The neurobiology of alcoholism in humans is still poorly understood. Experiments in rodents have suggested that the mesolimbic dopaminergic system is critically involved in the rewarding properties of alcohol, and that a deficit of mesolimbic dopamine (DA) transmission might constitute a risk factor for developing alcoholism. Furthermore, it has been suggested that low mesolimbic D2 receptor transmission might be implicated in alcohol craving and vulnerability to relapse. However, relatively little data is available to support the relevance of these preclinical studies to alcoholism in humans. Recent developments in brain imaging technology make it possible to test these hypotheses in alcoholic subjects. The general aim of this proposal is to test the hypothesis that alcoholism is associated with a deficit in mesolimbic DA function. Using neuroreceptor imaging and a state of the art positron emission tomography (PET) scanner, the investigators propose to evaluate the association between alcoholism and alteration in pre- and post synaptic parameters of dopamine transmission in the ventral striatum: 1) D2 receptor availability; 2) amphetamine-induced intrasynaptic dopamine release. D2 receptors's availability will be measured as the binding potential of the radiotracer [~ ~C]raclopride. The amphetamine-induced intrasynaptic DA release will be evaluated by the displacement of [~C]raclopride from D2 receptors following the amphetamine challenge. D2 receptor availability (specific aim #1) and amphetamine-induced intrasynaptic DA release (specific aim #2) will be measured in 24 recently abstinent alcoholics (within 3 to 4 weeks of abstinence) and 24 healthy controls matched for age, gender, ethnicity, parental socioeconomic status and nicotine dependence. The hypotheses are that, compared to matched control subjects, alcoholics will display lower D2 receptors availability and blunted amphetamine-induced DA release in the ventral striatum, and that these abnormalities will correlate with severity of alcoholism and intensity of alcohol craving. This study will provide a comprehensive description of synaptic dopaminergic parameters in alcoholism. If indeed deficits in DA function are found in chronic alcoholics, the investigators can examine as a second step, possibly in the renewal of this application, whether these deficits represent a toxic effect of alcohol or a vulnerability factor. Understanding the neurochemical abnormalities underlying vulnerability to alcoholism would guide future treatment interventions and risk prevention strategies.
| Martinez, Diana; Gil, Roberto; Slifstein, Mark et al. (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58:779-86 |
