Chronic administration of cannabinoids (delta 9-THC) result in an unusua l degree of tolerance in which physiological and behavioral functions revert to near normal (control) levels but important second messenger pathways remain altered Understanding of the cellular mechanisms involved in the development of tolerance to chronic cannabinoid treatment will provide insight into processes responsible for tolerance to other frequently administered or abused drugs. Investigation of these processes can benefit from implementation of new strategies to quickly examine potentially altered expression profiles across large numbers of genes in order to determine those that might be involved in producing tolerance. Preliminary data using large scale cDNA microarray screening technology revealed that a significant number of genes related to various aspects of cannabinoid system function showed altered expression patterns across a 21 day treatment period. These patterns were assessed in two different brain regions, hippocampus and cerebellum and revealed similar time courses to cannabinoid (CBl) receptor and second messenger signaling changes. It is hypothesized that, common systems and their respective molecular counterparts may participate in adaptation to chronic drug exposure but this may differ across particular brain regions specific cell types. We propose to adapt and extend use of cDNA microarrays to delineate further the changes in altered gene expression during chronic exposure to cannabinoids. Specific Aim 1 will characterize the differential gene expression patterns in these and 3 other brain regions at different time points (i.e. days) during chronic cannabinoid treatment. Specific Aim 2 will take the analysis one step further by assessing changes in gene expression profiles during precipitated withdrawal from chronic cannabinoid exposure. Specific Aim 3 will assess the specific brain regions in which these gene expression changes occur utilizing in situ hybridization to determine the regional and cellular distribution of genes whose expression is changed during chronic exposure and during precipitated withdrawal (Specific Aims 1 and 2).

R01DA013778

2000-09-30

2004-07-31