The use of marijuana by young people in our society continues to be a problem. It is the illicit drug that is most commonly used by youths today. Estimates of worldwide regular users exceed one hundred million individuals. However we still know little of the neurobiological consequences of its use by humans. It is clear that a better understanding of its actions in the human brain will benefit the development of innovative methods to deal with the increase in marijuana use and abuse. At present, functional sites for the action of marijuana in the human brain are poorly understood. As a result of significant technological advances in human functional brain imaging, it is now possible to directly examine the effects of marijuana and its chronic use on the human brain. The long range goal of this project is to elucidate sites of action A9-tetrahydrocannabinol (THC), the major psychoactive constituent of marijuana, in human brain and to determine those that are mechanistically related to the drug's intoxicating and self-administration properties and its impairment of cognitive and perceptual motor behavior. This project will be conducted entirely on experienced human marijuana users. Functional magnetic resonance imaging (FMRI) will be used as the imaging modality in all studies. fMRI is a specialized application of MRI that permits an examination of functional cerebral activity without the use of X-rays or ionizing radiation. Its excellent temporal (seconds) and spatial (2-4 mm) resolution permits virtual """"""""real time' brain imaging and within subjects designs that are not possible with other current non-invasive or minimally invasive procedures. This project has four specific aims: 1) To determine the neuronal and non-neuronal (vascular) mechanisms underlying the changes in fMRl signal induced by A9-THC. This will be accomplished by using both arterial spin labeling based perfusion studies and first pass Gd-DTPA blood volume mapping. These results will expand our basic understanding of the dynamics of cannabinoid effects on brain neuronal and vascular function and will be applied to the analysis and interpretation of the studies from Aims 2, 3 and 4. 2) To further quantify A9-THC action using BOLD imaging to determine its pharmacodynamic properties within the human brain and to relate them in time and intensity to observed physiological and behavioral actions of intravenous ^9-THC. 3) To determine the ability of ^9-THC to aRer functional brain activity using perceptual-motor and cognitive tasks that activate specific brain regions containing cannabinoid receptors as experimental probes. 4) To determine the effects of heavy, chronic marijuana use and cessation on regional neuronal responsivity by comparing neuronal responses to task activation and acute drug challenge as a function of use and/or withdrawal. It is proposed that THC produces distinct changes in the activity of the human brain, both at rest and during the performance of cognitive and perceptual-motor tasks that are measurable using fMRl measures of blood oxygenation, flow and volume, It is further hypothesized that the unique behavioral and physiological effects of THC and marijuana in humans is due to unique patterns of brain regions activated and/or inhibited following acute drug administration, and that these responses will be both dose and time specific. The successful completion of these studies will increase our knowledge of the locus of marijuana action in humans and may indicate new strategies for dealing with its increasing use in our youth.
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