Primary astrocyte cultures from neonatal rat cerebral hemispheres were treated chronically for up to 3 weeks with the tricyclic antidepressants amitryptyline (AMT) or desipramine (DMI), or acutely with AMT and DMI added at the same time as the agonist, norepinephrine (NE). AMT and DMI were added at concentrations from 10(-9) to 10(-5) M. Both types of treatment did not decrease the increase in cyclic AMP (cAMP) content of these cells in response to a 10 min exposure to 10(-5) M NE. Chronic exposure to the antidepressants also did not affect stimulation of cAMP by isoproterenol (iso) in both rat and mouse primary astrocyte cultures. In contrast to the lack of effect of the tricyclic antidepressants pretreatment of the cultures with 10(-5) M NE resulted in total inhibition of the cAMP response after 2 h, with a 50% decrease occurring in about 45 min. This is similar to the agonist-induced desensitization of the beta-receptor-adenylate cyclase system seen in many other cells. This effect could, in part, be a direct response to increased intracellular cAMP since pretreatment with 0.25 and 1.0 mM N6-2'-O-dibutyryl cAMP (DBcAMP) also resulted in total inhibition of the cAMP response after 4 h. Receptor labelling experiments using [125I]cyanopindolol showed no decreases in apparent binding sites up to 3 h after exposure to 10(-5) M norepinephrine, suggesting that the rapid desensitization of the cAMP response was primarily due to an uncoupling of the receptor from the adenyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)