Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers

Abstract

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 approximately 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 approximately 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.

Figure 1.

Brain metabolic images at the thalamic and cerebellar levels for the four conditions: (1) expected placebo received placebo, (2) expected placebo received MP, (3) expected MP received MP, and (4) expected MP received placebo. Scale is to the right and reflects micromoles/100 gm per minute. Note the larger increases in metabolism when MP was expected than when it was not expected.

Figure 2.

Brain maps obtained with SPM after normalization for the global metabolic increases to reveal the areas where MP induced the largest increases in metabolism both for unexpected and expected MP (areas in red). Comparisons are with the “expected placebo received placebo” condition, and significance was set at p < 0.005. Note that the largest increases with MP occurred in cerebellum, occipital cortex, and thalamus. Note also the much larger areas of activation in thalamus for expected MP and in lateral orbitofrontal cortex for unexpected MP.

Figure 3.

Brain maps obtained with SPM after normalization for the global metabolic increases to reveal the areas where MP induced relative decreases in metabolism for both unexpected and expected MP (areas in blue). Comparisons are with the expected placebo received placebo condition, and significance was set at p < 0.005. Note the relative decreases for both conditions in limbic regions (NAc, Brodmann area 25, insula, amygdala) and in motor cortices.

Figure 4.

A,Brain maps obtained with SPM showing the areas where the increases were significantly larger for expected versus unexpected MP (areas in red) and where they were significantly smaller for expected than unexpected MP (areas in blue). Significance was set at p < 0.005. B, Volumes of the areas of activation (number of pixels where activation was at the p < 0.005 level) for thalamus, vermis, and Brodmann area 47 for unexpected and expected MP. The volumes were significantly larger for expected MP in thalamus (p < 0.001) and vermis (p < 0.05) and for unexpected MP in Brodmann area 47 (p < 0.002). The numbers within the parentheses correspond to the total number of pixels for each region and were used to establish the scale in the ordinate axis.

Figure 5.

A, Self-reports of drug effects. MP (unexpected and expected) significantly increased self-report of high (repeated measures ANOVA; F = 32; p < 0.0001), drug liking (F = 34; p < 0.0001), feel drug (F = 26; p < 0.0001), and restlessness (F = 4; p < 0.05). Asterisk indicates significant differences (p < 0.05) between MP when unexpected (PL/MP) versus when expected (MP/MP). B, Correlations between the changes in metabolism in thalamus and the increases in self-reports of high and drug liking after unexpected and expected MP.