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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA004200-10A3
Application #
2043053
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1988-05-01
Project End
1997-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
East Carolina University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Greenville
State
NC
Country
United States
Zip Code
27858
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Myers, R D; Robinson, D E (1999) Tetrahydropapaveroline injected in the ventral tegmental area shifts dopamine efflux differentially in the shell and core of nucleus accumbens in high-ethanol-preferring (HEP) rats. Alcohol 18:83-90
Myers, R D; Robinson, D E (1999) Mmu and D2 receptor antisense oligonucleotides injected in nucleus accumbens suppress high alcohol intake in genetic drinking HEP rats. Alcohol 18:225-33
Jones, E A; McMillen, B A (1999) The cardiovascular effects of amperozide: interactions with cocaine. Pharmacol Toxicol 84:53-8
West, M W; Kalmus, G; Myers, R D (1998) Limited access to ethanol in genetic drinking rats is suppressed while feeding is enhanced by the mixed 5-HT1A agonist/5-HT2A antagonist FG5938. Pharmacol Biochem Behav 60:823-8
West, M W; Biggs, T A; Tavares, E et al. (1998) Drinking patterns in genetic low-alcohol-drinking (LAD) rats after systemic cyanamide and cerebral injections of THP or 6-OHDA. Alcohol 15:239-47
Wilcox, R E; McMillen, B A (1998) The rational use of drugs as therapeutic agents for the treatment of the alcoholisms. Alcohol 15:161-77
Myers, R D; Robinson, D E; West, M W et al. (1998) Genetics of alcoholism: rapid development of a new high-ethanol-preferring (HEP) strain of female and male rats. Alcohol 16:343-57

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