Effects of aging on 5-HT(1A) receptors and their functional response to 5-HT(1a) agonist in the living brain: PET study with [carbonyl-(11)C]WAY-100635 in conscious monkeys.

Abstract

Age-related changes in the serotonin 5-HT(1A) receptors in the living brains of conscious young (5.9 +/- 1.8 years old) and aged (19.0 +/- 3.3 years old) monkeys (Macaca mulatta) were evaluated by [carbonyl-(11)C]WAY-100635 and high-resolution positron emission tomography (PET). The regional distribution pattern of [carbonyl-(11)C]WAY-100635 at 60-91 min postinjection was the highest in the cingulate gyrus and hippocampus, high in the frontal and temporal cortices, lower in the occipital cortex, striatum, thalamus, and raphe nuclei, and lowest in the cerebellum in both young and aged monkeys. Graphical Logan plot analysis with metabolite-corrected plasma radioactivity as an input function into the brain was applied to evaluate 5-HT(1A) receptor binding in vivo. Significant age-related decreases in 5-HT(1A) receptor binding were observed only in the frontal and temporal cortices. In the hippocampus, although 5-HT(1A) receptor binding indicated no significant age-related changes, it showed an inverse correlation with individual cortisol levels in plasma. When the 5-HT(1A) receptor agonist 8-OH-DPAT was administered intravenously at a dose of 0.1, 0.3, or 1 mg/kg 30 min after tracer injection, binding of [carbonyl-(11)C]WAY-100635 was displaced in both age groups in a dose-dependent manner. However, the degree of displacement was more marked in young than in aged monkeys. These observations demonstrated the usefulness of [carbonyl-(11)C]WAY-100635 as an indicator of the age-related changes in cortical 5-HT(1A) receptors measured noninvasively by PET. In addition, these observations suggested that the age-related impairment of 5-HT(1A) receptor responses to 8-OH-DPAT might be related to the reduced efficacy of antidepressant therapy in elderly patients with depression.