Neurotransmitter receptors coupling to the adenylate cyclase (AC) system were studied in the human neuroblastoma SH-SY5Y cell line. Vasoactive intestinal polypeptide (VIP) caused an up to 40-fold enhancement of the AC activity, while prostaglandin E1 (PGE1) was able to increase the cAMP accumulation 2.5-fold. Stimulation either by VIP or PGE1 was attenuated with either morphine (MOR) or oxotremorine (OXO). Prolonged exposure to MOR and OXO caused a ligand-specific, i.e. homologous desensitization of the opioid and muscarinic acetylcholine receptors, respectively. Preceding desensitization, a supersensitive response of the AC system to VIP was observed. Pretreatment of cells with PT overnight reduced the inhibitory effects of both MOR and OXO. Nevertheless, in cells pretreated with PT and then also with OXO, MOR and OXO inhibited the VIP-induced AC response. Apparently, there are both PT-sensitive and -insensitive pathways to AC inhibition in SH-SY5Y cells.