tolcapone and Substance-Withdrawal-Syndrome

Dopamine levels in the prefrontal cortex (PFC) are thought to play an important role in cognitive function and nicotine dependence. The catechol-O-methyltransferase (COMT) inhibitor tolcapone, an FDA-approved treatment for Parkinson's disease, increases prefrontal dopamine levels, with cognitive benefits that may vary by COMT genotype. We tested whether tolcapone alters working memory-related brain activity and performance in abstinent smokers.. In this double-blind crossover study, 20 smokers completed 8 days of treatment with tolcapone and placebo. In both medication periods, smokers completed blood oxygen level-dependent (BOLD) fMRI scans while performing a working memory N-back task after 24h of abstinence. Smokers were genotyped prospectively for the COMT val(158)met polymorphism for exploratory analysis.. Compared to placebo, tolcapone modestly improved accuracy (p=0.017) and enhanced suppression of activation in the ventromedial prefrontal cortex (vmPFC) (p=0.002). There were no effects of medication in other a priori regions of interest (dorsolateral PFC, dorsal cingulate/medial prefrontal cortex, or posterior cingulate cortex). Exploratory analyses suggested that tolcapone led to a decrease in BOLD signal in several regions among smokers with val/val genotypes, but increased or remained unchanged among met allele carriers. Tolcapone did not attenuate craving, mood, or withdrawal symptoms compared to placebo.. Data from this proof-of-concept study do not provide strong support for further evaluation of COMT inhibitors as smoking cessation aids.

Topics: Adolescent; Adult; Affect; Aged; Behavior, Addictive; Benzophenones; Brain; Brain Mapping; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Female; Genotype; Humans; Magnetic Resonance Imaging; Male; Memory, Short-Term; Middle Aged; Nitrophenols; Polymorphism, Single Nucleotide; Smoking; Smoking Cessation; Smoking Prevention; Substance Withdrawal Syndrome; Tobacco Use Cessation Devices; Tolcapone; Young Adult

Forty patients affected by severe Parkinson's disease (PD) were treated with tolcapone as an adjunctive therapy to L-DOPA, for 3-7 months, until this drug was discontinued because of side-effects (2 diarrhoea, one of them with orthostatic hypotension, 2 increments of liver enzymes) or because of mandatory indications of the European drugs authority. All patients, after 3-6 months of L-DOPA therapy adjustments, received entacapone for 3 months again followed by withdrawal. L-DOPA daily dosage was significantly reduced by tolcapone and entacapone (p = 0.01 and 0.05). "On" time was increased by 15% during tolcapone treatment (p < 0.05), and by 8% during entacapone treatment. "Off" time was decreased by 16% during tolcapone and by 7% during entacapone treatment. Entacapone was withdrawn in the same patient who experienced diarrhoea and orthostatic hypotension during tolcapone because of recurrence of side-effects, in 6 patients because of increment of dyskinesias (with hallucinations) and in 1 patients because of rhythmic, jerking myoclonus.

Topics: Aged; Antiparkinson Agents; Benzophenones; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Levodopa; Male; Mental Disorders; Middle Aged; Nitriles; Nitrophenols; Parkinson Disease; Substance Withdrawal Syndrome; Tolcapone

Topics: Aged; Aged, 80 and over; Akathisia, Drug-Induced; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Confusion; Female; Humans; Levodopa; Neuroleptic Malignant Syndrome; Nitrophenols; Substance Withdrawal Syndrome; Tolcapone