Comparative recovery kinetics of 5-hydroxytryptamine 1A, 1B, and 2A receptor subtypes in rat cortex after receptor inactivation: evidence for differences in receptor production and degradation.
The present study investigates the comparative repopulation kinetics of 5-hydroxytryptamine (5-HT)1A, 5-HT1B, and 5-HT2A receptors in rat cortex homogenates after irreversible receptor inactivation by N-ethoxycarbonyl-1,2-ethoxydihydroquinoline. Adult male rats were administered a single subcutaneous dose of vehicle (1:1 ethanol/water) or N-ethoxycarbonyl-1,2-ethoxydihydroquinoline (10 mg/kg), and the recovery of 5-HT receptor subtypes was measured at various times after injection (4-336 hr). Despite comparable control Bmax values for 5-HT1A (84 +/- 2 fmol/mg of protein) and 5-HT1B (94 +/- 4 fmol/mg) subtypes, marked differences were noted in their 1) receptor production rates (r = 0.349 versus 0.235 fmol/mg of protein/hr), 2) receptor degradation rate constants (k = 0.0056 versus 0.0033 hr-1), and 3) half-lives of receptor recovery (124.1 versus 212.5 hr). For 5-HT2A receptors, both r and k for agonist [(+/-)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane]- or antagonist ([3H]ketanserin)-labeled sites were markedly greater than the respective values for the 5-HT1 subtypes. In addition, the significantly different Bmax values for agonist- versus antagonist-labeled 5-HT2A receptors (79 +/- 4 versus 206 +/- 10 fmol/mg) were reflected exclusively as a 2.6-fold difference in receptor production rates, because degradation rate constants (k) were identical. Moreover, the stoichiometry of agonist-labeled to antagonist-labeled 5-HT2A receptors was not altered at any time point during recovery. These data indicate that 1) comparable receptor steady state Bmax values for 5-HT receptor subtypes may be due to markedly different receptor kinetic parameters (r and k), 2) differences in r and k are greater between 5-HT receptor families (i.e., 5-HT1 versus 5-HT2) than among subtypes within a family (i.e., 5-HT1A versus 5-HT1B), and, 3) despite marked changes in 5-HT2A receptor density, the percentage of receptors in the agonist-labeled, high affinity state is maintained.
Pinto
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Neuroscience Program, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153.
Battaglia
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D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D007650:Ketanserin / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism
D000662:Amphetamines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine