Many abused drugs signal through the G protein pathway. All of the known opioid receptors are Gi coupled. The role of Gi in drug addiction will be explored using a novel system that provides direct control of Gi signaling in vivo, with temporal, spatial and pharmacological specificity. Genetically modified Gi-coupled kappa-opioid receptors can be activated only by the synthetic ligand spiradoline, and not by endogenous ligands. Inducible expression of this Receptor Activated Solely by Synthetic Ligand (RASSL) in selected brain regions of transgenic mice will be used to assess the functional consequences of Gi stimulation in those regions.
Specific Aim 1 : To gain control of Gi signaling in brain regions that contribute to the development of addiction. The kappa-opioid RASSL has been placed under the control of the tetracycline-controlled, inducible, tissue-specific expression system. This allows the RASSL to be expressed specifically in neural reward regions and activated by an exogenous drug, spiradoline, at precise times.
Specific Aim 2 : To characterize which specific behaviors associated with addiction, such as drug-seeking, drug taking, or withdrawal, are mediated by Gi signaling. Stimulation of the RASSL in neural reward regions should evoke some of the behaviors associated with addiction. Techniques to assess the behavioral response to RASSL stimulation will include drug, self-administration, conditioned place preference, and evaluation of withdrawal symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA006045-02
Application #
6378481
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2001-07-01
Project End
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$40,196
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
047120084
City
San Francisco
State
CA
Country
United States
Zip Code
94158