Dopamine inhibits responses of astroglia-enriched cultures to lipopolysaccharide via a β-adrenoreceptor-mediated mechanism

Abstract

We here investigated the effect of the catecholaminergic neurotransmitter dopamine (DA), on the release of two major inflammatory effectors, TNF-α and nitric oxide, in rat astroglia-enriched cultures stimulated with the bacterial endotoxin lipopolysaccharide (LPS). Upon LPS challenge, we observed a dramatic increase in the culture medium of the TNF-α protein, an effect thereafter followed by an increase of nitric oxide synthase type 2 (NOS2) mRNA and, at later times, of nitrite accumulation, an index of nitric oxide (NO) production. DA substantially inhibited the release of TNF-α and NO evoked by LPS, an effect not mimicked by selective agonists nor prevented by selective antagonists of the DA receptors. The inhibitory effects of DA were mimicked by noradrenalin and isoproterenol and fully reverted by propranolol, a selective antagonist of the β-adrenergic receptors. In addition, selective antagonists of β-adrenergic receptor type 1 (metoprolol) and type 2 (ICI-118,551) counteracted the inhibitory effects of DA on LPS-induced TNF-α and NO release. Accordingly, agents capable of elevating intracellular cyclic 3′,5′-adenosine monophosphate (cAMP), such as forskolin and dibutyryl-cAMP, mimicked DA inhibitory effects on LPS-evoked accumulation of TNF-α and nitrite. These data, consistent with a role of DA as local modulator of glial inflammatory responses, uncover the existence of an interaction between DA and heterologous β-adrenergic receptors in astroglial cells.