A further understanding of the multiple genetic and environmental risk factors associated with anxiety and mood disorders is greatly needed to advance courses of treatment and provide relief for humans suffering from these devastating illnesses. Disruption of the serotonin (5-HT) system has been implicated in anxiety and depression and a 5-HT related genetic predisposition for these psychiatric illnesses has been identified in the length polymorphism of the 5-HT transporter promoter region (5-HTTLPR) for carriers of the short (s) allele, with s carriers displaying reduced gene 5-HTT transcription. Rhesus monkeys, also carry this genetic variant and provide an invaluable resource for studying gene x environment interactions. The overall goal of this proposal is to utilize a novel 5-HT1A radioligand and PET imaging methods in the rhesus monkey to examine the potential relationship between 5-HTTLPR polymorphisms, prenatal stress and 5-HT1A binding indices. PET scans will be acquired on a well characterized and tightly controlled cohort of 28 rhesus monkeys, from a colony originally supported by NIMH funding to study prenatal stress. [F-18]Mefway will be used to measure 5- HT1A autoreceptor and postsynaptic receptor density (Bmax) and apparent KD in single PET imaging experiments. We hypothesize that the largest reduction in 5-HT1A Bmax will be seen in the prenatally stressed group with the s allele polymorphism, suggesting the gene x environment interaction will be the dominant component of the variance. The work outlined in this project will provide the framework for extending this research of 5-HT1A PET imaging to investigate environmental variables that may play a vital role in psychopathology predisposition and genotype expression in larger cohorts of nonhuman primates and for eventual translation into human populations.

Public Health Relevance

Stressful life experiences may render some individuals more vulnerable than others to anxiety-related or mood disorders. Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. In this proposal, our goal is to use PET imaging of the serotonin system in the nonhuman primate model to study the effects of prenatal stress on the serotonin 5HT1A receptor. Particularly, to examine if carriers with a short variation of the gene for encoding the serotonin transporter are more profoundly affected by prenatal stress than those with long gene variation. This work holds great potential for advancing our knowledge of how environmental experiences interact with genes in the development of anxiety-related illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH086014-02
Application #
7835573
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Nadler, Laurie S
Project Start
2009-05-07
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$218,870
Indirect Cost
Name
University of Wisconsin Madison
Department
Physics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hillmer, Ansel T; Wooten, Dustin W; Farhoud, Mohammed et al. (2013) The effects of lobeline on ?4?2* nicotinic acetylcholine receptor binding and uptake of [(18)F]nifene in rats. J Neurosci Methods 214:163-9
Christian, Bradley T; Wooten, Dustin W; Hillmer, Ansel T et al. (2013) Serotonin transporter genotype affects serotonin 5-HT1A binding in primates. J Neurosci 33:2512-6
Wooten, Dustin W; Hillmer, Ansel T; Moirano, Jeffrey M et al. (2013) 5-HT1A sex based differences in Bmax, in vivo KD, and BPND in the nonhuman primate. Neuroimage 77:125-32
Hillmer, Ansel T; Wooten, Dustin W; Farhoud, Mohammed et al. (2013) PET imaging of acetylcholinesterase inhibitor-induced effects on ?4?2 nicotinic acetylcholine receptor binding. Synapse 67:882-6
Wooten, Dustin W; Hillmer, Ansel T; Moirano, Jeffrey M et al. (2012) Measurement of 5-HT(1A) receptor density and in-vivo binding parameters of [(18)F]mefway in the nonhuman primate. J Cereb Blood Flow Metab 32:1546-58
Hillmer, A T; Wooten, D W; Moirano, J M et al. (2011) Specific ?4?2 nicotinic acetylcholine receptor binding of [F-18]nifene in the rhesus monkey. Synapse 65:1309-18
Wooten, Dustin; Hillmer, Ansel; Murali, Dhanabalan et al. (2011) An in vivo comparison of cis- and trans-[18F]mefway in the nonhuman primate. Nucl Med Biol 38:925-32
Wooten, D W; Moraino, J D; Hillmer, A T et al. (2011) In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate. Synapse 65:592-600