University of Washington School of Medicine researchers have discovered how methamphetamine works its long-lasting, addictive effects on the brain.

Mice given methamphetamines for 10 days (roughly equivalent to a human using it for two years) had suppressed activity in the striatum, a forebrain region that has been linked to habit-forming behavior.

Much to their surprise, while normal function did not return even when the drug was stopped, it did when they administered a single dose of the drug again after the mice had been in withdrawal.

They believe the key lies in neurons found in the striatum that release the neurotransmitter acetylcholine, which acts like a “memory switch.” When dopamine is released by meth use, it lessens acetylcholine levels in the striatum, which 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.

If researchers can pinpoint the resetting mechanism, it would enable them to design nonaddictive drugs to trigger it.