Changes with age in central nervous system alpha(1)-adrenergic receptors and associated signalling mechanisms in the rat

This dissertation focused on the study of how age affects three sequential biochemical processes associated with the central noradrenergic nervous system in the rat. The first hypothesis tested was that aging reduces the density of alpha{dollar}sb1{dollar}-adrenergic receptors (ARs) in the brain in a region selective manner. In vitro radioligand binding using the alpha{dollar}sb1{dollar}-AR-selective antagonist {dollar}sp{lcub}125{rcub}{dollar}I-BE-2254 and quantitative receptor autoradiography were used to measure receptors in several circumscribed areas of the brain. Saturation binding analysis revealed that small but significant receptor losses of 15-44% occur in the thalamus, olfactory tubercle, and cerebral cortex of aged rats. In no brain area was receptor affinity altered with aging. These results suggest that the loss of alpha{dollar}sb1{dollar}-ARs may account for some but not all of the age-related functional deficits previously reported to occur in various brain regions.; The second hypothesis tested was that aging reduces the ability of agonists to stimulate hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP{dollar}sb2{dollar}) via alpha{dollar}sb1{dollar}-ARs. Tissue minces from several brain regions were prelabelled with {dollar}sp3{dollar}H-inositol and then exposed to alpha{dollar}sb1{dollar}-AR agonists to stimulate accumulation of inositol phosphates. Dose-response curves revealed that agonist efficacy is reduced by approximately 30% in the cerebral cortex and thalamus of aged rats, while agonist potency is unaltered. These results support the hypothesis that loss of alpha{dollar}sb1{dollar}-ARs with aging is functionally significant.; The third hypothesis tested was that aging reduces the agonist properties of the second messenger inositol 1,4,5-triphosphate (IP{dollar}sb3{dollar}). The ability of IP{dollar}sb3{dollar} to elicit calcium mobilization was examined in microsomes isolated from various brain regions. Dose-response analysis revealed that the efficacy of IP{dollar}sb3{dollar} is significantly reduced by 50% in the cerebral cortex of aged cohorts. These results suggest that aging reduces neurotransmission via receptors which are coupled to the PIP{dollar}sb2{dollar} signal transduction system in the cerebral cortex by altering the calcium mobilizing properties of IP{dollar}sb3{dollar}.; It is concluded that changes in the number of alpha{dollar}sb1{dollar}-ARs, in their coupling to PIP{dollar}sb2{dollar} hydrolysis, and in the calcium mobilizing properties of IP{dollar}sb3{dollar} are likely to contribute to the decreased responsiveness of neurons to the effects of norepinephrine in some but not all brain regions.