens, which presumably helps to perpetuate the cravings, and may be responsible for the high incidence of relapse that occur in treated drug addicts.

Regulator of G-protein Signaling 9-2 (RGS 9-2) has recently been the subject of several animal knockout studies. Animals lacking RGS 9-2 appear to have increased sensitivity to dopamine receptor agonists such as cocaine and amphetamines; over-expression of RGS 9-2 causes a lack of responsiveness to these same agonists. RGS 9-2 is believed to catalyze inactivation of the G-protein coupled D2 receptor by enhancing the rate of GTP hydrolysis of the G alpha subunit which transmits signals into the interior of the cell.

Mechanisms of effect

The mechanisms by which different substances activate the reward system vary among drug classes.

• Depressants such as alcohol and benzodiazepines, and narcotics such as morphine and methadone, work by mimicking endorphins—chemicals produced naturally by the body which have effects similar to dopamine—or by disabling the neurons that normally inhibit the release of dopamine. These substances (sometimes called "downers") typically facilitate relaxation and pain-relief.

• Stimulants such as amphetamines and nicotine increase dopamine signaling, either by directly stimulating its release, or by blocking its absorption (see "reuptake"). These substances (sometimes called "uppers") typically cause heightened alertness and energy.

The most common drug addictions are to legal substances such as:

• Alcohol
• Nicotine in the form of tobacco, particularly cigarettes
• Caffeine in the form of tea, coffee, and caffeinated sodas

Many prescription or over the counter drugs can become addictive if abused. Steroidal medications, for example, are extremely addictive. In addition, a large number of other substances are currently considered to have no medical value and are not available over the counter or by prescription. Depending on the jurisdiction, these drugs may be legal only as part of a government sponsored study, illegal to use for any purpose, illegal to sell, or even illegal to merely possess.

In 1972, United States President Richard Nixon declared a war on illegal drugs in an attempt to control the growing problem of drug addiction and drug-related crime. It is unclear, though, whether laws against drugs do anything to stem usage and dependency. In jurisdictions where addictive drugs are illegal, they are generally supplied by drug dealers, who are often involved with organized crime. Even though the cost of producing most illegal addictive substances is very low, their illegality combined with the addict's need permits the seller to command a premium price, often hundreds of times the production cost. As a result, the addict must often turn to crime to support their habit.

 

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