Exposure of primary rat astrocyte cultures to bacterial endotoxin lipopolysaccharide (LPS) causes expression of a Ca(2+)-independent form of nitric oxide synthase (NOS). In these cells, the presence of norepinephrine (NE) caused a dose-dependent inhibition of the LPS induction of NOS activity, with an IC50 value of 100 nM and significant suppression at 100 pM. Short incubations (5-40 min) with NE were as effective as 24-h continuous exposure, and inhibition was observed up to the longest incubation period measured (56 h). In contrast, previously induced NOS activity was not affected by exposure to NE. The effects of NE were mediated primarily by binding to beta-adrenergic receptors (beta-ARs) because (a) the beta-AR antagonist propranolol, but not the alpha-AR antagonist phentolamine, could reverse the effects of NE; (b) the beta-AR agonist isoproterenol, but not the alpha-AR agonist phenylephrine, was as effective as NE in blocking the effects of LPS; and (c) incubation with the cyclic AMP analogue dibutyryl cyclic AMP replicated the effects of NE. In contrast to astroglial cultures, LPS induction of NOS activity in RAW 264.7 macrophage cells was not affected by NE or dibutyryl cyclic AMP. These results indicate that in brain, inducible NOS in astrocytes can be regulated by neurotransmitter binding to glial receptors.