Smoking-induced Dopamine Release: a [11C]-(+)-PHNO PET Study in Humans

Does the Insula Control Smoking-induced Dopamine Release? A TMS/[11C]-PHNO Study in Humans. Part I: Smoking-induced Dopamine Release: a [11C]-(+)-PHNO PET Study in Humans.

This study will evaluate effects of smoking on the dopaminergic system by using PET tomography with new radioligand, [11C]-(+)-PHNO. Our primary hypothesis is that smoking a cigarette will produce dopamine release and this release can be measured using PET imaging and the [11C]-(+)-PHNO radiotracer. The secondary hypothesis is that this smoking induced dopamine release will be correlated with subjective craving and anxiety ratings.

Study Overview

• Status: Completed
• Conditions: Tobacco Use Disorder

Detailed Description

This will be a within-subjects study in healthy male and female smokers. There will be one within factor condition: Smoking and Non Smoking. Therefore, there will be a repeated measure of PET scans using [11C]-(+)-PHNO under two different conditions. Ten subjects (n=5 male and n=5 female) included in the study will come on two different days and will have a Smoking or Non smoking session performed just before the PET study. Subjective assessments will be conducted at each experimental condition.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5S 2S1
      • Centre for Addiction and Mental Health - 33 Russell St

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Healthy smokers

Description

Inclusion Criteria:

• Adult males or females
• Regular smoking of at least 10 cigarettes, excluding ultra-low nicotine cigarettes, per day for at least two years
• Score on the Fagerstrom Test for Nicotine Dependence of 4 or more
• No intention to quit or reduce tobacco use, and no treatment for tobacco dependence currently
• No history of abuse of or dependence on any other drug, defined by DSM-IV criteria

Exclusion Criteria:

• Pregnancy
• Presence of metal objects in the body or implanted electronic devices, that preclude safe MR scanning
• Claustrophobia
• Cardiovascular or cerebrovascular diseases
• Major psychiatric disorders including mood, anxiety or psychotic disorders
• History of or current neurological illnesses including seizure disorders, migraine, multiple sclerosis, movement disorders, head trauma, CVA or CNS tumor
• Gross structural brain abnormalities as revealed by T1 weighted images
• Current use or use during the previous month of medication that may affect the CNS (e.g. neuroleptics, bupropion)
• Learning disability, amnesia or other conditions that impede memory and attention

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Healthy smokers; Healthy male and female smokers. Each subject will undergo PET scan (along with craving and anxiety questionnaires) on two conditions - Smoking and Non-smoking - on two separate visits.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
[11C]-(+)-PHNO binding potential	The process of imaging requires the injection of a positron-emitting radiotracer (here, [11C]-(+)-PHNO) that binds to the protein of interest (here, dopamine receptor DRD2/3) followed by the measurement of this binding using the PET scanner. Dopamine release increases DRD 2/3 occcupancy which results in decreased radiotracer's binding potential, and vice versa. [11C]-(+)-PHNO binding potential will be measured on two different conditions (Smoking vs. Non-smoking) on two separate days.	Up to 14 days between PET scans

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective reports of craving	Levels of subjective craving will be assessed prior to and after each condition (Smoking vs. Non-smoking) on two separate days. Minnesota Nicotine Withdrawal Scale, Tiffany Questionnaire of Smoking Urges, The Urge to Smoke scale, Tobacco Craving Questionnaire, and 21-item Visual Analogue Scale will be used.	Up to 14 days between PET scans
Subjective reports of anxiety	Subjective reports of anxiety will be collected prior to and after each condition (Smoking vs. Non-smoking) on two separate days. State anxiety questions from the Spielberg State-Trait Anxiety Inventory will be used.	Up to 14 days between PET scans

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: Pfizer
• Investigators: Principal Investigator: Bernard Le Foll, MD, Centre for Addiction and Mental Health

Publications and helpful links

General Publications

• Brody AL, Olmstead RE, London ED, Farahi J, Meyer JH, Grossman P, Lee GS, Huang J, Hahn EL, Mandelkern MA. Smoking-induced ventral striatum dopamine release. Am J Psychiatry. 2004 Jul;161(7):1211-8. doi: 10.1176/appi.ajp.161.7.1211.
• Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, Houle S, Seeman P, Ginovart N. Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. J Med Chem. 2005 Jun 16;48(12):4153-60. doi: 10.1021/jm050155n.
• Le Foll B, Goldberg SR, Sokoloff P. The dopamine D3 receptor and drug dependence: effects on reward or beyond? Neuropharmacology. 2005 Sep;49(4):525-41. doi: 10.1016/j.neuropharm.2005.04.022.
• Le Foll B, Schwartz JC, Sokoloff P. Dopamine D3 receptor agents as potential new medications for drug addiction. Eur Psychiatry. 2000 Mar;15(2):140-6. doi: 10.1016/s0924-9338(00)00219-4.
• Le Foll B, Goldberg SR, Sokoloff P. Dopamine D3 receptor ligands for the treatment of tobacco dependence. Expert Opin Investig Drugs. 2007 Jan;16(1):45-57. doi: 10.1517/13543784.16.1.45.
• Brody AL, Mandelkern MA, Olmstead RE, Scheibal D, Hahn E, Shiraga S, Zamora-Paja E, Farahi J, Saxena S, London ED, McCracken JT. Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch Gen Psychiatry. 2006 Jul;63(7):808-16. doi: 10.1001/archpsyc.63.7.808.
• Boileau I, Guttman M, Rusjan P, Adams JR, Houle S, Tong J, Hornykiewicz O, Furukawa Y, Wilson AA, Kapur S, Kish SJ. Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease. Brain. 2009 May;132(Pt 5):1366-75. doi: 10.1093/brain/awn337. Epub 2009 Jan 19.

Helpful Links

• Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: February 22, 2011
• First Submitted That Met QC Criteria: February 22, 2011
• First Posted (Estimate): February 24, 2011

Study Record Updates

• Last Update Posted (Estimate): March 5, 2013
• Last Update Submitted That Met QC Criteria: March 4, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Smoking-induced dopamine release; [11C]-(+)-PHNO PET Study
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Tobacco Use Disorder
• Other Study ID Numbers: 143/2010