Effects of postmortem delay on serotonin and (+)8-OH-DPAT-mediated inhibition of adenylyl cyclase activity in rat and human brain tissues

The reproducibility of serotonin (5-HT) and (+)8-OH-DPAT-mediated inhibitio n of adenylyl cyclase activity was assessed in membranes, stimulated by for skolin, of rat frontal cortex postmortem as well as of human fronto-cortica l, hippocampal and dorsal raphe tissues obtained from autopsy brains. The r esults revealed that differences between basal and forskolin-stimulated enz yme activities were still significant after 48 h postmortem in rat cortex a nd in all human brain regions up to 46 h after death. However, a decrease o f about 17 and 26% in forskolin-stimulated adenylyl cyclase activity was ob served at 24 and 48 h, respectively, in rat cortex. 5-HT and the 5-HT1A rec eptor agonist, (+)8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT), were a ble to inhibit forskolin-stimulated adenylyl cyclase activity in a dose-dep endent manner for 48 h after death in rat and human brain. In rat cortex, b oth 5-HT and (+)8-OH-DPAT potencies (EC50, nM) and efficacies (percent of m aximum inhibition capacity, %) varied significantly with postmortem delay. Conversely, in human tissues, postmortem delay and subject age did not modi fy agonist potencies and efficacies. Furthermore, a regionality of 5-HT pot ency and efficacy was revealed in the human brain. 5-HT was equally potent in cortex and raphe nuclei, while being more potent but less effective in h ippocampus. (+)8-OH-DPAT was more active in hippocampus and raphe nuclei th an in cortex. (+)8-OH-DPAT behaved as an agonist in all areas, as its effic acy was similar or greater than those obtained with 5-HT. The (+)8-OH-DPAT dose-response curve was completely reversed by 5-HT1A receptor antagonists in rat cortex and all human brain areas. In conclusion, we suggest here tha t differences between rat and human brain might exist at the level of postm ortem degradation of 5-HT-sensitive adenylyl cyclase activity. In human bra in, 5-HT1A receptor-mediated inhibition of adenylyl cyclase seems to be rep roducible, suggesting that reliable experiments can be carried out on postm ortem specimens from patients with neuropsychiatric disorders. (C) 1999 Els evier Science B.V. All rights reserved.