Behavioral and Cardiovascular Effects of Intravenous Methylphenidate in Normal Subjects and Cocaine Abusers

Wang, Gene‐Jack; Volkow, Nora D.; Hitzemann, Robert; Wong, Christopher; Angrist, Burton; Burr, Gail; Pascani, Kathy; Pappas, Naomi; Lu, Angela; Cooper, Thomas B.; Lieberman, Jeffrey A.

doi:10.1159/000259147

Cited by 61 publications

(39 citation statements)

References 14 publications

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“…Subjective ratings (high, restlessness, drug effects, and anxiety) were measured using self-reports (range: 1-10) that were recorded before administration of placebo or MP and periodically over the duration of the [ 11 C]raclopride scans (33). At the end of the study, participants were asked to rate the drug's potency (scale of 1-10).…”

Section: Methodsmentioning

confidence: 99%

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Volkow

Wang

Telang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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195

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Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [ 11 C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [ 11 C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BP ND )] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BP ND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.nucleus accumbens | amotivation | cannabinoid 1 receptors | brain imaging | midbrain D espite the high prevalence of marijuana consumption, the effects of marijuana abuse in the human brain are not well understood. Marijuana, like other drugs of abuse, stimulates brain dopamine (DA) signaling in the nucleus accumbens (1, 2), which is a mechanism believed to underlie the rewarding effects of drugs (3-5) and to trigger the neuroadaptations that result in addiction (reviewed in ref. 6). Indeed, in humans, imaging studies have shown that drugs of abuse increase DA release in striatum (including the nucleus accumbens), and these increases have been associated with the subjective experience of reward (7-9). However, for marijuana, the results have been inconsistent: One study reported striatal DA increases during intoxication (10); two studies showed no effects (11, 12); and one study reported DA increases in individuals with a psychotic disorder and in their relatives, but not in controls (13). Imaging studies of the brain DA system in marijuana abusers have also shown different findings from those reported for other types of substance abusers. Specifically, substance abusers (cocaine, methamphetamine, alcohol, heroin, and nicotine), but not marijuana abusers (14-16), show reduced baseline availability ...

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Section: Methodsmentioning

confidence: 99%

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Volkow

Wang

Telang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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195

147

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“…Before and at 27 min after the first and the second MP (or placebo) dose, subjects rated drug effects (high, desire for MP, desire for cocaine, restlessness, and mood) on a 0 -10 analog scale (Wang et al, 1997). When asked about the "desire for MP" subjects were asked to rate the desire to have the drug that they had just received (placebo or MP).…”

Section: Methodsmentioning

confidence: 99%

“…We selected MP because it is similar pharmacologically to cocaine; both drugs increase DA by blocking DA transporters (DATs) with similar potencies (Volkow et al, 1995) and induce similar changes in regional brain activation (Dirckx et al, 2004). Moreover, cocaine-addicted subjects report that intravenous MP has similar effects to cocaine (Wang et al, 1997). We chose two sequential doses rather than a single dose because this mimics better the pattern of drug intake in cocaine abuse (multiple administrations).…”

Section: Introductionmentioning

confidence: 99%

Activation of Orbital and Medial Prefrontal Cortex by Methylphenidate in Cocaine-Addicted Subjects But Not in Controls: Relevance to Addiction

Volkow¹,

Wang²,

et al. 2005

J. Neurosci.

276

192

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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.

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“…MP was used because it has similar reinforcing properties to those of cocaine (5,6) [its affinity for DAT is about twice that of cocaine (2)], its intravenous administration induces a high indistinguishable from that of cocaine (7), and it has longer pharmacokinetics than cocaine (half life in striatum >90 min versus 20 min for cocaine) which allows its repeated administration while there is still significant DAT blockade (4). We tested the ability to block or attenuate the high by prior DAT blockade by comparing the responses between the first and the second of two MP doses given 60 min apart.…”

mentioning

confidence: 99%

Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.

Volkow

Wang

Fowler

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

136

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The ability ofcocaine to inhibit the dopamine transporter (DAT) appears to be crucial for its reinforcing properties. The potential use of drugs that produce longlasting inhibition of the DAT as a mean of preventing the "high" and reducing drug-seeking behavior has become a major strategy in medication development. However, neither the relation between the high and DAT inhibition nor the ability to block the high by prior DAT Cocaine addiction is one of the most devastating of the behavioral diseases. Despite its seriousness, there are no effective treatment medications. This has prompted a major effort in the development of pharmacological agents to treat cocaine addiction. One of the main strategies is the development of medications that would interfere with cocaine binding to the dopamine transporter (DAT) and block its effects (1). This "cocaine substitute" strategy is based on the good correlation found between the affinities of cocaine and cocaine like drugs for the DAT and their reinforcing effects (2, 3) and the fact that the "high" is associated with the fast uptake of these drugs in brain but not with their continuous presence (4). However, neither the relation between the high and acute DAT inhibition nor the ability to block the high by long lasting DAT inhibitors has ever been demonstrated.In this study we evaluated the relationship between DAT blockade and the high using methylphenidate (MP) as the pharmacological challenge. MP was used because it has similar reinforcing properties to those of cocaine (5, 6) [its affinity for DAT is about twice that of cocaine (2)], its intravenous administration induces a high indistinguishable from that of cocaine (7), and it has longer pharmacokinetics than cocaine (half life in striatum >90 min versus 20 min for cocaine) which allows its repeated administration while there is still significant DAT blockade (4). We tested the ability to block or attenuate the high by prior DAT blockade by comparing the responses between the first and the second of two MP doses given 60 min apart. At 60 min the high from MP has returned to baseline, but the brain retains 75-80% of the peak drug concentration (4). Thus the two sequential dose strategy allowed us to evaluate the effects that DAT inhibition by the first dose had on the perception of the high induced by the second dose. We also assessed the relation between DAT occupancy and the subjective perception of the high after single and after two sequential doses of MP. Occupation of DAT by MP was measured with positron-emission tomography (PET) using [11C]d-threo-MP (the labeled active isomer of MP) as a DAT ligand (8). Four scans, including a baseline, were obtained in each subject to estimate MP-induced DAT occupancies at the times when the high induced after a single and after two sequential doses of MP occurs and to estimate DAT occupancies at 60 min after MP, which was the time selected to give the second of the two sequential MP doses. METHODSSubjects. Subjects were nine normal healthy male volunteers (25-35...

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Behavioral and Cardiovascular Effects of Intravenous Methylphenidate in Normal Subjects and Cocaine Abusers

Cited by 61 publications

References 14 publications

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Activation of Orbital and Medial Prefrontal Cortex by Methylphenidate in Cocaine-Addicted Subjects But Not in Controls: Relevance to Addiction

Relationship between psychostimulant-induced "high" and dopamine transporter occupancy.

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