A team of researchers has reported progress in testing a new approach involving the dopamine system that they hope may help reduce symptoms of post-traumatic stress disorder (PTSD).

Led by 2014 BBRF Young Investigator Josh M. Cisler, Ph.D., of the University of Wisconsin-Madison, the team set out to enhance a process in the brain called fear-extinction learning. This kind of learning occurs in patients who are helped by a therapeutic approach called exposure therapy. In such therapy, a traumatized person is exposed under carefully controlled conditions to situations related to their trauma and which trigger traumatic memories but pose no actual danger. The objective is for patients to extinguish fear aroused by these trauma-related but safe situations.

According to Dr. Cisler and colleagues including 2012 BBRF Young Investigator Ryan J. Herringa, M.D., Ph.D., remission rates in exposure therapy are 50% to 60%, a rate they would like to increase as much as possible.

The team recruited 91 women between ages 21 and 50, all of whom had a current PTSD diagnosis that was related to experience(s) of violent assault. The women were randomly assigned to one of three groups. Two of the groups received the drug L-DOPA (one group at 100 mg per dose, the other at 200 mg); the third group received a placebo.

L-DOPA, which occurs naturally in the body, is a molecular precursor of the neurotransmitter dopamine as well as several other neurotransmitters. L-DOPA can cross the protective membrane called the blood-brain barrier and thus can enter the brain, whereas dopamine cannot. L-DOPA has been administered for decades as a treatment for Parkinson’s Disease, which affects the dopamine pathway.

The team proceeded from several sets of past animal and human experiments suggesting that the dopamine pathway plays an important role in the learning of fear-extinction memories, as well as the consolidation and subsequent recall of such memories.

One objective of the study was to determine whether L-DOPA at either dosage, if delivered during a narrow window in time when consolidation of fear-extinction learning is taking place, has the effect of decreasing fear responses after the drug is administered—specifically, within 45 minutes after learning and then tested 24 hours later.

The study consisted of experiments in which participants' fear responses to specific stimuli were assessed. This involved, first, associating certain geometric shapes shown on a computer screen with the imminent delivery of a mild shock (harmless but a bit uncomfortable). Next, the team showed participants these same geometric shapes, but this time they were not followed by a shock—enabling the subjects to form new memories, in which seeing the shapes is no longer predictive of discomfort. Subsequent experiments tested which memory would be stronger a day later—the original fear memory associating the shapes with the shock, or the new fear-extinction memory of the shapes not predicting a shock. The responses were assessed in the three groups of participants: the two receiving L-DOPA at different dosages and the third receiving placebo.

This design enabled researchers to gauge an important phenomenon called reinstatement, which refers to situations in which the newer fear-extinction memory is not strong enough to prevent recall of the original fear memory. In PTSD patients treated with exposure therapy, reinstatement can result in a relapse.

Resting-state scans of the brain were made in each participant before they began the tasks assigned by researchers and again 45 minutes after ingestion of L-DOPA or placebo. This enabled the team to measure the impact of L-DOPA on nerve-cell activation patterns involved in fear-extinction memory while such memory was being consolidated. fMRI scans were made 24 hours later testing fear recall, extinction recall, and reinstatement. Still other tests based on sensors attached to the skin were made to gauge the fear responses of the participants.

The team reported in Translational Psychiatry that compared with those who received a placebo, participants who received L-DOPA at both dosages, but optimally those receiving the lower 100 mg dose, demonstrated increased reactivation of neural patterns involved in fear-extinction during the acute memory consolidation period 45 minutes following extinction learning. Both L-DOPA groups also exhibited decreases relative to the placebo group in reinstatement of fear memories 24 hours after the drug was administered.

“These results support a role for dopamine,” the team concluded, in boosting processes in the amygdala involved in reactivating fear-extinction memories, specifically during the window in which these memories are being consolidated. There was also evidence that dopamine was involved in reducing reinstatement of fear memories.

Among several suggestions for follow-up research, the team proposed the inclusion of men, a longer period of experimentation, the inclusion of participants who have suffered diverse kinds of trauma, as well as study of how L-DOPA might affect the function of the serotonin neurotransmitter system in addition to its impact on dopamine.