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2010 Jun;67(6):632-44.
Ersche KD, Bullmore ET, Craig KJ, Shabbir SS, Abbott S, Müller U, Ooi C, Suckling J, Barnes A, Sahakian BJ, Merlo-Pich EV, Robbins TW.
University of Cambridge, Behavioural and Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, England.
Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence.
CONTEXT: There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. OBJECTIVE: To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges. DESIGN: Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. SETTING: Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. PARTICIPANTS: Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18). INTERVENTIONS: Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. MAIN OUTCOME MEASURES: Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. RESULTS: Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. CONCLUSIONS: Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.
2010 Jan;67(1):27-32.
Brodsky MA, Park BS, Nutt JG.
Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, OP-32, Portland, OR 97239. brodskym@ohsu.edu.
Effects of a dopamine agonist on the pharmacodynamics of levodopa in Parkinson disease.
BACKGROUND: Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood. OBJECTIVE: To examine the effects of a dopamine agonist on the motor response to levodopa. DESIGN: Double-blind, randomized, placebo-controlled, crossover clinical trial. SETTING: Ambulatory academic referral center. Patients Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia. INTERVENTIONS: Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment. MAIN OUTCOME MEASURES: Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to "ON" (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC. RESULTS: Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute x minutes (P = .006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P = .02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P = .004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion. CONCLUSIONS: Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia.
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