Noradrenaline acting on astrocytic β₂-adrenoceptors induces neurite outgrowth in primary cortical neurons.

The neurotransmitter noradrenaline (NA) has anti-inflammatory properties and promotes expression of neurotrophic factors in the central nervous system (CNS) via activation of glial adrenoceptors. Here we examined the ability of conditioned media (CM) from NA-treated glial cells to impact upon neuronal complexity. Primary rat cortical neurons were treated either directly with NA (1-10 μM), or treated with CM from NA-stimulated primary mixed glial cells. Neuronal complexity was assessed using Sholl analysis. Exposure of neurons to CM from NA-stimulated glial cells increased all indices of neuronal complexity, whereas direct exposure of neurons to NA did not. CM from NA-stimulated astrocytes, but not microglia, also increased neuronal complexity indicating a key role for astrocytes. The β-adrenergic subtype was implicated in this response as the increase was blocked by the β-adrenoceptor antagonist propanolol, but not by the α-adrenoceptor antagonist phentolamine. CM from glial cells treated with the β₂-adrenoceptor agonists salmeterol and clenbuterol, but not the β₁-adrenoceptor agonist xamoterol, mimicked the ability of NA to increase neuronal complexity. NA induced expression of a range of growth factors (BDNF, NGF-β, GDNF, FGF-2 and IL-6) in glial cells. In addition to this, the phosphatidylinositol 3-kinase (PI3K), mitogen activated protein kinase (MAPK) and JAK-STAT signalling pathways are implicated in NA CM-induced neuritic growth as inhibition of these pathways attenuated NA CM-induced neuritic growth. In conclusion, this study indicates a novel role for NA acting at glial β₂-adrenoceptors to induce neuritic growth through the expression of soluble factors that elicit a neurotrophic action and increase neuronal complexity.