Distribution of serotonin receptors and transporters in the human brain : implications for psychosis
Author: Varnäs, Katarina
Date: 2005-05-13
Location: Kugelbergsalen, R2:U1, Karolinska Sjukhuset
Time: 10.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
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Thesis (2.177Mb)
Abstract
The serotonin (5-HT) system is thought to be involved in different
psychiatric disorders, including depression and anxiety disorders, and is
a major target for the pharmacological treatment of these conditions. The
involvement of the 5-HT system in psychosis has been suggested, as 5-HT
receptor agonism is a common mechanism of different classes of
hallucinogenic drugs and several antipsychotics are 5-HT receptor
antagonists.
In this study, the distribution of 5-HT transporters and G-protein-coupled 5-HT receptors in the human brain was characterized using whole hemisphere autoradiographic techniques. In addition, a pilot investigation was performed to compare the densities of 5-HT binding sites in brain tissue from patients who suffered from schizophrenia-like psychosis and control subjects.
We found higher levels of 5-HT transporters in several regions of the greater limbic lobe (subcallosal area, anterior cingulate gyrus, posterior uncus, insular and entorhinal cortices, and the temporal pole) as compared to the isocortex. Higher levels of 5-HT1A receptors were also found in limbic cortices (subcallosal area, temporal pole, hippocampus, and entorhinal cortex) compared to isocortical structures. Dense binding to 5-HT1B receptors was found in the ventral striato-pallidal system of the human brain. 5-HT1B receptor mRNA expression was detected in the striatum with the highest levels in ventral striatal regions. We found no evidence for mRNA expression in the substantia nigra and pallidum, where the highest levels of receptor binding sites were found, in support of the localization of 5-HT1B receptors in axon terminals in these regions. Conversely, high levels of mRNA expression was identified in thalamic nuclei, where binding to 5-HT1B receptors was very low or absent, suggesting the localization of these receptors in thalamic projections. 5-HT1B receptor binding sites and mRNA expression were detected in the isocortex with a region- and layer-specific distribution pattern. 5-HT1D receptors seemed to be confined to the substantia nigra and pallidum, where densities were markedly lower as compared to 5-HT1B receptor densities. The use of a high sensitivity radioligand allowed the detection of 5-HT4 receptors in low-density regions, including thalamus and raphe nuclei. Our results demonstrate that 5-HT6 receptors are concentrated in nigrostriatal regions, whereas 5-HT7 receptors are densely localized in the anterior thalamus, hippocampal formation and the anterior cingulate gyrus, regions involved in the modulation of learning and memory and affective behavior, respectively.
There was a trend towards lower levels of 5-HT transporters in the striatum and the temporal cortex, as well as lower levels of 5-HT2A receptors in cortical regions and 5-HT7 receptors in the lateral frontal cortex and pulvinar thalamus of psychotic patients compared to controls. Data also indicated lower levels of 5-HT1A and 5-HT1B receptors in the hippocampal formation, and in the ventral pallidum and orbitofrontal cortex, respectively. Future large-scale studies are required to verify these findings.
It can be concluded that the different 5-HT receptors have unique distribution patterns in the human brain, reflecting their different physiological effects. The general localization in regions belonging to limbic cortico-striato-pallido-thalamic circuits is consistent with the documented role for 5-HT in the modulation of mood and emotion, as well as with the suggested involvement of this system in the pathophysiology of psychiatric disorders.
In this study, the distribution of 5-HT transporters and G-protein-coupled 5-HT receptors in the human brain was characterized using whole hemisphere autoradiographic techniques. In addition, a pilot investigation was performed to compare the densities of 5-HT binding sites in brain tissue from patients who suffered from schizophrenia-like psychosis and control subjects.
