Relationships between β- and α 2-adrenoceptors and G coupling proteins in the human brain: effects of age and suicide

Abstract

Interactions between brain α 2- and β-adrenoceptors are of interest in physiological (aging) and pathological (major depression) processes involving both receptors. In this study, total β-adrenoceptors and β 1/2-subtypes were quantitated in postmortem human brains to investigate their relationships with α 2A-adrenoceptors and specific G proteins during the process of aging and in brains of suicide victims. Analysis of [ 3H]CGP12177 binding, in the presence of CGP20712A (β 1-antagonist), indicated that the predominant β-adrenoceptor in the frontal cortex is the β 1-subtype (65–75%). The density of total β- ( r=−0.60, n=44) or β 1-adrenoceptors ( r=−0.78, n=22), but not the β 2-subtype, declined with aging (3–80 years). The density of total β- or β 1-adrenoceptors, but not the β 2-subtype, correlated with the number of α 2-adrenoceptors quantitated in the same brains with the agonist [ 3H]UK14304 ( r=0.71–0.81) or the antagonist [ 3H]RX821002 ( r=0.61–0.66). Interestingly, the ratios α 2/β- or α 2/β 1-adrenoceptors did not correlate with the age of the subject at death, indicating that the proportion of α 2/β-adrenoceptors in brain remains rather constant during the process of aging. The density of β-adrenoceptors correlated with the immunodensity of Gαs ( r=0.55) and Gβ ( r=0.61) proteins, and that of α 2-adrenoceptors with those of Gαi 1/2 ( r=0.88) and Gβ ( r=0.65). In brains of suicides, compared to controls, the ratio between α 2- and β- or β 1-adrenoceptors (α 2-full agonist sites/β-sites) was greater (1.3- to 2.0-fold; P<0.05). The results demonstrate a close interdependence between brain α 2- and β-adrenoceptors during aging, and in brains of suicides. The quantitation of the α 2A/β-adrenoceptor ratio could represent a relevant neurochemical index in the study of brain pathologies in which both receptors are involved.