GENES REGULATED BY ABUSED DRUGS IN BRAIN--GENES INVOLVED IN NEURAL SIGNALING

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Abused drugs-induce long-term behavioral disorders that are thought to be maintained by biological mechanisms in the central nervous system that are largely unknown. Work in this group during previous FYs has developed a approaches to identifying such genes and documented candidate genes whose expression are regulated by abused drugs, including amphetamine, cocaine and morphine. Several genes that can be readily identified as possible participants in neuronal signalling have been identified. During this FY, the localized expression and functional regulation of more genes have been characterized and the functional implications of G-beta and cfos overexpression documented using intraventricular and intracerebral injection of antisense oligonucleotides. AntiGbeta oligonucleotides that are effective iin reducing levels of Gbeta immunoreactivity are able to block establishment of cocaine-induced sensitization, but are ineffective in blocking the expression of sensitization when they are administered following sensitizing doses. Theses effects are reversible over several weeks. Intracerebral injections of anti-cfos antisense oligonucleotides also reverse some of the features of cocaine withdrawal. These results support the likelihood that some of the products of genes identified as up- or downregulated by acute and chronic administration are likely to play roles in addictive phenomena.