Astrocytic Adrenoceptors: A Major Drug Target in Neurological and Psychiatric Disorders?

Abstract

Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodal, long-term memory, which is reinforced by β-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occurs at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

How Do Astrocytes Participate in Neural Plasticity?

“…Astrocytes express Gq-linked, as well as Giand Gs-linked metabotropic receptors that are activated by norepinephrine, acetylcholine, serotonin, and likely other neuromodulators (Hertz et al 2004;Verkhratsky et al 2012). One of the characteristics of neuromodulators is that they typically target multiple cells via volume transmission and diffusion across considerable distances before receptor binding (Callado and Stamford 2000;Cragg et al 2001).…”

Noradrenaline Induces Clock Gene Per1 mRNA Expression in C6 Glioma Cells Through β2-Adrenergic Receptor Coupled With Protein Kinase A – cAMP Response Element Binding Protein (PKA–CREB) and Src-Tyrosine Kinase – Glycogen Synthase Kinase-3β (Src–GSK-3β)

“…In addition to the SCN, reports also have demonstrated that NA generates circadian-clock oscillation in peripheral organs and cells (16,17). Thus, since various roles of NA and several types of adrenergic receptor expression in astrocytes have been reported (18), the possibility also exists that clock-gene expression in astroglial cells might be mediated by NA -adrenergic receptor cascades.…”

Nerve Driven Immunity: Noradrenaline and Adrenaline

“…Accordingly, downregulation of the astrocytic b 2 -AR-pathway might be involved into a number of neurological conditions such as multiple sclerosis, Alzheimer's disease, human immunodeficiency virus encephalitis, stroke and hepatic encephalopathy (reviewed in Hertz et al (2004) and Laureys et al (2010)). It has been recently reported however that b-AR stimulation together with TNF-receptor triggering may also induce synergistic IL-6 expression in astrocytes, an effect which warrants further investigation also in view of the role of uncontrolled expression of IL-6 in the CNS in neurodegeneration and glioma development (Spooren et al 2011).…”