Age-Related Change in 5-HT₆ Receptor Availability in Healthy Male Volunteers Measured with ¹¹C-GSK215083 PET

Abstract

Serotonin receptor 6 (5-hydroxytrypamine-6, or 5-HT) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5-HT receptor availability using C-GSK215083, a PET ligand with affinity for 5-HT in the striatum and 5-HT in the cortex. Twenty-eight healthy male volunteers (age range, 23-52 y) were scanned withC-GSK215083 PET. Time-activity curves in regions of interest were fitted using a multilinear analysis method. Nondisplaceable binding potential () was calculated using the cerebellum as the reference region and corrected for partial-volume effects. In 5-HT-rich areas, regional C-GSK215083 showed a negative correlation between and age in the caudate ( = -0.41, = 0.03) (14% change per decade) and putamen ( = -0.30, = 0.04) (11% change per decade) but not in the ventral striatum or pallidum. A negative correlation with age was also seen in cortical regions ( = -0.41, = 0.03) (7% change per decade), consistent with the literature on 5-HT availability. To our knowledge, this was the first in vivo study on humans to examine the effect of age on 5-HT receptor availability. The study demonstrated a significant age-related decline in 5-HT availability () in the caudate and putamen.

Age-Related Alterations in the Behavior and Serotonin-Related Gene mRNA Levels in the Brain of Males and Females of Short-Lived Turquoise Killifish (Nothobranchius furzeri)

“…The age-dependent decline in the mRNA levels of Htr4 and Htr6 genes in the brain of N. furzeri males shown in our study is in good concordance with that in the 5-HT4 [70] and 5-HT6 [69,71] binding sites in brains of aged humans.…”

Molecular and connectomic vulnerability shape cross-disorder cortical abnormalities

“…Receptor densities were estimated using PET tracer studies for a total of 18 receptors and transporters, across 9 neurotransmitter systems. These include dopamine (D 1 [59], D 2 [96,105,108,131], DAT [33]), norepinephrine (NET [8,22,31,95]), serotonin (5-HT 1A [98], 5-HT 1B [6,41,73,76,77,85,97,98], 5-HT 2A [9], 5-HT 4 [9], 5-HT 6 [87,88], 5-HTT [9]), acetylcholine (α 4 β 2 [6,52], M 1 [78], VAChT [1,7]), glutamate (mGluR 5 [32,106]), GABA (GABA A [80]), histamine (H 3 [42]), cannabinoid (CB 1 [34,79,81,93]), and opioid (MOR [60]). Volumetric PET images were registered to the MNI-ICBM 152 nonlinear 2009 (version c, asymmetric) template, aver-aged across participants within each study, then parcellated to 68 cortical regions.…”

Aged Brains Express Less Melanocortin Receptors, Which Correlates with Age-Related Decline of Cognitive Functions

“…Similarly, a significant decrease in the expression of the GABA B receptor in the prefrontal cortex was found in aged rats, and was found to be negatively associated with working memory performance in the older animals [9,10]. The 5-HT 6 receptor and the mGlu2/3 receptors also showed age-dependent expression levels in the central nervous system [11,12]. Thus, GPCRs have become important drug targets to be explored for restoring cognitive function in aged people as well as in MCI and Alzheimer's disease patients [13][14][15][16].…”