Abstract
The response to drugs of abuse is affected by expectation, which is modulated in part by dopamine (DA), which encodes for a reward prediction error. Here we assessed the effect of expectation on methylphenidate (MP)-induced striatal DA changes in 23 participants with an active cocaine use disorder (CUD) and 23 healthy controls (HC) using [11C]raclopride and PET both after placebo (PL) and after MP (0.5 mg/kg, i.v.). Brain dopamine D2 and D3 receptor availability (D2R: non-displaceable binding potential (BPND)) was measured under four conditions in randomized order: (1) expecting PL/receiving PL, (2) expecting PL/receiving MP, (3) expecting MP/receiving PL, and (4) expecting MP/receiving MP. Expecting MP increased pulse rate compared to expecting PL. Receiving MP decreased D2R in striatum compared to PL, indicating MP-induced striatal DA release, and this effect was significantly blunted in CUD versus HC consistent with prior findings of decreased striatal dopamine responses both in active and detoxified CUD. There was a group × challenge × expectation effect in caudate and midbrain, with expectation of MP increasing MP-induced DA release in HC but not in CUD, and expectation of PL showing a trend to increase MP-induced DA release in CUD but not in HC. These results are consistent with the role of DA in reward prediction error in the human brain: decreasing DA signaling when rewards are less than expected (blunted DA increases to MP in CUD) and increasing them when greater than expected (for PL in CUD reflecting conditioned responses to injection). Our findings also document disruption of the expectation of drug effects in dopamine signaling in participants with CUD compared to non-addicted individuals.
Highlights
There is growing evidence that the context under which a drug is administered can affect the behavioral, physiological, and the neurochemical response to the drug
We have studied the effects of expectation on the effects of the stimulant drug methylphenidate (MP) on regional brain glucose metabolism and on behavior[4,8]
We showed that the expectation of receiving MP while receiving PL significantly activated brain glucose metabolism in the nucleus accumbens (NAc) and ventral cingulate cortex (Brodmann area 25), and effects were strongest in subjects who, because of experimental randomization, had not experienced MP before[8]
Summary
There is growing evidence that the context under which a drug is administered can affect the behavioral, physiological, and the neurochemical response to the drug. The response to drugs of abuse is affected by expectation, which in turn is sensitive to prior drug experiences[1,2,3]. This is modulated in part by dopamine (DA), which is a neurotransmitter involved with reward and expectation of reward. In human cocaine abusers the behavioral and regional brain metabolic responses to stimulants have been shown to be stronger when stimulants are expected versus when placebo (PL) is expected[4].
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