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Serotonin transporter availability in dorsal raphe nucleus predicts serotonin-1A receptor binding in striatum —A multitracer PET study with [Carbonyl-11C]WAY and [11C]DASB
T156
Abstracts / NeuroImage 41 (2008) T58–T200
Poster Presentation No.: P096
Serotonin transporter availability in dorsal raphe nucleus predicts serotonin-1A receptor binding in striatum —A multitracer PET study with [Carbonyl- 11 C]WAY and [ 11 C]DASB Rupert Lanzenberger,a W. Wadsak,b M. Savli,a M. Mitterhauser,b,c M. Fink,a L.K. Mien,b,c A. Hahn,a D. Haeusler,b C. Spindelegger,a U. Moser,a P. Stein,a K. Kletter,b and S. Kaspera a b
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria Department of Nuclear Medicine, PET Centre, Medical University of Vienna, Austria c Department of Pharmaceutical Technology, University of Vienna, Austria
Introduction: In the human brain the highest concentrations of both the serotonin transporter (120 pmol/g) and the major inhibitory serotonergic (serotonin-1A, 5-HT1A) receptor (140 pmol/g) have been found in the dorsal raphe nucleus (DRN) [1]. Serotonergic firing of the DRN is mainly modulated by this 5-HT1A autoreceptor and serotonin transporter (5-HTT) regulating the level of extracellular serotonin. Combined PET and fMRI studies have shown that the 5-HT1A autoreceptor binding potential (BP) and regional 5-HTT BP predict amygdala activation [2, 3]. Therefore, the expression of 5-HT1A receptors and 5-HT transporters in cortical and subcortical areas might be modulated by their concentration in the dorsal raphe nucleus. The aim of this multitracer PET study was to investigate the influence of (1) the raphe 5-HT1A receptor on the 5-HT transporter binding and vice versa (2) the raphe 5-HT transporter on the 5-HT1A receptor binding in 12 selected brain areas in vivo. Methods: Eight healthy male subjects underwent two scans each using a GE Advance PET camera (total acquisition time of 90 min, 30 time frames, 35 slices, slice thickness 4.25 mm, matrix 128 ⁎ 128, FWHM = 4.36 mm). The 5-HT1A receptor and 5HT transporter BP were quantified using the radioligands [Carbonyl-11C]WAY 100635 and [11C]DASB, respectively. Calculation of BP was done using the Simplified-Reference-Tissue-Model (SRTM2), the cerebellum as reference region with very low specific binding and the software PMOD 2.95. Twelve regions of interest (ROI) were investigated using a normalized ROI template in MNI stereotactic space (AAL): dorsal raphe nucleus (DRN), amygdala, hippocampus (caput), anterior/medium/ posterior cingulate cortices (ACC, MCC, PCC) expressing medium levels of both 5-HT1A and 5-HTT, subgenual cortex (part of ACC), insula, thalamus, striatum, and subparts of the striatum (putamen, N. caudatus) expressing high levels of 5-HTT. Pearson's correlation (2-tailed) and the regression analyses were performed in SPSS15 using an adjustment for multiple comparison (p b 0.0042, Bonferroni). Results: We found a significant correlation between 5-HTT binding in the DRN and the 5-HT1A receptor BP in the N. caudatus (r = 0.975, p = 0.00004), putamen (r = 0.754, p = 0.03), striatum (r = 0.889, p = 0.003), hippocampus (r = 0.778, p = 0.02), PCC (r = − 0.740, p = 0.04). The positive correlation in striatum and the N. caudatus survived the Bonferroni correction. The 5-HT transporter BP in the dorsal raphe nucleus explained 76% of the variability of 5-HT1A receptor binding in the striatum (corrected r2 = 0.756, p = 0.003). In contrast, there was no significant correlation (p N 0.05) between the 5-HT1A BP in the raphe nucleus and any regional 5-HTT BP investigated even in the DRN. Conclusion: Our findings are consistent to an influence of raphe 5-HT transporter binding on 5-HT1A receptor levels in other brain areas. Reduced 5-HT transporter levels in the raphe region might increase regional extracellular serotonin levels and increase autoinhibition via presynaptic 5-HT1A receptors. This might result in decreased serotonergic firing as well as serotonin release in the striatum and cortical areas associated with a down-regulation of inhibitory postsynaptic 5-HT1A receptors. This model is in good agreement with a recent PET study in patients with anxiety disorders treated with the SSRI escitalopram for 12 weeks [4]. Blocking of 5-HTT was associated with a significant decrease of 5-HT1A binding in several areas. [1] [2] [3] [4]
Varnas K., Halldin C., and Hall H. Hum Brain Mapp: 22(3), pp. 246–260, 2004. Fisher P.M., Meltzer C. C., Ziolko S. K., et al. Nat Neurosci: 9(11), pp. 1362–1363, 2006. Rhodes R. A., Murthy N. V., Dresner M. A., et al. J Neurosci: 27(34), pp. 9233, 2007. Spindelegger C., Lanzenberger R., Wadsak W., et al. Molecular Psychiatry (in press), 2008.
