The cannabinoid receptor, in addition to being the initial site of action for the abuse drug marijuana, serves important physiological roles in pain perception and motor coordination. The overall goal of this project is to understand the molecular mechanisms of regulation of the neuronal cannabinoid receptor (CB1). It has been well established that tolerance develops to the effects of cannabinoids. We have evidence that alterations in levels of the cannabinoid receptor occur during tolerance. Therefore, specific aim 1 will examine the regulation of the cannabinoid receptor during chronic exposure to cannabinoids in transfected cells.
This aim will address post-transcriptional regulation of the CB1 receptor by utilizing CH0 cells transfected with CB1 receptor cDNA. These cell lines facilitate the study of drug effects on receptor levels, receptor localization and alterations in signal transduction. The studies proposed in specific aim 2 address transcriptional and post-transcriptional regulation of the endogenous cannabinoid receptor. These studies are conducted in neuronal cell lines and primary culture in which receptors are not overexpressed, and although CB1 receptor binding cannot be easily assessed, change in CB1 gene expression can be studied. Cerebellar neurons in primary culture will be studied since they can form synapses and thus mimic normal neuronal relationships.
Specific aim 3 will address the regulation of the CB1 receptor gene in an in vivo system. These studies will complement in specific aim 4 which is to characterize the gene for the mouse brain cannabinoid receptor and identify elements in the gene which may be responsible for regulation of receptor expression. Although the mouse is one of the primary animal models for the study of cannabinoids, the sequence of the gene encoding this receptor has not been elucidated. We have cloned the mouse brain cannabinoid receptor gene from a genomic library, and will characterize the 5' and 3' regions of this gene to determine regulatory regions. Understanding the molecular mechanisms underlying the regulation of the neuronal cannabinoid receptor will contribute significantly to our knowledge of this receptor at which marijuana and the endogenous cannabinoids act. This, in turn, may lead to a better understanding of marijuana abuse in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA009978-04
Application #
6089034
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Colvis, Christine
Project Start
1996-09-30
Project End
2000-12-31
Budget Start
1999-08-17
Budget End
1999-12-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94107
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