I am interested in the cellular and molecular mechanisms by which neurotransmitter receptor systems compensate or change in disease states (e.g. major depressive disorder, alcoholism) or in response to repeated drug treatment. Because the treatment of many psychiatric disorders involves long-term pharmacological intervention, compensatory changes in the sensitivity of central receptor systems may be involved in the mechanism by which drugs produce their therapeutic or side effects. I have focused my research primarily on the regulation of serotonin receptor function. To date there have been identified some fourteen subtypes of receptor for serotonin which are targets for a wide variety of drugs (e.g. hallucinogens, and drugs used to treat schizophrenia, anxiety, migraine). Serotonergic neurotransmission is altered by several classes of antidepressant drugs as well. In my laboratory we have taken both in vivo and in vitro approaches to examine the processes underlying the regulation of serotonin receptor function and expression. In vitro systems (i.e. cells in culture) allow us to examine the regulation of serotonin receptors in more mechanistic studies. Cell lines, which have been transfected to express serotonin receptor subtypes, as well as cell lines which endogenously express these receptors, are used. Our findings from these studies are compared to what has been observed to occur in the brain. We utilize molecular probes (e.g. antibodies, dominant negative mutants, antisense oligonucleotides) to examine the cellular processes by which serotonin receptor function is regulated. Receptor function is assessed using biochemical, physiological and behavioral assays. We are currently utilizing [35S]GTPgammaS autoradiography to investigate the regulation of serotonin-1A receptor function at the level of receptor-G protein interaction in discrete brain regions following administration of psychoactive drugs such as antidepressants. These studies may further our understanding of the regulation of serotonin receptor function, and may have impact on our understanding of the regulation of G-protein coupled receptors as a superfamily. The serotonergic system in brain has been implicated in substance abuse and addiction, as well as many psychiatric disorders. We have begun studies to identify differences in serotonin receptors and in the serotonin transporter in genetically modified mice, which may prove useful models in which to examine the role of the serotonin system in alcohol and drug abuse, as well as affective disorders. For example, we are interested in examining in mice deficient in brain-derived neurotrophic factor (BDNF) the neurochemical and behavioral effects of decreases in BDNF expression, the interaction of stress with this BDNF deficiency, as well as neurobiological changes in the serotonergic system that underlie alcohol preference, and depression.
Selected Publications:
Hensler, J.G., Advani, T., Monteggia, L.M. Regulation of 5-HT1A receptor function in inducible BDNF knock-out mice following administration of corticosterone. Biol. Psychiatry 2007 Mar; [Epub ahead of print]
Daws, L.C., Munn, J.L., Valdez, M.F., Frosto-Burke, T. Hensler, J.G. Serotonin Transporter Function, but not expression, is dependent on Brain Derived Neurotrophic Factor (BDNF): In Vivo Studies in BDNF-deficient Mice. J. Neurochem. Jan 24, 2007 [Epub ahead of print].
Advani, T., Hensler, J.G. Koek, W. Effect of early rearing conditions on alcohol drinking and 5-HT1A receptor function in C57BL/6 mice. Int. J. Neuropsychopharmacol. 2006 Nov 30:1-13 [Epub ahead of print].
Hensler, J.G. Serotonergic Modulation of the Limbic System. Neuroscience and Behavioral Reviews 30:203-214, 2006.
Rossi D.V., Valdez M., Gould G.G., and Hensler J.G. Chronic administration of venlafaxine fails to attenuate 5-HT1A receptor function at the level of receptor-G protein interaction. Int J. Neuropsychopharmacol. 8:1-14, 2005.
Hensler J.G., Hodge C.W., and Overstreet D.H.: Reduced 5-HT3 receptor binding and lower baseline plus maze anxiety in the alcohol-preferring inbred fawn-hooded rat. Pharmacol Biochem Behavior 77:281-289, 2004.
N.R. Sullivan, T. Burke, A. Siafaka-Kapadai, Javors, M. and Hensler, J.G.: Effect of valproic acid on 5-HT2A receptor signaling in C6 glioma cells. J. Neurochem. 90:1269-1275, 2004.
Hensler J.G.: Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life Sciences 72: 1665-1682, 2003.
Hensler J.G., Ladenheim E.E. and Lyons W.E: Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice. J. Neurochem. 85:1139-1147, 2003.
Valdez M., Burke T.F. and Hensler J.G.: Selective heterologous regulation of 5-HT1A receptor-stimulated [35S]GTPγS binding in the anterior cingulate cortex as a result of 5-HT2 receptor activation. Brain Research 957:174-182, 2002.
Hensler J.G. Differential regulation of 5-HT1A receptor-G protein interactions in brain following chronic antidepressant administration. Neuropsychopharmacology 26:565-573, 2002.
Hanley N.R. and Hensler J.G.: Mechanisms of ligand-induced desensitization of the 5-HT2A receptor. J. Pharmacol. Exp. Ther. 300:468-477, 2002.
Anji A., Sullivan Hanley N.R., and Hensler J.G.: The role of PKC in the regulation of serotonin2A (5-HT2A) receptor expression. J Neurochem. 77:589-597, 2001.
Hensler J.G. and Durgam H.: Regulation of 5-HT1A receptor-stimulated [35S]GTPγS binding as measured by quantitative autoradiography following chronic agonist administration. Brit. J. Pharmacol. 132:605-611, 2001.
Scalzitti J.M. and Hensler J.G. The design and efficacy of a serotonin-2A receptor Antisense oligodeoxynucleotide. In: Methods in Enzymology, Antisense Techniques, M.I. Phillips (ed), pp 76-89, Academic Press, 1999.
Hensler J.G., Cervera, L.S., Miller H.A. and Corbitt J.: Expression and modulation of 5-HT1A receptors in P11 cells. J. Pharmacol. Exp. Therap. 278:1138-1145, 1996.
