Changes That Occur With Chronic Drug Abuse

During the early phase of an individual's drug experimentation, neurotransmission normalizes as intoxication wears off and the substance leaves the brain. Eventually, however, drugs wreak changes in cellular structure and function that lead to long-lasting or permanent neurotransmission abnormalities. 

These alterations underlie drug tolerance, addiction, withdrawal, and other persistent consequences.

Some longer term changes begin as adjustments to compensate for drug-induced increases in neurotransmitter signaling intensities.

For example, drug tolerance typically develops because sending cells reduce the amount of neurotransmitter they produce and release, or receiving cells withdraw receptors or otherwise dampen their responsiveness.

Scientists have shown, for example, that cells withdraw opioid receptors into their interiors (where they cannot be stimulated) when exposed to some opioid drugs; when exposed to morphine, however, cells appear instead to make internal adjustments that produce the same effect—reduced responsiveness to opiate drugs and natural opioids.2 Over time, this and related changes recalibrate the brain's responsiveness to opioid stimulation downward to a level where the organ needs the extra stimulation of the drug to function normally; without the drug, withdrawal occurs.

The drug-related mechanisms producing cumulative changes in neurotransmission sometimes are genetic in nature. While a drug cannot change a person's genes, drugs can prod some genes to increase their production of proteins, leading to changes in cell function or even actual reshaping of the physical structure of cells.

For example, in rats, cocaine and amphetamine stimulate genes that produce the proteins used to build dendrites, branch-like cell structures that contain neurotransmitter receptors.

Brains normally sprout new dendrites as they register new learning; the accelerated dendrite formation stimulants induce may partially account for these drugs' unusual hold on an abuser's attention.

Some drugs are toxic to nerve cells, and the effect accumulates with repeated exposures. For example, the club drug methylenedioxymethamphetamine (MDMA, ecstasy) damages axons that release serotonin;

the result is disruption of serotonin neurotransmission that likely underlies the long-lasting memory problems experienced by abusers.

Similarly, methamphetamine, over time, damages enough dopamine-sending cells to cause significant defects in thinking and motor skills; with abstinence, dopamine function can partially recover, but it is unclear whether cognitive and motor capabilities come back as well.

Experimental Methods

To determine whether or how a drug affects a particular neurotransmitter, researchers typically will compare individuals who have a history of drug exposure with others who do not.

If researchers are investigating links between a drug's impact on neurotransmission and a drug-related behavior or symptom, they may compare individuals who exhibit the behavior or symptom with others who do not.

The subjects in these experiments may be animals or people. In the case of animals, drug exposure often takes place under laboratory conditions designed to mimic human drug consumption.

Studies can be divided into those in which measurements are made in living animals or people and those in which animal brain tissue is removed and examined.

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