The primary aim of this project is to increase our understanding of the role of the serotonergic neurotransmitter system in behavior. Animal model studies described in this project are often done in parallel with analogous neuropharmacologic and genetic studies of serotonergic neurotransmission in healthy humans and in patients with obsessive-compulsive disorder and other anxiety disorders as described in our other project reports. Major studies completed this year helped to clarify neuronal adaptational processes mediated by serotonin receptors in response to repeated administration of selective serotonin-agonists and serotonin reuptake inhibiting antidepressants in rats. In addition, N-Methyl-D-aspartic acid (NMDA) neurons were demonstrated to modulate the development of serotonin receptor adaptational subsensitivity. In order to take advantage of transgenic technology, we have shifted from studies in rats to studies in mice. This year, we documented a role for free radicals in the production of serotonin projection field lesions using transgenic mice with high levels of superoxide dismutase activity. We have also completed the initial characterization of the consequences of a 50% reduction (in +/- mice) and a complete lack of the mouse cell membrane serotonin transporter (in -/- mice) produced by disruption of the gene for this transporter via homologous recombination. The structure of the gene for the mouse serotonin transporter has been elucidated, and the cellular localization and expression of the transporter in mouse brain has been described.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH000332-19
Application #
6162820
Study Section
Special Emphasis Panel (LCS)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
1997
Total Cost
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Bischoff, Stephan C; Mailer, Reiner; Pabst, Oliver et al. (2009) Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol 296:G685-95
Carroll, Jenna C; Boyce-Rustay, Janel M; Millstein, Rachel et al. (2007) Effects of mild early life stress on abnormal emotion-related behaviors in 5-HTT knockout mice. Behav Genet 37:214-22
Kalueff, Allan V; Ren-Patterson, Renee F; Murphy, Dennis L (2007) The developing use of heterozygous mutant mouse models in brain monoamine transporter research. Trends Pharmacol Sci 28:122-7
Kalueff, A V; Wheaton, M; Murphy, D L (2007) What's wrong with my mouse model? Advances and strategies in animal modeling of anxiety and depression. Behav Brain Res 179:1-18
Kalueff, Allan V; Aldridge, J Wayne; LaPorte, Justin L et al. (2007) Analyzing grooming microstructure in neurobehavioral experiments. Nat Protoc 2:2538-44
Fox, Meredith A; Jensen, Catherine L; Gallagher, Pamela S et al. (2007) Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice. Neuropharmacology 53:643-56
Kalueff, Allan V; Murphy, Dennis L (2007) The importance of cognitive phenotypes in experimental modeling of animal anxiety and depression. Neural Plast 2007:52087
Schmitt, A; Benninghoff, J; Moessner, R et al. (2007) Adult neurogenesis in serotonin transporter deficient mice. J Neural Transm 114:1107-19
Numachi, Yohtaro; Ohara, Arihisa; Yamashita, Motoyasu et al. (2007) Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. Eur J Pharmacol 572:120-8
Kalueff, Allan V; Jensen, Catherine L; Murphy, Dennis L (2007) Locomotory patterns, spatiotemporal organization of exploration and spatial memory in serotonin transporter knockout mice. Brain Res 1169:87-97

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