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 [18 F]deoxyglucose to compare the brain metabolic responses (marker of brain function) of cocaine-addicted subjects (n ϭ 21) and controls (n ϭ 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 [ 11 C]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.

Dysregulation of Dopamine and Glutamate Release in the Prefrontal Cortex and Nucleus Accumbens Following Methamphetamine Self-Administration and During Reinstatement in Rats

“…In contrast to decreased basal metabolic function, neuroimaging studies in psychostimulant dependent subjects have consistently reported that upon exposure to drug-related cues or low doses of psychostimulants, metabolic activity increases in the anterior cingulate, dorsolateral prefrontal cortex (PFC), and NAc (Bonson et al, 2002;Volkow et al, 2005). Our results showed that GLU efflux increased in both the dmPFC and NAc during cue-induced and meth-primed reinstatement.…”

Neurobiology of apathy in Alzheimer's disease

“…when triggered by stress, drug cues or drug per se, reinstatement constitutes a highly motivated behavior 104 , and is virtually abolished by lesions in ventral tegmental area 105 or dopamine antagonist infusion into dorsal striatum 106 . Additionally, human functional neuroimaging data suggest that the intense desire that motivates drug seeking depends on primary processing of drug-related cues in oFc [107][108][109] .…”

Brain macrostructural and microstructural abnormalities in cocaine dependence

“…Recent magnetic resonance (MR) imaging studies have provided strong evidence that cocaine abuse is associated with structural brain abnormalities in both gray matter (GM) and white matter (WM) (Bartzokis et al, 2002;Fein et al, 2002;Franklin et al, 2002;Lim et al, 2002;Moeller et al, 2005). Evidence from functional neuroimaging studies and investigations of neuropsychological deficits also point to long-term changes in brain status associated with cocaine abuse (Bolla et al, 2000;Goldstein et al, 2004;Volkow et al, 2005). Fully characterizing the nature of the underlying structural abnormalities in cocaine abusers is critical to understanding the impact of the drug on long-term functioning.…”