Roles for alpha4beta2alpha5 and alpha7 type neuronal acetycholinergic receptors in behavioral responses to alcohol and nicotine.

摘要

Health problems arising from the abuse of alcohol and the smoking of cigarettes are serious policy issues in the United States. The mortality resulting from alcohol abuse and cigarette smoking in the United States is estimated to be approximately 100,000 and 400,000 people each year, respectively. Approximately 80% of alcoholics smoke cigarettes, and there is evidence that the two drugs share common genetic mechanisms. Animal models were used to determine if there are common genes mediating responses to alcohol and nicotine. Quantitative Trait Locus (QTL) mapping was conducted in recombinant inbred lines of mice to determine if there are common genes mediating responses to alcohol and nicotine. The results of the QTL analysis suggested α4 containing neuronal acetylcholinergic nicotinic receptors (nAChRs) regulate behavioral responses to alcohol and nicotine. There are 11 genes identified encoding the neuronal nicotinic receptor subunits α2–α7, α9, α10 and β2–β4. These subunits form a number of different combinations to make functional heteromeric and homomeric receptors. The α4β2 and α7 type nAChRs are the most widely expressed nAChRs in the mammalian brain and are influenced by alcohol in vitro. The α4β2 containing receptors also may contain the α5 subunit. Therefore, the role of the α4β2α5 and α7_nAChRs in behavioral responses to alcohol and nicotine was further investigated using mice containing targeted mutations in the α4, β2, α5 and α7 subunits of the nAChRs. The animals carrying targeted mutations were used to provide additional lines of evidence for the role of α4β2α5 and α7 nAChRs in mediating behavioral responses to alcohol and nicotine. The results suggest that the α4β2α5 and α7 type nAChRs mediate some behavioral responses to nicotine and alcohol. These results have significant implications for the treatment of alcoholism and tobacco use individually, as well as treatment of patients abusing both of these drugs. One possible treatment method derived from these results may be the use of α4β2α5 or α7 type nAChR antagonists as a pharmacotherapy for the treatment of alcohol abuse.