This competitive renewal investigates the mechanisms and significance of dopaminergic (DA) and serotonergic (5HT) neurotransmission systems in Tourette's syndrome (TS) using PET neuroreceptor imaging which should provide a more complete understanding of pathophysiology and possible treatments. Our recruitment strategies have focused on completing our original DA and 5HT measure sample size, originally funded for only 45% at Year 1 of this R01. We now request funds to complete this sample size given that we have substantial progress including (1) sustained elevations of dopamine release (DArei) with a new PET scanner which is a reproduction of our published paper, (2) demonstrate reductions in SERT in our TS subject, (3) uniquely carrying out amphetamine induced DArei in TS but also pre synaptic DA transporters (DAT) and receptor density (D2Bmax) in the same individuals, (4) similarly also studying both serotonin transporters (SERT) and 5HT2A receptors in the same subjects. Completion of the sample will determine what the inter-relationships are between these pre, post and intra synaptic measures for dopamine and for serotonin transporters and postsynaptic receptors in TS. In addition to our findings in TS alone, we have found an interesting contrast between TS subjects with and without co-morbid OCD (TS + OCD). In particular we found that TS + OCD had elevated DArei compared to TS - OCD and both elevated compared to controls. We found a significant decline in SERT in midbrain in 9 TS + OCD vs. 2 TS - OCD with trends for elevations for TS + OCD vs. TS - OCD for 5HT2A. In 3 subjects who had both DA and 5HT measures, we found correlations between SERT, DArei and 5HT2A which along with the DA and 5HT group differences were suggestive of the co-morbid effect of OCD in TS. This suggested that lower intrasynaptic 5HT resulted in elevated DArei and 5HT2A and lower SERT in these subjects. Further evaluation in AIM 4 with both DA and 5HT measures will help us directly test the hypothesis about the role of 5HT in modulating our tonic/phasic DA model of TS by additionally incorporating features of OCD. At the end of this renewal, we will have completed our originally funded AIMS and examined new possibilities of 5HT and DA interrelationships and role of co morbid OCD and TS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH078175-07
Application #
7653715
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Grabb, Margaret C
Project Start
2001-04-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$610,019
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
George, Noble; Gean, Emily G; Nandi, Ayon et al. (2015) Advances in CNS Imaging Agents: Focus on PET and SPECT Tracers in Experimental and Clinical Use. CNS Drugs 29:313-30
Oswald, Lynn M; Wand, Gary S; Wong, Dean F et al. (2015) Risky decision-making and ventral striatal dopamine responses to amphetamine: a positron emission tomography [(11)C]raclopride study in healthy adults. Neuroimage 113:26-36
Oswald, Lynn M; Wand, Gary S; Kuwabara, Hiroto et al. (2014) History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine. Psychopharmacology (Berl) 231:2417-33
Takayanagi, Yoichiro; Gerner, Gwendoly; Takayanagi, Mizuho et al. (2013) Hippocampal volume reduction correlates with apathy in traumatic brain injury, but not schizophrenia. J Neuropsychiatry Clin Neurosci 25:292-301
Rosenberg, Paul B; Wong, D F; Edell, S L et al. (2013) Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography. Am J Geriatr Psychiatry 21:272-8
Cascella, Nicola G; Santora, Debby; Gregory, Patricia et al. (2013) Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull 39:867-71
Takayanagi, Mizuho; Wentz, Jacqueline; Takayanagi, Yoichiro et al. (2013) Reduced anterior cingulate gray matter volume and thickness in subjects with deficit schizophrenia. Schizophr Res 150:484-90
Kuwabara, Hiroto; McCaul, Mary E; Wand, Gary S et al. (2012) Dissociative changes in the Bmax and KD of dopamine D2/D3 receptors with aging observed in functional subdivisions of the striatum: a revisit with an improved data analysis method. J Nucl Med 53:805-12
Takayanagi, Yoichiro; Cascella, Nicola G; Sawa, Akira et al. (2012) Diabetes is associated with lower global cognitive function in schizophrenia. Schizophr Res 142:183-7
Rahmim, Arman; Zhou, Yun; Tang, Jing et al. (2012) Direct 4D parametric imaging for linearized models of reversibly binding PET tracers using generalized AB-EM reconstruction. Phys Med Biol 57:733-55

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