AGONIST-INDUCED DESENSITIZATION OF ADENYLYL-CYCLASE ACTIVITY MEDIATEDBY 5-HYDROXYTRYPTAMINE(7) RECEPTORS IN RAT FRONTOCORTICAL ASTROCYTES

Our previous study has demonstrated that astrocytes derived from the r at frontal cortex contain 5-hydroxytryptamine (5-HT)(7) receptors posi tively coupled to adenylyl cyclase. In this study, we observed a desen sitization of 5-HT7; receptors induced by a treatment with agonists (0 .1, 1, and 10 mu M, 0.5 to 3.5 h). Maximum responses, but not the EC50 values, in the concentration-response curve of 5-HT-induced cyclic AM P formation were decreased after pretreatment with 5-HT. Pretreatment with 5-carboxamidotryptamine (5-CT) elicited a potent desensitization of 5-HT-induced cyclic AMP formation. Neither 2-methyl-5-HT nor alpha- methyl-5-HT caused the desensitization. When the astrocytes were treat ed with isoproterenol, N-ethylcarboxamidoadenosine, and dibutyryl cycl ic AMP (all of which increase intracellular cyclic AMP levels), fi-HT- induced cyclic AMP responses were not affected. Conversely, adenylyl c yclase activity mediated by either isoproterenol or N-ethylcarboxamido adenosine was attenuated by pretreatment with each of these agonists, but not 5-HT. In addition, our study showed that the administration of 5-HT, 5-CT, and 8-hydroxy-2-(di-n-propylamino)tetralin to the astrocy tes stimulated cyclic AMP formation both in the presence and absence o f forskolin, whereas in neuron-rich cultures of the frontal cortex, th ese agonists did not change basal cyclic AMP levels and decreased fors kolin-stimulated cyclic AMP formation. Neurons may predominantly conta in 5-HT1A receptors that are negatively coupled to adenylyl cyclase. T hese results suggest that 5-HT, receptors are highly expressed in astr ocytes but not in neuronal cells, and that pretreatment with their ago nists results in a homologous desensitization of the receptors. (C) 19 98 Elsevier Science B.V.