Loss of cortical serotonin2A signal transduction in senescent rats: reversal following inhibition of protein kinase C.
Using grease gap recordings, age-related changes in serotonin2A receptors were assessed in sensorimotor regions of the cortex by examining serotonin-induced facilitation of the N-methyl-D-aspartate depolarization in cortical wedges prepared from young adult (3-6 months) and senescent (22-34 months) Fisher 344 rats. Serotonin (10-100 microM) facilitated the N-methyl-D-aspartate depolarization in wedges from young adult rats in a concentration-dependent manner, whereas no facilitation was observed in wedges from senescent rats. Similar results were obtained when +/- 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, a mixed serotonin2A and serotonin2C receptor agonist, was substituted for serotonin. In contrast, agonists at alpha 1A-adrenoceptors, metabotropic glutamate receptors and muscarinic cholinoceptors facilitated the N-methyl-D-aspartate depolarization in wedges from both young adult and senescent rats. Chelerythrine and staurosporine, inhibitors of protein kinase C, but not concanavalin A, myo-inositol or calmodulin antagonists, restored the serotonin facilitation in wedges from senescent animals. In situ hybridization histochemistry revealed that serotonin2A receptor messenger RNA was present in layers II-VI of the cortex, with the highest density of silver grains located in layers III and V of both young adult and senescent rats. Detailed examination of layer V showed that silver grains were significantly higher than background only over pyramidal cells. We conclude that serotonin2A receptors are expressed by pyramidal cells in both young adult and senescent rats and that serotonin acts directly on these receptors to facilitate the N-methyl-D-aspartate depolarization. Moreover, in senescent rats, signal transduction at cortical serotonin2A receptors involved with facilitation of the N-methyl-D-aspartate response is compromised as a result of protein kinase C activation.
Rahman
S
S
Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.
McLean
J H
JH
Darby-King
A
A
Paterno
G
G
Reynolds
J N
JN
Neuman
R S
RS
D000375:Aging / Q000378:metabolism*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D004594:Electrophysiology; D017403:In Situ Hybridization; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D019311:Staurosporine
D000470:Alkaloids; D011985:Receptors, Serotonin; D012701:Serotonin; D016202:N-Methylaspartate; D011493:Protein Kinase C; D019311:Staurosporine