The broad objective of this application is to elucidate the etiological mechanisms underlying the abnormal drinking of alcohol in relation to monoamine neurotransmitters an amine-aldehyde adducts present endogenously in the brain. The long-term goal is to understand how tetrahydropapaveroline (THP), a precursor of morphine, or a tetrahydro- beta-carboline (THBC), a benzodiazepine receptor antagonist, evokes a dose- dependent change in the volitional intake of alcohol when either aldehyde adduct is delivered directly to sites in the brain's mesolimbic system. The induced preference for alcohol is permanent and is accompanied by elevated levels of blood alcohol and signs of physical dependence and withdrawal. Morphological mapping studies reveal that sites in the brain of the rat reactive to THP are found in limbic-midbrain and limbic- forebrain structures. These include ventral tegmental area, medial forebrain bundle, substantia nigra, nucleus accumbens, olfactory tubercle, and hippocampus. The objectives of the three major projects proposed are as follows.
The first aim i s to determine whether THP or THBC or both aldehyde adducts evoke alcohol drinking in the genetic non-drinking rat by virtue of their potential action as neurotoxins of dopaminergic and serotonergic neurons, respectively.
The second aim i s to elucidate specific cellular responses that may occur in relation to adduct-induced drinking as delineated by agonism or blockade of specific receptor subtypes of dopaminergic and serotonergic neurons within THP or THBC-reactive sites.
The third aim i s to characterize synaptic changes that may occur in vivo in alkaloid-reactive structures, in terms of release and turnover of dopamine and serotonin and their respective metabolites, in response to THP and THBC perfused by push pull cannulae or dialytrodes positioned in these structures. In these experiments unrestrained genetically derived alcohol drinking and non-drinking rats will be used. The health-related significance of these projects is the demonstration and further clarification of the neurochemical substrates of alcohol drinking as characterized at specific anatomical sites in the mesolimbic system. As a consequence, chemotherapeutic strategies to be developed for the treatment of the disease of alcoholism hopefully will be enhanced.
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