Marijuana has been the most prevalent illicit drug of abuse for many years; yet, major questions remain regarding the health consequences of long-term use. The pharmacological and toxicological properties of smoked marijuana have not been thoroughly investigated because of the challenges posed by inhalation studies, particularly with a smoked plant material. Instead, the research emphasis has been on the major psychoactive constituent in marijuana, delta-9-tetrahydrocannabinol (THC). The gap in our knowledge has led to speculation that constituents other than THC contribute to marijuana's effects. Equally important is the question of what adverse effects result from long-term use of marijuana for either recreational or medicinal purposes. Our first goal is to determine whether the effects of marijuana are due solely to THC. We will expose mice acutely to marijuana smoke as well as THC vapor to determine whether the effects on motor activity, pain sensitivity, body temperature, and memory are identical. We will examine marijuana samples with different quantities of cannabinoids, as well as spike them with known cannabinoids. Blood and brain levels of THC will be determined by mass spectrometry to establish dosimetry and pharmacokinetic factors. The second goal will be to determine whether chronic exposure of marijuana smoke and THC inhalation in mice produces similar degrees of drug dependence, cognitive impairment, immunosuppression in lung, and tumor proliferation. Mice will be exposed repetitively to marijuana smoke or THC inhalation for either one week, two weeks, and three months. At the end of each exposure period, they will be challenged with the CB1 receptor antagonist SR 141716A to assess the degree of dependence. The Morris water maze will be used to assess alterations in reference and working memory. Finally, immune function and tumor proliferation, as well as the histopathology, will be evaluated in the lungs of animals exposed for varying periods of time. The discovery of the central and peripheral endocannabinoid systems consisting of CB1 and CB2 cannabinoid receptors, signal transduction pathways, endocannabinoids [i.e., anandamide (AEA) and 2-arachidonyl glycerol (2-Ara-GI)], putative AEA membrane transporter (AMT) and AEA's metabolic enzyme fatty acid amidohydrolase (FAAH), provides an opportunity to determine which effects of marijuana smoke are mediated through this system
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