The serotonin neurotransmitter system and one of its key components, the serotonin transporter (SERT), is the primary target of this project. The development of the SERT knockout mouse in the LCS provided a new living tool to study SERT and serotonin receptors, the target molecules for the largest numbers of neuropsychiatric drugs used in the world. 30 plus neurochemical, behavioral and other phenotypic changes have been discovered in the serotonin knockout mouse. The resulting data is helping to guide the LCS and other laboratories in investigations of the multiple functional variants recently discovered in the human SERT gene. The broad goal of our studies is a better understanding of the serotonin neurotransmitter system and its contributions to physiology, behavior and human disorders, especially neuropsychiatric disorders. Serotonin has been implicated in almost every physiological function known. The serotonin transporter (SERT) recycles serotonin after its release, thereby terminating the action of serotonin at its receptors. In our attempt to better understand serotonin's function, we have generated a mouse model which either lacks the serotonin transporter or has a 50% reduction in serotonin transporter expression. These SERT -/- and +/- mice have gene-proportionate increases in extracellular fluid serotonin (5-HT) concentrations. i.e., 9- and 5-fold excesses respectively over +/+ mice, with the SERT deficiency present since conception. In models of anxiety, the SERT deficient mice exhibit markedly greater anxiety-like behaviors. Similarly, these mice have substantially greater activation of the HPA and sympathoadrenal systems in responses to minor stressful stimuli such as handling and saline injections, with high plasma ACTH and epinephrine increases, and more marked reductions in pituitary and adrenal gland hormones. The anxiety behaviors are restored to near normal levels by treatment with a serotonin 1A receptor antagonist. As serotonin has a trophic effect on neuronal cells, we are investigating the role of the serotonin transporter and certain neurotrophic factors such as BDNF in neuronal function, survival, and development. We have successfully developed a mouse SERT x BDNF double knockout mouse model to further investigate the role of the serotonin transporter and BDNF in the developing nervous system, as human genetic studies have separately implicated both genes in the development of affective and other neuropsychiatric disorders. Similarly, we have studied other gene x gene (epistatic) interactions of SERT with DAT, NET, and MAO genes in these mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Intramural Research (Z01)
Project #
1Z01MH000332-26
Application #
6970028
Study Section
(LCS)
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2004
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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