Protocol Number: 09-M-0040

Title:

Imaging Cannabinoid CB1 Receptors in Alcohol Dependence

Number:

09-M-0040

Summary:

Alcohol dependence (alcoholism) is a chronic medical illness with a relapsing course and a major public health problem. Alcoholism is clinically characterized by periods of uncontrolled alcohol consumption and withdrawal, during which counter-adaptive mechanisms such as stress and dysphoria are recruited. Neurobiological research into the pathophysiology of the illness suggest that both the primary rewarding effects of ethanol as well as neuroadaptive changes that occur during chronic alcohol exposure involve persistent changes in various brain neurotransmission systems, such as the dopamine, glutamate, and gamma-amino butyric acid (GABA) systems. Recent views of the illness also emphasize the long-lasting recruitment of the brain stress system. Unfortunately, despite this progress, available pharmacological agents for the treatment of alcoholism are too few and not sufficiently efficacious.

The brain endocannabinoid (EC) system is a recently discovered brain neurotransmission system, which involves endogenous cannabinoid agents (ECs) that act upon specific receptors (CB1 and CB2). CB1 receptor is abundant in the human brain and acts as an inhibitory modulator of classical neurotransmitters. ECs and CB1 receptors appear to modulate the brain reward system, and animal studies have demonstrated an important role of CB1 receptor stimulation in alcohol- and drug-related behaviors. During chronic alcohol exposure, EC levels in the brain are elevated and CB1 receptor levels are consequently reduced; this appears to be reversible following withdrawal. Animal studies suggest that CB1 receptor blockade in the abstinent phase may reduce alcohol craving and relapse. To what extent ECs and CB1 receptors are involved in the pathophysiology of alcohol dependence in humans is currently unknown. The lack of suitable methods to reliably quantify CB1 receptors in the living human brain has to date hindered the progress in this field.

In this protocol, we outline studies aiming at elucidating the role CB1 receptors in alcohol dependence by using positron emission tomography (PET) and the recently developed radiotracer for CB1 receptors, [11C]MePPEP. The aim of this project is to explore CB1 receptor abnormalities at various stages of alcohol dependence in humans. The primary hypothesis is that CB1 receptors are downregulated during chronic alcohol exposure and upregulated during protracted abstinence. Insight into the role of CB1 receptor function in human alcoholism may help guide future development of pharmacotherapies.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male

Referral Letter Required: No

Population Exclusion(s): Female

Children

Eligibility Criteria:

INCLUSION CRITERIA:

Alcohol Dependent Subjects:

Must be male, 18-65 years of age and be able to give written informed consent.

Must be healthy based on history, physical examination, and have no clinically significant coagulopathies or laboratory abnormalities other than those related to alcohol dependence.

Must fulfill DSM-IV criteria (American Psychiatric Association 1987) for alcohol dependence. In addition, they must have an alcohol consumption of 35 or more standard drinks per week, as measured by timeline follow-back during the 28-day period preceding admission, as well as during the 7-day period immediately preceding it.

Healthy Subjects:

Must be male, 18-65 years of age and be able to give written informed consent.

Must be healthy based on history, physical examination, and have no clinically significant laboratory abnormalities.

About half of the healthy subjects will currently smoke cigarettes and about half will not.

EXCLUSION CRITERIA:

Alcohol Dependent Subjects:

Any serious medical condition as judged by the investigator in consultation with the attending physician in the NIAAA program.

Past or present diagnosis of schizophrenia, bipolar illness or any other psychotic disorder; any current disorder that has required psychoactive medication (other than oxazepam) within the preceding 28-day period (42 days for fluoxetine). Oxazepam is a relatively short acting benzodiazepine and is used clinically during alcohol withdrawal. Any past or present substance abuse other than alcohol, including marijuana use.

Positive test for HIV.

Metallic foreign bodies that would be affected by the MRI scanner magnet, or fear of enclosed spaces likely to make the subject unable to undergo an MRI scan.

Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.

History of fetal alcohol syndrome or other neurodevelopmental disorder.

History of seizures, other than in childhood and related to fever.

Recent exposure to radiation (i.e., PET from other research) which when combined with this study would be above the allowable limits.

Positive urine drug screen.

Inability to lie flat on camera bed for about 2.5 hours

Healthy Subjects:

Any current Axis I diagnosis; and any past or present substance abuse including marijuana use.

Recent heavy use of alcohol. That is, subjects must have an alcohol audit score of less than or equal to 6 for males. In addition, subjects must agree not to consume any alcohol in the three days prior to the PET scan.

Psychotropic medication use (including benzodiazepines and illicit drugs) during the 28 days (42 days for fluoxetine) prior to the PET scan.

Serious medical problems.

Positive test for HIV.

Metallic foreign bodies that would be affected by the MRI magnet, or fear of enclosed spaces likely to make the subject unable to undergo an MRI scan.

Head trauma resulting in a period of unconsciousness lasting longer than 10 minutes.

History of fetal alcohol syndrome or other neurodevelopmental disorder.

History of seizures, other than in childhood and related to fever.

Recent exposure to radiation (i.e., PET from other research) which when combined with this study would be above the allowable limits.

Positive urine drug screen.

Inability to lie flat on camera bed for about 2.5 hours.

Special Instructions:

Currently Not Provided

Keywords:

Positron Emission Tomograhy

Brain Imaging

Alcoholism

Recruitment Keyword(s):

None

Condition(s):

Alcoholism

Investigational Drug(s):

[11C]MePPEP

Investigational Device(s):

None

Intervention(s):

None

Supporting Site:

National Institute of Mental Health

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Basavarajappa BS, Hungund BL. Role of the endocannabinoid system in the development of tolerance to alcohol.Alcohol Alcohol. 2005 Jan-Feb;40(1):15-24. Epub 2004 Nov 18.

Brown AK, George DT, Fujita M, Liow JS, Ichise M, Hibbeln J, Ghose S, Sangare J, Hommer D, Innis RB. PET [11C]DASB imaging of serotonin transporters in patients with alcoholism. Alcohol Clin Exp Res. 2007 Jan;31(1):28-32.

Cippitelli A, Bilbao A, Hansson AC, del Arco I, Sommer W, Heilig M, Massi M,Bermœdez-Silva FJ, Navarro M, Ciccocioppo R, de Fonseca FR; The European TARGALC Consortium. Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats. Eur J Neurosci. 2005 Apr;21(8):2243-51.

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