Lines of evidence are converging in support of the popular theory in addiction research: that a common mechanism links intake of different kinds of addictive drugs with the orbitofrontal cortex, which is the seat of compulsive behavior and "go-no-go" decision-making. Fresh support today comes from researchers at the Brookhaven National Laboratory (BNL) in New York, who report that like abusers of cocaine and alcohol, users of the popular drug methamphetamine have fewer dopamine D2 receptors, and an associated decrease in metabolic activity of the brain region. Abstinence can restore the damaged dopamine terminals structurally, they report in a related study. But motor and cognitive function do not recover.

"One of the holy grails of addiction research is to uncover what brain areas are involved in regulating addiction and craving," said Bertha Madras, professor of psychobiology at Harvard Medical School. "The orbitofrontal cortex is beginning to emerge as the key region."

The stimulant methamphetamine - also known as "speed" or "crank" - releases large amounts of dopamine, which is associated with pleasure and reward, and is also essential for movement. Using positron emission tomography (PET) and a radiotracers that bind glucose (a marker for brain metabolism) and dopamine D2 receptors, Nora Volkow and her colleagues at BNL found that meth-induced depletion of D2 receptors increasingly disrupts orbitofrontal cortex. The results are published in the December American Journal of Psychiatry.

Cocaine, heroin and alcohol are all known to disrupt metabolic activity of the region, so "adding meth to the list of drugs that affect the region implies that it might be a common mechanism," Madras told BioMedNet News. Madras says she herself has soon-to-be published data supporting this hypothesis, but declined to elaborate.

Because of blunted orbitofrontal cortex activity, in drug abusers "ordinary stimuli are not strong enough to activate the circuits," or trigger a reward response, said lead investigator Volkow. Methamphetamine releases an enormous amount of dopamine and triggers all of its receptors; the only stimulus able to boost orbitofrontal cortex activity, it becomes irresistible to addicts. Meth users also have significantly depleted dopamine transporters, reduced cognitive and motor functions, and perhaps a predisposition to Parkinson's disease or similar disorders.

In a second study, appearing tomorrow in the Journal of Neuroscience, Volkow and her colleagues report that prolonged abstinence from the drug can restore levels of dopamine transporters, but do not significantly improve cognitive and motor function. "It's very important to have this information out to the public," said Madras, who called the irreversible losses "alarming." Most studies rely on post-mortem analysis, and there's little or no information about irreversible effects of drug use.

There may be several reasons why structural repair does not presage cognitive recovery: Meth abuse also damages serotonin and glutamate systems, for example, and meth users are prone to mild depression. PET scanning may also not pick up changes like neuroplasticity and response to stimulus, Madras says, and while the terminals are grossly restored, they "may not have rewired exactly as they were originally."

Vokow and her colleagues are now trying to address that question by examining meth's effects on the serotonin system. Because most meth users smoke, they're also investigating whether nicotine may play a neuroprotective role in users.