Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction

Abstract

Drugs of abuse are rewarding to addicted and nonaddicted subjects, but they trigger craving and compulsive intake only in addicted subjects. Here, we used positron emission tomography (PET) and [18F] deoxyglucose to compare the brain metabolic responses (marker of brain function) of cocaine-addicted subjects (n = 21) and controls (n = 15) to identify brain regions that are uniquely activated in addicted subjects by intravenous methylphenidate (a drug that cocaine-addicted subjects report to be similar to cocaine). In parallel, we also measured the changes in dopamine (DA) induced by intravenous methylphenidate (using PET and [11C] raclopride) in the striatum and in the thalamus. Metabolic responses between groups differed significantly only in the right medial orbital prefrontal cortex [Brodmann's area (BA) 25 and medial BA 11], where methylphenidate increased metabolism in addicted subjects but decreased metabolism in controls. These changes were associated in all subjects with increased "desire for methylphenidate" and in the addicted subjects with "cocaine craving." In addicted subjects, increases in BA 25 were also associated with mood elevation. Methylphenidate-induced increases in metabolism in the medial orbital prefrontal cortex were associated with its increase of DA in the thalamus but not in the striatum. These findings provide evidence that enhanced sensitivity of BA 25 (region involved with emotional reactivity) and BA 11 (region involved with salience attribution and motivation) in cocaine-addicted subjects may underlie the strong emotional response to the drug and the intense desire to procure it that results in craving and compulsive drug intake. It also suggests that the mesothalamic DA pathway may contribute to these processes.

Figure 1.

Diagram of experimental design. Subjects were tested on two separate days. On each day, they were scanned first with [¹¹C]raclopride, and this was followed by an FDG scan. On the first day of the study, subjects received intravenous placebo before each radiotracer injection, and on the second day, they received intravenous MP before each radiotracer injection.

Figure 2.

Brain regions where MP significantly (p < 0.005) increased (red) or decreased (blue) metabolism in controls and in cocaine-addicted subjects are shown.

Figure 3.

A, Brain regions where the response to MP differed between controls and cocaine-addicted subjects. The results are presented with respect to the controls. B, Relative metabolic measures in the right OMPFC in controls and in cocaine-addicted subjects for the placebo and for MP conditions. Metabolism was significantly lower in addicted subjects than in controls for the placebo condition. MP decreased metabolism in controls but increased metabolism in addicted subjects (values correspond to means and SDs). R OMPFC, Right OMPFC. C, Relationship between the changes in metabolism induced by MP and the self-reports for desire for MP (r = 0.55; p < 0.0005). R Bd 25, Right Brodmann area 25.

Figure 4.

Correlation between MP-induced changes in OMPFC metabolism and the changes in thalamic DA. R OMPFC, Right OMPFC.