neural substrates in nicotine withdrawal

Conditions: Tobacco Use Disorder

Summary: this study will test the hypothesis that a medication called tolcapone (brand name: tasmar) will help reduce cognitive problems that smokers experience when they quit. this study will also determine whether the benefits of this medication differ depending on a smokers' genetic background.

tolcapone, an fda-approved treatment for parkinson's disease, improves cognitive performance in healthy controls with comt val/val genotypes, putatively by increasing prefrontal dopamine levels. we propose a within-subject double-blind cross-over neuroimaging study of short-term (11 days) treatment with tolcapone (vs. placebo). thirty chronic smokers (15 with val/val genotypes and 15 with val/met or met/met genotypes) will undergo blood oxygenation level dependent (bold) fmri during the two medication periods: 1. after 24 hours of monitored abstinence while on tolcapone, and 2. after 24 hours of monitored abstinence while on placebo (medication order counterbalanced with at least a 10-day washout). the bold fmri data will be acquired while subjects perform a working memory task (fractal n-back), a sustained attention task (continuous performance task; cpt), and a response inhibition task (go/no-go). the primary outcome is medication effects (within subject) on task-related bold activation after 24 hours of abstinence. changes in behavioral performance and subjective symptoms will be examined in relation to brain activity changes. the proposed study will provide a critical mechanistic understanding of the role of comt in abstinence-induced cognitive symptoms that promote smoking relapse. information obtained in this study may further establish cognitive performance measures as endophenotypes for nicotine dependence.

Eligibility criteria:
inclusion criteria: * smokers who are between 18 and 65 years of age who self-report smoking at least 10 cigarettes (menthol and non-menthol) per day for at least the last 6 months. * healthy as determined by the study physician, based on a medical evaluation including medical history and physical examination, psychiatric evaluation, and liver function tests (lfts and ggt enzyme levels). * capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and hipaa form. * women of childbearing potential must consent to use a medically accepted method of birth control while participating in the study (e.g., condoms and spermicide, oral contraceptive, depo-provera injection, contraceptive patch, tubal ligation) and have 3 months of regular menstrual cycles. * capable of providing a carbon monoxide (co) breath test reading greater than 10 parts per million (ppm) at the medical screening visit. exclusion criteria: smoking behavior * current enrollment or plans to enroll in another research or smoking cessation program in the next 3 months. * provide a co reading less than or equal to 10ppm at the medical screening visit. * plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) while enrolled in the study. alcohol/drug exclusion: * history (past 2 years) or current diagnosis of substance abuse and/or currently receiving treatment for substance abuse (alcohol, thc, cocaine, pcp, amphetamines, methamphetamines, mdma/ecstasy, opiates, methadone, benzodiazepines, tricyclic antidepressants, and barbiturates). * current alcohol consumption that exceeds 21 standard drinks/week over the last 6 months. * positive urine drug screen (for substances listed previously) at the medical screening visit or either testing day. * breath alcohol concentration (brac) assessment greater than or equal to 0.01 at medical screening visit or either testing day. medication exclusion criteria: current use or recent discontinuation (within last 28 days) of any medication including the following: * any form of psychotropic medications including: antipsychotics; mood-stabilizers (e.g., lithium, valproic acid, carbamazepine/tegretol); anti-depressants (tricyclics, ssri's, maoi's, non-selective maois, wellbutrin, st. john's wort); anti-anxiety/anti-panic agents; anti-obsessive agents; prescription stimulants (e.g., provigil, ritalin); diet pills/anorectics; systemic steroids; daily medication for chronic pain (e.g., opiates) or muscle spasms; daily use of over the counter stimulants in pill form (e.g., ephedrine) * anti-coagulants (e.g., warfarin) * any heart medications (e.g., dobutamine, isoproterenol) * daily medication for asthma * parkinson's disease medications (e.g., levodopa, methyldopa, apomorphine) * sympathomimetic (e.g., albuterol, pseudoephedrine) * other smoking cessation medications (wellbutrin/zyban, chantix/varenicline) medical exclusion criteria: * women who are pregnant, planning a pregnancy within the next 3 months, or lactating. * history or current diagnosis of any axis 1 disorder as identified by the mini (mini international neuropsychiatric interview) or self-report. for major depression, only a current diagnosis will be exclusionary. * history or current diagnosis of attention-deficit hyperactivity disorder (adhd). * serious or unstable disease (e.g., cancer within the past 6 months \[except squamous cell carcinoma\], hiv, parkinson's disease). * history of epilepsy or a seizure disorder. * history or current diagnosis (last 6-months) of abnormal rhythms and/or tachycardia (\>100 beats/minute); history or current diagnosis of copd, cardiovascular disease (stroke, angina, coronary heart disease); heart attack in the last 6 months; uncontrolled hypertension (sbp\>150 or dbp\>90). * history or current kidney and/or liver failure (including transplant), disease, or impairment (e.g., cirrhosis); history or current diagnosis of hepatitis (excluding hepatitis a); liver function tests more than 20% outside of the normal range; gamma-glutamyl transpepsidase (ggt) values greater than 20% outside the normal range. * allergy to the study medication, tolcapone (tasmar). * history of severe, uncontrolled muscle movements (e.g., uncontrolled jerking, twitching) or a certain severe muscle problem (rhabdomyolysis). * low or borderline intellectual functioning - determined by receiving a score of less than 90 on the shipley institute of living scale (sils) which correlates with the wechsler adult intelligence scale-revised (wais-r) estimated iq test (administered at the medical screening visit). * experience of dizziness or lightheadedness upon standing on a daily basis. * lifetime history of stroke. fmri exclusion criteria: * self-reported history of claustrophobia. * left-handedness. * color blindness. * any impairment preventing subjects from using response pad necessary for cognitive testing. * circumstances or conditions that may interfere with magnetic resonance imaging (mri). * having a cochlear implant or wearing bilateral hearing aids. * self-reported history of head trauma (including being knocked unconscious for 3 minutes or greater and diagnosis of a concussion) or cns tumor. * self-reported use of pacemakers, certain metallic implants, or presence of metal in the eye as contraindicated for mri. * history of gunshot wound. * weight greater than 300lbs. at medical screening or either testing day. * completion of cognitive testing in study #810493 or #811325 within the last 6 months. genetic profile exclusion criteria: * in order to balance the distribution of males and females, some participants who meet genotype and other eligibility criteria may not be enrolled in the study. general exclusion criteria: * any medical condition or concomitant medication that could compromise subject safety or treatment, as determined by the principal investigator and/or study physician. * inability to provide informed consent or complete any of the study tasks as determined by the principal investigator and/or study physician.

Keywords: genetics nicotine cognition fmri