SIGN OF CHANGE: Researchers have discovered how methamphetamine works its long-lasting, addictive effects on the brain.
© ISTOCKPHOTO/GEORGE PETERS

Scientists for the first time have identified long-term changes in mice brains that may shed light on why addicts get hooked on drugs—in this case methamphetamines—and have such a tough time kicking the habit. The findings, reported in the journal Neuron, could set the stage for new ways to block cravings—and help addicts dry out.

Researchers, using fluorescent tracer dye, discovered that mice given methamphetamines for 10 days (roughly equivalent to a human using it for two years) had suppressed activity in a certain area of their brains. Much to their surprise, normal function did not return even when the drug was stopped, but did when they administered a single dose of it again after the mice had been in withdrawal.

Study co-author Nigel Bamford, a pediatric neurologist at the University of Washington School of Medicine, says that if similar changes occur in humans, it will indicate that an effective way to fight addiction may be to design therapies that target the affected area—the striatum, a forebrain region that controls movement but also has been linked to habit-forming behavior.

Previous research has shown that the drug stimulates nerve cells in the midbrain to release dopamine into the synapses (connections between neurons) in the striatum. Dopamine (which is connected to reward processing, motivation and attention) is one of the brain's primary neurotransmitters, the chemical messengers by which one neuron triggers its neighbor to fire a nerve impulse.

In this case, Bamford says, the excess dopamine affected the flow of information from the cortex (the brain's central processing unit) to the striatum. Specifically, it appeared to partially block nerve cells in the cortex from releasing glutamate, another neurotransmitter, which is responsible for excitation. "Dopamine provides a filtering effect that may help you concentrate on the novel object or pleasurable stimulus," Bamford says. Too much could explain addictive or compulsive behavior, because it would help a user ignore other things and focus a lot of attention on one particular goal.

Researchers found that chronic use of the drug kept the brain in this state of "chronic depression," in essence suppressing the neural terminals controlling the flow of signals between the cortex and striatium—even after a long period of several weeks. But normal activity resumed after the drug was reintroduced.

Bamford believes the key lies in other neurons found in the striatum, which release the neurotransmitter acetylcholine that, he says, acts like a "memory switch". When dopamine is released by meth use, it lessens acetylcholine levels in the striatum; continued drug use reduces it to as low as 10 percent. This decrease, in turn, affects glutamate levels, which also drop perilously low, thereby resulting in the chronic depression of information flow in the brain.

When methamphetamine is administered after a period of withdrawal, however, the dopamine released by the midbrain neurons has the opposite effect on the acetylcholine cells, prompting them to release the chemical into the striatum. This, in turn, stimulates the production of glutamate, somehow causing the system to reset itself to a pre-addictive state.

Bamford says that if researchers can pinpoint the resetting mechanism, it would enable them to design nonaddictive drugs to trigger it.

"The identification of this quite complicated mechanism gives you different opportunities to address the root of the problem so the synapse can be renormalized without the use of the psychostimulant," he says. "A better target would be to determine how these [acetylcholine neurons] are learning to stay depressed and work directly with those."