Placebo Effect Seems Related to Reward Expectations, Dopamine Activity

Marlene Busko

August 15, 2007

August 15, 2007 — In a recent study, the release of dopamine into the nucleus accumbens of subjects who received a placebo after a pain challenge correlated with their anticipation of receiving a reward (an analgesic agent). In a second part of the study, subjects who expected to receive a monetary reward for playing a game exhibited a similar placebo-induced increase in dopamine activity in this area of the brain.

"Individual variations in nucleus accumbens response to reward expectation accounted for 28% of the variance in the formation of placebo analgesia," the group, led by David J. Scott, from the University of Michigan, in Ann Arbor, writes.

The study is published in the July 19 issue of Neuron.

Corresponding author Jon-Kar Zubieta, MD, also from the University of Michigan, told Medscape: "Individuals who were not activating the nucleus accumbens in response to the expectation of a monetary reward were the same individuals who didn't release much dopamine in response to placebo administration, and they were the same individuals who didn't have much of an analgesic placebo effect." He added that interindividual differences in the function of this transmitter system are linked with the capacity to experience a placebo effect (a beneficial effect from positive expectations).

The group writes that the physiological processes that underlie placebo effects remain to be elucidated. They aimed to investigate whether variations in dopamine release in the nucleus accumbens (an area of the brain involved in experiencing pleasure and also in addiction) are related to variability in placebo effects in a sample of healthy subjects. They recruited 30 healthy volunteers (23 men and 7 women, with a mean age 24 years).

A total of 14 volunteers took part in the first phase of the study, a pain challenge. The subjects were told they were participating in a randomized control trial of a painkiller (analgesic agent) and would either receive this analgesic agent or a placebo; in fact, the subjects either received placebo or no placebo.

Each subject underwent 2 positive emission tomography (PET) scans with the tracer11C-raclopride (which binds to dopamine receptor sites). During each session with PET, the subjects were asked to rate their anticipated reduction in pain intensity prior to a pain challenge that consisted of administration of a painful 5% hypertonic saline solution into the jaw muscle, which was given with and without a placebo (a nonpainful 0.9% isotonic saline solution).

As a group, the study subjects experienced a significant reduction in pain when they received a placebo vs no placebo, but this did not correlate with changes in dopamine activity in the nucleus accumbens. Dividing the group into high placebo responders (above the median, n = 7) vs low placebo responders (below the median, n = 7), did reveal significantly more dopamine activity in the left nucleus accumbens in the high responders than in the low responders. The high responders were the same individuals who had also anticipated that the "painkiller" would bring them good pain relief. Four of the low responders reported increases in pain intensity during placebo administration — a nocebo (negative placebo) effect.

In a second part of the study, which was conducted separately from the pain study, the 30 volunteers underwent functional magnetic resonance imaging (fMRI) scans while they participated in a gambling game with monetary rewards of up to $5. The fMRI detected significant increases in the blood oxygenation levels in the neurons in the bilateral nucleus accumbens of the subjects who were anticipating rewards.

The subjects who had the most activity in their nucleus accumbens during the monetary reward game were the same individuals who had shown the strongest anticipation of an analgesic effect from a "painkiller" and the strongest placebo response in the pain challenge.

"The present results indicate that intrinsic differences in the function of neurobiological mechanisms involved in reward anticipation processing, such as the mesolimbic dopaminergic pathway, explain a substantial proportion of the variance in placebo effects," the group writes.

Dr. Zubieta explained that the implications are that randomized controlled clinical trials can be designed to try to predict and minimize a placebo effect to be able to better determine whether a particular intervention is effective. In other instances, it might be better to try to enhance the placebo effect, to try to take advantage of the body's resiliency mechanism, he noted.

No financial disclosures were reported.

Neuron. 2007;55:325-336. Abstract


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