Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings
Introduction
Approximately 90% of the total body amount of serotonin (5-HT) acts in the gastrointestinal system. Only 1–2% is present in the central nervous system where 5-HT receptors are generally involved in sleep, pain, behavior, learning, and memory [5], [10]. More specifically, serotonin type 2A (5-HT2A) receptors have been implicated in several brain functions, such as appetite control, sexuality, thermoregulation, and sustained attention and play an important role in the pathophysiology of mood, depressive, anxiety, and psychotic disorders, schizophrenia, aging and also Alzheimer’s disease (AD) [2], [5], [9], [18], [30], [31], [42].
AD, the most common form of dementia, is typically characterized by progressive impairment of recent memory. However, in the course of AD, other cognitive dysfunctions, behavioral and psychiatric symptoms emerge and become at least equally important [21]. The role of the 5-HT2A receptor in AD is manifold. Firstly, the 5-HT2A receptor has been suggested to play a role in the amyloid precursor protein secretion. Since this is linked to the β-amyloid fibrillogenesis, this could eventually lead to the subsequent formation of amyloid plaques, typically seen in AD [24], [25], [35], [36]. Second, several genetic associations between 5-HT2A receptor polymorphisms and the AD symptomatology, e.g. visual or auditory hallucinations have been reported [23], [34]. Third, 5-HT has a role in natural immunity in general, and more specifically in the superoxide production, phagocytosis, and the optimal accessory cell function of macrophages for natural killer and T-cells, which could eventually influence the removal of amyloid plaques [32]. Moreover, the cerebral availability of plasma tryptophan, the precursor of 5-HT, decreases with activation of the immune system, the latter believed to be upregulated in AD [1], [8]. Finally, a decrease in serotonergic cells in the central nervous system could eventually lead to a disturbance of functional interactions between the serotonergic on one hand and the cholinergic or dopaminergic system on the other hand [16], [19], [40], [44].
radiolabeled R91150 is a radio-iodinated 5-HT2A receptor antagonist with high affinity (KD=0.11±0.01 nM). The selectivity of this ligand for 5-HT2A receptors as compared to other neurotransmitter receptor binding sites such as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, 5-HT3, dopamine D2 receptors, α1 and α2 adrenoreceptors and histamine H1 receptors, is at least a factor of 50. -5-I-R91150 binding is saturable and displaceable with the known 5-HT2A receptor antagonist ketanserin and proved suitable for the imaging of 5-HT2A receptors with single photon emission computed tomography (SPECT) in the human brain [11].
The objectives of the present study were, firstly, to study the age and gender effect of the 5-HT2A receptor binding potential (BP) in a large group of healthy subjects (n=26) with an age range of 22–85 years and, second, to determine whether there are abnormalities in the 5-HT2A receptor BP in AD patients compared to age-matched healthy controls, and if so, whether these abnormalities are correlated with cognitive defects or depressive symptomatology.
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Patients
The study was approved by the medical ethics committee of the Ghent University Hospital and all patients gave informed (proxy-)consent. Nine AD patients (two males, mean age 81±6 years, range 73–88 years) according to the NINCDS-ADRDA criteria were included with the diagnosis made by a board-certified neurologist [27]. The diagnosis was supported by the fact that there was evidence of cerebral atrophy on computed tomography or magnetic resonance imaging in all AD patients and by the fact that
Results
Age, sex, GDS, MMSE-score, and cognitive deficits of the AD patients are presented in Table 1.
Discussion
The present findings concerning age dependency of 5-HT2A receptor density are in agreement with previous ex vivo distribution studies demonstrating a general decrease in cortical 5-HT and more specifically 5-HT2A receptor density [39]. This decline is also consistent with clinical observations of age-related changes in behaviors such as sleep or executive functioning, known to be linked to serotonergic function [15], [33]. Moreover, peak minus baseline prolactin responses to fenfluramine (a
Acknowledgements
This work was financially supported by the “Internationale stichting Alzheimer onderzoek.” The authors wish to thank Nuclear Diagnostics and SUN Microsystems for their technical support in the Division of Nuclear Medicine of the Ghent University Hospital.
References (51)
- et al.
Inflammation and Alzheimer’s disease
Neurobiol. Aging
(2000) - et al.
A review of central 5-HT receptors and their function
Neuropharmacology
(1999) - et al.
Sex difference in 5-HT2 receptor in the living human brain
Neurosci. Lett.
(1996) Serotonin receptors in cognitive behaviors
Curr. Opin. Neurobiol.
(1997)- et al.
Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides
Neuropharmacology
(1984) - et al.
The influence of prolactin response to d-fenfluramine on executive functioning in major depression
Biol. Psychiatry
(1999) - et al.
The antidepressant activity of inositol in the forced swim test involves 5-HT(2) receptors
Behav. Brain Res.
(2001) - et al.
“Mini-mental state”. A practica l method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Autoradiographic analysis of age-dependent changes in serotonin 5-HT2 receptors of the human brain postmortem
Brain Res.
(1990) - et al.
Reduced binding of []altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correction
Brain Res.
(1998)