Imaging Cannabinoid CB1 Receptors in Alcohol Dependence
Condition: Alcoholism
MeSH terms: Alcoholism
Study type: Observational

Summary: 
      The cannabinoid type 1 (CB1) receptor is a protein found in the brain that is involved with
      the effects of marijuana; it may also play a role in the effects of alcohol dependence and
      withdrawal. Earlier animal studies have shown that although long-term alcohol use decreases
      the number of CB1 receptors in the brain, the number returns to normal after alcohol use
      stops. This study will use positron emission tomography (PET) and magnetic resonance imaging
      (MRI) scans to trace a radioactive chemical called [11C]MePPEP, which can locate and measure
      the number of CB1 receptors in the brain. Researchers will study the CB1 receptors in the
      brains of people with alcohol dependence, and compare the results to the CB1 receptors in the
      brains of people without alcohol dependence. The results of this study will be used to
      further research into appropriate treatment procedures for alcohol dependence.

      This study will include 30 men with alcohol dependence and 50 men without alcohol dependence.
      All of the men must be between 18 and 65 years of age. Participants in both groups must not
      have any medical conditions that will prevent them from undergoing PET or MRI scans.

      For the PET scan, participants will be injected with a small amount of [11C]MePPEP and will
      then be brought to the PET scanner. The scan will take between 3 and 4 hours, but
      participants will be allowed to take breaks over the course of the scan. The MRI scan will
      not require any injections and will take approximately 1 hour to complete.

      Participants without alcohol dependence will make three visits to the National Institutes of
      Health Clinical Center. Blood and urine samples will be taken during one visit, and
      participants will arrange to have an MRI scan on one visit and a PET scan on the other visit,
      in whichever order they prefer.

      Participants with alcohol dependence will undergo two PET scans: the first will be performed
      between 3 and 7 days after the participant last consumed alcohol, and the second will be
      performed approximately 2 to 4 weeks after the first scan (with no alcohol consumption
      permitted in the interval). Participants will alcohol dependence will also undergo an MRI
      scan and will provide blood and urine samples.
    

Detailed description: 
      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 of CB1 receptors in
      alcohol and cannabis dependence by using positron emission tomography (PET) and the recently
      developed radiotracer for CB1 receptors, [(18)F]FMPEP-d2. The aim of this project is to
      explore CB1 receptor abnormalities at various stages of alcohol and cannabis dependence in
      humans. For the studies in alcohol dependence, the primary hypothesis is that CB1 receptors
      are downregulated during chronic alcohol exposure and upregulated during extended abstinence.
      For the studies in cannabis users, our primary hypothesis is that CB1 receptors are
      downregulated during chronic cannabis use and upregulated during extended abstinence. Insight
      into the role of CB1 receptor function in human alcoholism and in chronic cannabis use may
      help guide future development of pharmacotherapies.
    

Time perspective: Prospective
Keywords: Positron Emission Tomography; Brain Imaging; Alcoholism