Volkow ND, Wang GJ, Ma Y, Fowler JS, Wong C, Ding YS et al. Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J Neurosci 25: 3932-3939

National Institute of Drug Abuse, Rockville, Maryland 20857, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 05/2005; 25(15):3932-9. DOI: 10.1523/JNEUROSCI.0433-05.2005
Source: PubMed


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.

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    • "Intravenous cocaine delivery in short-term abstinent cocaineaddicted patients is associated with positive blood oxygen leveldependent (BOLD) responses in multiple prefrontal cortical regions, including dorsolateral prefrontal cortex (dlPFC), anterior cingulate (ACC), anterior orbital gyrus, orbitofrontal cortex (OFC), medial orbital gyrus, and frontopolar cortex (FPC) (Breiter et al., 1997; Kufahl et al., 2008, 2005; Risinger et al., 2005). These prefrontal responses may be enhanced in cocaine addicts, as intravenous methylphenidate (which cocaine addicts report as being similar to cocaine) increases metabolic responses in right medial orbital prefrontal cortex in addicted subjects, but decreases metabolism in control subjects (Volkow et al., 2005). Prefrontal responses to cocaine appear to be mediated, at least in part, by expectation of drug, as BOLD signals are significantly enhanced in lateral OFC, FPC, and ACC after expected vs. unexpected cocaine delivery (Kufahl et al., 2008). "
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    ABSTRACT: The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction. This dichotomy of mPFC function may be a general attribute, as similar dorsal-ventral distinctions exist for expression vs. extinction of fear conditioning. However, other results indicate that the role of mPFC neurons in reward processing is more complex than a simple PL-seek vs. IL-extinguish dichotomy. Both PL and IL have been shown to drive and inhibit drug seeking (and other types of behaviors) depending on a range of factors including the behavioral context, the drug-history of the animal, and the type of drug investigated. This heterogeneity of findings may reflect multiple subcircuits within each of these PFC areas supporting unique functions. It may also reflect the fact that the mPFC plays a multifaceted role in shaping cognition and behavior, including those overlapping with cocaine seeking and extinction. Here we discuss research leading to the hypothesis that dorsal and ventral mPFC differentially control drug seeking and extinction. We also present recent results calling the absolute nature of a PL vs. IL dichotomy into question. Finally, we consider alternate functions for mPFC that correspond less to response execution and inhibition and instead incorporate the complex cognitive behavior for which the mPFC is broadly appreciated.
    Brain Research 12/2014; DOI:10.1016/j.brainres.2014.12.024 · 2.84 Impact Factor
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    • "Significance was P FWE 5 0.05, corrected for multiple comparisons at the cluster level with a family-wise error (FWE corrected). All findings were corroborated with an independent region of interest analysis that used an automated extraction method based on the Talairach atlas (Talairach and Tournoux, 1988), described previously (Volkow et al., 2005). The absolute metabolic measures from the region of interest analysis (quantified as mmol/100 g/min) were used to assess the correlations between the regions that differed in participants with ataxia-telangiectasia and their motor performance with significance set at P 5 0.05. "
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    ABSTRACT: Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and (18)F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as ┬Ámol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P < 0.001), anterior vermis (40%, P < 0.001) and fusiform gyrus (20%, P < 0.001) compared with controls or siblings, and lower metabolism in hippocampus (12%, P = 0.05) compared with controls, and showed significant intersubject variability (decreases in vermis ranged from 18% to 60%). Participants with ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives suggests that heterozygocity influences the function of these brain regions.
    Brain 04/2014; 137(6). DOI:10.1093/brain/awu092 · 9.20 Impact Factor
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    • "Yet, previous studies have also shown that methylphenidate can produce contrasting responses in healthy controls and drug addicts. Intravenous administration of methylphenidate increased brain metabolism in cocaine addicts but decreased metabolism in healthy controls (Volkow et al. 2005b). These data suggest that the brain's response to methylphenidate varies with (ab)normal fluctuations of glutamatergic and GABAergic neurotransmission in the limbic circuit. "
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    ABSTRACT: Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.
    Psychopharmacology 04/2013; 229(2). DOI:10.1007/s00213-013-3105-x · 3.88 Impact Factor
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