Genetic variation in the 5-HT2A receptor and altered neocortical [3H] ketanserin binding in Alzheimer's disease.
A common intronic single nucleotide polymorphism (T102C) in the 5-HT2A receptor gene is associated with the development of different neuropsychiatric symptoms, including hallucinations and depressive symptoms in Alzheimer's disease (AD). Differential 5-HT2A receptor binding has also been associated with the development of these symptoms in AD. However, the relationship between 5-HT2A (T102C) genotype and 5-HT2A receptor binding in AD and control human brains has not been examined. We examined the association between different 5-HT2A (T102C) genotypes and [(3)H] ketanserin binding in the temporal and frontal cortex of 20 AD and 14 control human brains. In homozygotes, but not heterozygotes, there was a significant reduction in B(max) values for [(3)H] ketanserin binding in both areas of cortex in AD compared with control subjects. This study suggests a mechanism for the generation of different neuropsychiatric symptoms in AD from a single nucleotide polymorphism with reduced receptor binding in T102C 5-HT2A receptor gene homozygotes correlating with susceptibility to depressive symptoms, whereas the relative preservation of receptor binding in heterozygotes with AD correlating with susceptibility to hallucinations.
Holmes
C
C
University of Southampton, Clinical Neurosciences Research Division, Memory Assessment and Research Centre, Moorgreen Hospital, Botley Rd., Southampton, United Kingdom. c.holmes@soton.ac.uk
McCulley
M
M
Nicoll
J A R
JA
Alder
J T
JT
Chen
C P L-H
CP
Francis
P T
PT
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006212:Hallucinations / Q000209:etiology / Q000235:genetics / Q000523:psychology; D006801:Humans; D066298:In Vitro Techniques; D007650:Ketanserin / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D019579:Neocortex / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics* / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism
D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D007650:Ketanserin