Opposite Age-Dependent Changes of α2A-Adrenoceptors and Nonadrenoceptor [3H]Idazoxan Binding Sites (I2-Imidazoline Sites) in the Human Brain: Strong Correlation of I2 with Monoamine Oxidase-B Sites

Abstract: In the postmortem human brain (27 specimens of frontal cortex, Brodmann area 9), the specific binding of the antagonists ³H]RX 821002 (2-methoxyidazoxan) to α_2A-adrenoceptors and that of ³H]idazoxan to l₂-imidazo-line sites (a nonadrenoceptor mitochondrial site) were determined in parallel to study the effect of aging (range, 4–89 years) on both brain proteins. The density of α_2A-adrenoceptors and age were negatively correlated (r=-0.71; p < 0.001). In contrast, the density of l₂-imidazo-line sites was positively correlated with aging (r= 0.59; p < 0.005). The ratio of receptor densities (α_2A/l₂) also showed a marked negative correlation with age (r=-0.76; p < 0.001). In an age-selected group (range, 10–89 years), the density of monoamine oxidase (MAO)-B sites labeled by ³H]Ro 19–6327 (lazabemide) also showed a positive correlation with age (r= 0.80; p < 0.005). In these subjects, the density of l₂-imidazoline sites correlated well with the density of MAO-B sites (r= 0.70; p < 0.005). The ratio of the density of these sites (MAO-B/l₂) did not correlate with the age of the subject at death (r=-0.15). In the human frontal cortex, idazoxan displayed very low affinity (K_i= 89 μM) against the binding of ³H]Ro 19–6327 to MAO-B, which discounted a direct interaction of ³H]idazoxan with the active center of the enzyme and indicated that the l₂-imidazoline site cannot be identified with MAO-B. However, l₂-imidazoline sites and MAO-B show a clear coexpression not only in the human frontal cortex during the process of aging, but also in various brain regions of the human and rat brains. It is suggested that the l₂-imidazoline site has a specific location on glial (astrocyte) cells.