In the hours that follow the use of addictive drugs, dopamine neurons in the brain dampen their signals. The pleasurable feelings triggered by the drug are replaced by the negative symptoms of withdrawal. Scientists at the University of Pittsburgh have shown that this decline in dopamine signaling is driven by hyperactivity in a part of the brain called the basolateral amygdala. In rats treated with amphetamine, quieting the basolateral amygdala with the drug ketamine prevented the withdrawal-related dopamine decline, suggesting that ketamine treatment might help reduce symptoms of withdrawal and thus, possibly, lower the risk of addiction in people.

Ketamine was originally used as an anesthetic. Its mind-altering side effects, which include hallucination, led to abuse of the drug. But in recent years it has also been used in clinical studies under controlled conditions for treatment-resistant depression. Its anti-depressive effects can be almost immediate in some patients, among them people depressed for many years for whom no other treatments have helped.

Anthony Grace, Ph.D., a NARSAD Distinguished Investigator in 1998 and member of the Foundation’s Scientific Council, led the new research on ketamine’s potential role in addiction treatment. His team reported their results July 1st in the journal Neuropsychopharmacology. NARSAD 2010 Young Investigator Pauline Belujon, Ph.D., is the first author of the publication.

To examine how the brain responds to withdrawal from a single instance of drug use, the scientists administered a single dose of amphetamine to laboratory rats. Eighteen hours after the drug was given, the activity of dopamine neurons involved in the brain's reward circuitry declined significantly. At the same time, the animals exhibited signs of despair: giving up when placed in a stressful situation from which untreated animals try to escape. These effects were temporary. Seventy-two hours after the amphetamine dose, the activity of dopamine neurons as well as the rats' behavior returned to normal.

Low doses of ketamine that have been found to eliminate the symptoms of depression, Grace's team had previously shown, restore normal dopamine signaling in a mouse model of depression. The team wondered whether ketamine might also relieve the symptoms of acute withdrawal, which mirror the symptoms of major depression––anxiety, an inability to feel pleasure, and loss of motivation for natural rewards.

Administering ketamine to animals during amphetamine withdrawal did restore normal signaling of dopamine neurons. However, the signs of despair in the animals did not diminish. According to the scientists, this suggests that the neural processes giving rise to negative emotions experienced during withdrawal are different than those that underlie depression.

The scientists theorize that by reversing changes to dopamine signaling during acute withdrawal, treatment with ketamine could help reduce the risk of further drug use.

Read the abstract.