Research report Agonist-induced desensitization of adenylyl cyclase activity mediated by 5-hydroxytryptamine receptors in rat frontocortical astrocytes

Our previous study has demonstrated that astrocytes derived from the rat frontal cortex contain 5-hydroxytryptamine 5-HT 7 receptors positively coupled to adenylyl cyclase. In this study, we observed a desensitization of 5-HT receptors induced by a treatment 7 . with agonists 0.1, 1, and 10 mM, 0.5 to 3.5 h . Maximum responses, but not the EC values, in the concentration-response curve of 50 . 5-HT-induced cyclic AMP 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 a-methyl-5-HT caused the desensitization. When the astrocytes were treated with isoproterenol, N-ethylcarboxamidoadenosine, and dibutyryl cyclic AMP all of . which increase intracellular cyclic AMP levels , 5-HT-induced cyclic AMP responses were not affected. Conversely, adenylyl cyclase activity mediated by either isoproterenol or N-ethylcarboxamidoadenosine 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 astrocytes stimulated cyclic AMP formation both in the presence and absence of forskolin, whereas in neuron-rich cultures of the frontal cortex, these agonists did not change basal cyclic AMP levels and decreased forskolin-stimulated cyclic AMP formation. Neurons may predominantly contain 5-HT receptors that are negatively coupled to adenylyl cyclase. These results suggest that 5-HT receptors are 1A 7 highly expressed in astrocytes but not in neuronal cells, and that pretreatment with their agonists results in a homologous desensitization of the receptors. q 1998 Elsevier Science B.V.