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The Journal of Neuroscience, December 10, 2003, 23(36):11461-11468

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Behavioral/Systems/Cognitive
Expectation Enhances the Regional Brain Metabolic and the Reinforcing Effects of Stimulants in Cocaine Abusers

Nora D. Volkow,^1,3 Gene-Jack Wang,¹ Yemin Ma,¹ Joanna S. Fowler,² Wei Zhu,⁴ Laurence Maynard,¹ Frank Telang,¹ Paul Vaska,¹ Yu-Shin Ding,² Christopher Wong,¹ and James M. Swanson⁵

¹Medical and ²Chemistry Departments, Brookhaven National Laboratory, Upton, New York 11973, Departments of ³Psychiatry and ⁴Applied Mathematics, State University of New York at Stony Brook, Stony Brook, New York 11794, and ⁵University of California at Irvine, Child Development Center, Irvine, California 92612

The reinforcing effects of drugs of abuse result from the complex interaction between pharmacological effects and conditioned responses. Here we evaluate how expectation affects the response to the stimulant drug methylphenidate in 25 cocaine abusers. The effects of methylphenidate (0.5 mg/kg, i.v.) on brain glucose metabolism (measured by [¹⁸F]deoxyglucose-positron emission tomography) and on its reinforcing effects (self-reports of drug effects) were evaluated in four conditions: (1) expecting placebo and receiving placebo; (2) expecting placebo and receiving methylphenidate; (3) expecting methylphenidate and receiving methylphenidate; (4) expecting methylphenidate and receiving placebo. Methylphenidate increased brain glucose metabolism, and the largest changes were in cerebellum, occipital cortex, and thalamus. The increases in metabolism were 50% larger when methylphenidate was expected than when it was not, and these differences were significant in cerebellum (vermis) and thalamus. In contrast, unexpected methylphenidate induced greater increases in left lateral orbitofrontal cortex than when it was expected. Methylphenidate-induced increases in self-reports of "high" were also 50% greater when subjects expected to receive it than when they did not and were significantly correlated with the metabolic increases in thalamus but not in cerebellum. These findings provide evidence that expectation amplifies the effects of methylphenidate in brain and its reinforcing effects. They also suggest that the thalamus, a region involved with conditioned responses, may mediate the enhancement of the reinforcing effects of methylphenidate by expectation and that the orbitofrontal cortex mediates the response to unexpected reinforcement. The enhanced cerebellar activation with expectation may reflect conditioned responses that are not linked to conscious responses.

Key words: imaging; cerebellum; FDG; addiction; context; dopamine; reinforcement; conditioned responses

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Received July 21, 2003; revised October 14, 2003; accepted October 14, 2003.

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