doi:10.1016/j.neuroimage.2008.04.124
Abstracts / NeuroImage 41 (2008) T58–T200
Poster Presentation No.: P096
Serotonin transporter availability in dorsal raphe nucleus predicts serotonin-1A receptor binding in striatum —A multitracer PET study with [Carbonyl- 11 C]WAY and [ 11 C]DASB Rupert Lanzenberger,a W. Wadsak,b M. Savli,a M. Mitterhauser,b,c M. Fink,a L.K. Mien,b,c A. Hahn,a D. Haeusler,b C. Spindelegger,a U. Moser,a P. Stein,a K. Kletter,b and S. Kaspera a b
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria Department of Nuclear Medicine, PET Centre, Medical University of Vienna, Austria c Department of Pharmaceutical Technology, University of Vienna, Austria
Introduction: In the human brain the highest concentrations of both the serotonin transporter (120 pmol/g) and the major inhibitory serotonergic (serotonin-1A, 5-HT1A) receptor (140 pmol/g) have been found in the dorsal raphe nucleus (DRN) [1]. Serotonergic firing of the DRN is mainly modulated by this 5-HT1A autoreceptor and serotonin transporter (5-HTT) regulating the level of extracellular serotonin. Combined PET and fMRI studies have shown that the 5-HT1A autoreceptor binding potential (BP) and regional 5-HTT BP predict amygdala activation [2, 3]. Therefore, the expression of 5-HT1A receptors and 5-HT transporters in cortical and subcortical areas might be modulated by their concentration in the dorsal raphe nucleus. The aim of this multitracer PET study was to investigate the influence of (1) the raphe 5-HT1A receptor on the 5-HT transporter binding and vice versa (2) the raphe 5-HT transporter on the 5-HT1A receptor binding in 12 selected brain areas in vivo. Methods: Eight healthy male subjects underwent two scans each using a GE Advance PET camera (total acquisition time of 90 min, 30 time frames, 35 slices, slice thickness 4.25 mm, matrix 128 ⁎ 128, FWHM = 4.36 mm). The 5-HT1A receptor and 5HT transporter BP were quantified using the radioligands [Carbonyl-11C]WAY 100635 and [11C]DASB, respectively. Calculation of BP was done using the Simplified-Reference-Tissue-Model (SRTM2), the cerebellum as reference region with very low specific binding and the software PMOD 2.95. Twelve regions of interest (ROI) were investigated using a normalized ROI template in MNI stereotactic space (AAL): dorsal raphe nucleus (DRN), amygdala, hippocampus (caput), anterior/medium/ posterior cingulate cortices (ACC, MCC, PCC) expressing medium levels of both 5-HT1A and 5-HTT, subgenual cortex (part of ACC), insula, thalamus, striatum, and subparts of the striatum (putamen, N. caudatus) expressing high levels of 5-HTT. Pearson's correlation (2-tailed) and the regression analyses were performed in SPSS15 using an adjustment for multiple comparison (p b 0.0042, Bonferroni). Results: We found a significant correlation between 5-HTT binding in the DRN and the 5-HT1A receptor BP in the N. caudatus (r = 0.975, p = 0.00004), putamen (r = 0.754, p = 0.03), striatum (r = 0.889, p = 0.003), hippocampus (r = 0.778, p = 0.02), PCC (r = − 0.740, p = 0.04). The positive correlation in striatum and the N. caudatus survived the Bonferroni correction. The 5-HT transporter BP in the dorsal raphe nucleus explained 76% of the variability of 5-HT1A receptor binding in the striatum (corrected r2 = 0.756, p = 0.003). In contrast, there was no significant correlation (p N 0.05) between the 5-HT1A BP in the raphe nucleus and any regional 5-HTT BP investigated even in the DRN. Conclusion: Our findings are consistent to an influence of raphe 5-HT transporter binding on 5-HT1A receptor levels in other brain areas. Reduced 5-HT transporter levels in the raphe region might increase regional extracellular serotonin levels and increase autoinhibition via presynaptic 5-HT1A receptors. This might result in decreased serotonergic firing as well as serotonin release in the striatum and cortical areas associated with a down-regulation of inhibitory postsynaptic 5-HT1A receptors. This model is in good agreement with a recent PET study in patients with anxiety disorders treated with the SSRI escitalopram for 12 weeks [4]. Blocking of 5-HTT was associated with a significant decrease of 5-HT1A binding in several areas. [1] [2] [3] [4]
Varnas K., Halldin C., and Hall H. Hum Brain Mapp: 22(3), pp. 246–260, 2004. Fisher P.M., Meltzer C. C., Ziolko S. K., et al. Nat Neurosci: 9(11), pp. 1362–1363, 2006. Rhodes R. A., Murthy N. V., Dresner M. A., et al. J Neurosci: 27(34), pp. 9233, 2007. Spindelegger C., Lanzenberger R., Wadsak W., et al. Molecular Psychiatry (in press), 2008.
doi:10.1016/j.neuroimage.2008.04.124