Alcohol is one of the most commonly used drugs of abuse. Alcohol acts on the mesolimbic dopamine system, a system that mediates the rewarding effects of this substance. Preclinical and clinical studies have revealed that varenicline, a drug targeting the nicotinic acetylcholine receptors (nAChRs), and currently used for smoking treatment, could also be useful for alcohol dependence treatment. Preliminary clinical trials have been promising, but direct evidence for the impact of varenicline on the mesolimbic dopamine system is lacking in humans. Imaging with positron emission tomography (PET) permits the measurement of neurochemicals in vivo. PET has become a powerful tool for neuroscientists to visualize and localize receptors and estimate the endogenous levels of neurotransmitters. The process of imaging requires the injection of a positron-emitting radiotracer (e.g. [11C]-raclopride or [11C]-(+)-PHNO) that binds to the protein of interest (e.g. DRD2/3) followed by the measurement of this binding using the PET scanner. To this date, no study has been performed to directly measure the influence of varenicline on dopamine transmission in human brains. The [11C]-(+)-PHNO radiotracer, developed at CAMH by the co-applicant Dr. Wilson, is a tracer that appears ideally suited to detect fluctuations in dopamine levels and is also the only radiotracer that allows for the measurement of transmission at the dopamine D3 receptor (DRD3) in human brain. Our primary outcome measure will be to determine the impact of varenicline on dopamine transmission using a brain imaging approach. [11C]-(+)-PHNO radiotracer binding will be analyzed in both DRD2/3 (caudate and putamen) and in DRD3-rich areas (ventral striatum, globus pallidus area, midbrain). The influence of chronic administration of varenicline will be evaluated under treatment and also after treatment phase. Analysis after a washout period will assess whether changes in dopamine return to normal, providing evidence that changes in this neurotransmitter are related to varenicline levels. These studies will improve our understanding of the action of varenicline in the human brain and could provide a marker of response allowing to determine which subjects could benefit from the use of varenicline to treat alcohol dependence.
At CAMH, we have developed the [11C]-(+)-PHNO radiotracer for positron emission tomography, a tracer that is ideally suited to detect fluctuations in dopamine levels in human brain and is the only radiotracer that allows for the measurement of dopamine transmission at the level of dopamine D3 receptors. Using a brain imaging approach, we will assess the impact of varenicline on dopaminergic transmission in subjects taking varenicline. These studies will lead to an advance in our understanding on the mechanisms of action of varenicline and guide future development of treatments for alcohol dependence.
