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Dana E. Selley, Ph.D. |
Education: University of Rochester, 1991
Research interests: Cellular tolerance and dependence; mechanisms of action of opiates, cannabinoids and alcohol; G-protein-mediated signal transduction
Research in my laboratory focuses on the mechanism of action of G-protein-coupled receptors, especially those that mediate the effects of psychoactive drugs, such as opiates, cannabinoids and antidepressants. Recent studies also have begun to examine the effects of ethanol on G-protein-coupled receptor action in the central nervous system. Molecular and biochemical techniques are used to study several issues related to G-protein-mediated signal transduction and psychoactive drug action, in both rodent brain and cell culture models. Major projects examine the molecular mechanisms underlying opioid and cannabinoid agonist efficacy, opioid and cannabinoid tolerance and dependence, efficacy and chronic effects of antidepressant/anxiolytic drugs, and involvement of G-protein-coupled receptors in ethanol intoxication and dependence.
G-protein activation by receptors can be measured directly using [35S]GTPgS binding and low Km GTPase assays. We have found that agonist efficacy correlates with several parameters of G-protein activation. Different G proteins modulate the activity of various effectors, such as adenylyl cyclase, phospholipase C and ion channel activity, which also can be measured directly. Because receptors typically couple to multiple G-proteins, different agonists may selectively activate different arms of the signal transduction pathway. This possibility can be tested using cell lines that have been selectively transfected to over-express specific G-protein subunits. Determining the selectivity of agonist-stimulated receptor signaling may lead to the development of drugs therapies that maximize medicinal effects while minimizing unwanted side effects.
Chronic administration of drugs can lead to both desirable and undesirable long-term effects. Tolerance to and dependence on opiates is a major problem both for drug-addicted individuals and for those who must take opiate pain medication for long time periods. On the other hand, some drugs, such as antidepressants and atypical anxiolytics, must be taken for several days to weeks in order produce a beneficial effect. Various drugs (opiates, cannabinoids, alcohol and buspirone) have been found to produce differential changes in the ability of receptors to activate G-proteins in different brain regions. Some produce widespread profound alterations, whereas others produce small changes confined to specific brain areas. The mechanisms underlying these chronic drug effects, and how they correlate with behavioral and physiological aspects of chronic drug action in animals, is being studied in numerous collaborative projects. In addition, cultured cell lines are being used in our laboratory to study these chronic drug effects in defined cellular systems
Recent publications:
Kinsey SG, Mahadevan A, Zhao B, Sun H, Naidu PS, Razdan
RK, Selley DE, Imad Damaj M, Lichtman AH. (2011) The CB(2) cannabinoid
receptor-selective agonist O-3223 reduces pain and inflammation without
apparent cannabinoid behavioral effects.
Neuropharmacology. 60(2-3):244-51.
Huffman JW, Hepburn SA, Lyutenko N, Thompson AL, Wiley JL,
Selley DE, and Martin BR. (2010)
1-Bromo-3-(1',1'-dimethylalkyl)-1-deoxy-Δ(8)-tetrahydrocannabinols: New
selective ligands for the cannabinoid CB(2) receptor.
Bioorg Med Chem. 2010 Nov 15;18(22):7809-15.
Schlosburg JE, Blankman JL, Long JZ, Nomura DK, Pan B,
Kinsey SG, Nguyen PT, Ramesh D, Booker L, Burston JJ, Thomas EA, Selley DE,
Sim-Selley LJ, Liu QS, Lichtman AH, and Cravatt BF. (2010) Chronic
monoacylglycerol lipase blockade causes functional antagonism of the
endocannabinoid system. Nat
Neurosci. 13(9):1113-9.
Burston JJ, Wiley JL, Craig AA, Selley DE, and Sim-Selley
LJ. (2010) Regional enhancement of cannabinoid CB₁ receptor
desensitization in female adolescent rats following repeated
Delta-tetrahydrocannabinol exposure.
Br J Pharmacol. 161(1):103-12.
Smith TH, Sim-Selley LJ, and Selley DE. (2010) Cannabinoid
CB1 receptor-interacting proteins: novel targets for central nervous system
drug discovery?
Br J Pharmacol. 160(3):454-66.
Nguyen PT, Selley DE, and Sim-Selley LJ. (2010) Statistical
Parametric Mapping reveals ligand and region-specific activation of
G-proteins by CB1 receptors and non-CB1 sites in the 3D reconstructed mouse
brain. Neuroimage.
52(4):1243-51.
Hoot MR, Sim-Selley LJ, Poklis JL, Abdullah RA, Scoggins
KL, Selley DE, and Dewey WL. (2010) Chronic constriction injury reduces
cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of
mice. Brain Res.
1339:18-25.
Falenski KW, Thorpe AJ, Schlosburg JE, Cravatt BF, Abdullah
RA, Smith TH, Selley DE, Lichtman AH, and Sim-Selley LJ. (2010) FAAH-/- mice
display differential tolerance, dependence, and cannabinoid receptor
adaptation after delta 9-tetrahydrocannabinol and anandamide administration.
Neuropsychopharmacology. 35(8):1775-87.