Brain α₂‐adrenoceptors in monoamine‐depleted rats: increased receptor density, G coupling proteins, receptor turnover and receptor mRNA

Abstract

1 This study was designed to assess the molecular and cellular events involved in the up-regulation (and receptor supersensitivity) of brain a 2 -adrenoceptors as a result of chronic depletion of noradrenaline (and other monoamines) by reserpine. (7)-adrenaline further indicated that chronic reserpine was associated with up-regulation of the high-anity state of a 2 -adrenoceptors. 3 In cortical membranes of reserpine-treated rats (0.25 mg kg 71 s.c., every 48 h for 20 days), the immunoreactivities of various G proteins (Gai 1/2 , Gai 3 , Gao and Gas) were increased (25 ± 34%). Because the high-anity conformation of the a 2 -adrenoceptor is most probably related to the complex with Gai 2 proteins, these results suggested an increase in signal transduction through a 2 -adrenoceptors (and other monoamine receptors) induced by chronic reserpine. 4 After a 2 -adrenoceptor alkylation, the analysis of receptor recovery (B max for [ 3 H]-UK14304) indicated that the increased density of cortical a 2 -adrenoceptors in reserpine-treated rats was probably due to a higher appearance rate constant of the receptor (Dr=57%) and not to a decreased disappearance rate constant (Dk=7%). 5 Northern-and dot-blot analyses of RNA extracted from the cerebral cortex of saline-and reserpine-treated rats (0.25 mg kg 71 , s.c., every 48 h for 20 days) revealed that reserpine markedly increased the expression of a 2a -adrenoceptor mRNA in the brain (125%). This transcriptional activation of the receptor gene expression appears to be the cellular mechanism by which reserpine induces up-regulation in the density of brain a 2 -adrenoceptors.

Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development

“…5). This dissociation between increases in A2AR agonist binding alongside no changes in antagonist binding has been documented in other studies that deplete norepinephrine in adult rats (Ribas et al, 2001). This has also been seen in the postmortem brain of suicide victims (Callado et al, 1998; Ordway et al, 1994), consistent with a norepinephrine deficiency in severe depression.…”

“…For example, 6-OHDA, which lesions noradrenergic and dopaminergic fibers, results in a doubling of [ 3 H]clonidine high affinity binding sites in cortex (U’Prichard et al, 1979). Reserpine, which depletes the brain of monoamines including norepinephrine, results in an up-regulation of high affinity A2AR binding by A2AR agonists [ 3 H]-UK14304 and [ 3 H]clonidine in the cortex and other brain regions (Giralt and Garcia-Sevilla, 1989; Ribas et al, 2001). A separate study of [ 3 H]p-aminoclonidine binding in adult rats lesioned with DSP4 found an increase in [ 3 H]p-aminoclonidine affinity in cortex, hippocampus, striatum and cerebellum.…”

Opposing Effects of α2- and β-Adrenergic Receptor Stimulation on Quiescent Neural Precursor Cell Activity and Adult Hippocampal Neurogenesis

“…Chronic stress models that result in hippocampal neurogenic decline have been reported to be associated with enhanced α2-adrenergic receptor expression and binding within limbic brain regions [37], [38]. In contrast, chronic treatments with antidepressants that exert powerful pro-neurogenic effects have been linked to a reduction in α2-adrenergic receptor expression and signaling [39]–[41].…”

Perturbations in brain monoamine systems during stress

“…During stress, numbers of adrenergic receptors change since concentrations of NA and/or adrenaline fluctuate: high concentrations of agonists lead to low numbers of adrenergic receptors (downregulation; Collins et al 1992), and vice versa, low agonist concentrations upregulate adrenergic receptors (Ribas et al 2001). Adrenoceptor downregulation may be due to reduced expression of the receptor gene, but also proteolytic degradation of receptor molecules may occur (Heck and Bylund 1998).…”