We found higher levels of 5-HT transporters in several regions of the greater limbic lobe (subcallosal area, anterior cingulate gyrus, posterior uncus, insular and entorhinal cortices, and the temporal pole) as compared to the isocortex. Higher levels of 5-HT1A receptors were also found in limbic cortices (subcallosal area, temporal pole, hippocampus, and entorhinal cortex) compared to isocortical structures. Dense binding to 5-HT1B receptors was found in the ventral striato-pallidal system of the human brain. 5-HT1B receptor mRNA expression was detected in the striatum with the highest levels in ventral striatal regions. We found no evidence for mRNA expression in the substantia nigra and pallidum, where the highest levels of receptor binding sites were found, in support of the localization of 5-HT1B receptors in axon terminals in these regions. Conversely, high levels of mRNA expression was identified in thalamic nuclei, where binding to 5-HT1B receptors was very low or absent, suggesting the localization of these receptors in thalamic projections. 5-HT1B receptor binding sites and mRNA expression were detected in the isocortex with a region- and layer-specific distribution pattern. 5-HT1D receptors seemed to be confined to the substantia nigra and pallidum, where densities were markedly lower as compared to 5-HT1B receptor densities. The use of a high sensitivity radioligand allowed the detection of 5-HT4 receptors in low-density regions, including thalamus and raphe nuclei. Our results demonstrate that 5-HT6 receptors are concentrated in nigrostriatal regions, whereas 5-HT7 receptors are densely localized in the anterior thalamus, hippocampal formation and the anterior cingulate gyrus, regions involved in the modulation of learning and memory and affective behavior, respectively.
There was a trend towards lower levels of 5-HT transporters in the striatum and the temporal cortex, as well as lower levels of 5-HT2A receptors in cortical regions and 5-HT7 receptors in the lateral frontal cortex and pulvinar thalamus of psychotic patients compared to controls. Data also indicated lower levels of 5-HT1A and 5-HT1B receptors in the hippocampal formation, and in the ventral pallidum and orbitofrontal cortex, respectively. Future large-scale studies are required to verify these findings.
It can be concluded that the different 5-HT receptors have unique distribution patterns in the human brain, reflecting their different physiological effects. The general localization in regions belonging to limbic cortico-striato-pallido-thalamic circuits is consistent with the documented role for 5-HT in the modulation of mood and emotion, as well as with the suggested involvement of this system in the pathophysiology of psychiatric disorders.
List of papers:
I. Varnas K, Hall H, Bonaventure P, Sedvall G (2001). "Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [(3)H]GR 125743. " Brain Res 915(1): 47-57
Pubmed
II. Varnas K, Hurd YL, Hall H (2005). "Regional expression of 5-HT1B receptor mRNA in the human brain." Synapse 56(1): 21-8
Pubmed
III. Varnas K, Halldin C, Pike VW, Hall H (2003). "Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710. " Eur Neuropsychopharmacol 13(4): 228-34
Pubmed
IV. Varnas K, Thomas DR, Tupala E, Tiihonen J, Hall H (2004). "Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970. " Neurosci Lett 367(3): 313-6
Pubmed
V. Varnas K, Halldin C, Hall H (2004). "Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. " Hum Brain Mapp 22(3): 246-60
Pubmed
VI. Varnas K, Thomas DR, Tupala E, Tiihonen J, Rasanen P, Halldin C, Hirst WD, Hall H (2005). "Brain 5-HT4, 5-HT6 and 5-HT7 receptor densities in shizophrenia-like psychosis: A whole hemisphere autoradiographic study." (Manuscript)
I. Varnas K, Hall H, Bonaventure P, Sedvall G (2001). "Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [(3)H]GR 125743. " Brain Res 915(1): 47-57
Pubmed
II. Varnas K, Hurd YL, Hall H (2005). "Regional expression of 5-HT1B receptor mRNA in the human brain." Synapse 56(1): 21-8
Pubmed
III. Varnas K, Halldin C, Pike VW, Hall H (2003). "Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710. " Eur Neuropsychopharmacol 13(4): 228-34
Pubmed
IV. Varnas K, Thomas DR, Tupala E, Tiihonen J, Hall H (2004). "Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970. " Neurosci Lett 367(3): 313-6
Pubmed
V. Varnas K, Halldin C, Hall H (2004). "Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. " Hum Brain Mapp 22(3): 246-60
Pubmed
VI. Varnas K, Thomas DR, Tupala E, Tiihonen J, Rasanen P, Halldin C, Hirst WD, Hall H (2005). "Brain 5-HT4, 5-HT6 and 5-HT7 receptor densities in shizophrenia-like psychosis: A whole hemisphere autoradiographic study." (Manuscript)
Issue date: 2005-04-22
Rights:
Publication year: 2005
ISBN: 91-7140-280-2
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