Serotonin1c receptor reserve in choroid plexus masks receptor subsensitivity.
This paper tests the hypothesis that spare serotonin 5-HT1c receptors are present in the rat choroid plexus and explores the possible influence of such sites on the adaptive regulation of the 5-HT1c receptor. The consequences of partial receptor inactivation were compared for the natural agonist 5-HT and the putative partial agonists trifluoromethylphenylpiperazine (TFMPP) and (+)-lysergic acid diethylamide (LSD). These studies showed approximately 50% reserve of 5-HT1c receptors in the rat choroid plexus. The calculated KA for 5-HT obtained by partial irreversible inactivation was 36 nM. Phenoxybenzamine reduced the maximum response elicited by TFMPP and LSD, without shifting the EC50 values, consistent with the interpretation that TFMPP and LSD are partial agonist at the 5-HT1c receptor in rat choroid plexus. The KA of TFMPP and LSD was 0.16 microM and 9 nM, respectively. Quantitative analysis of percentage of receptor occupancy vs. percentage of maximum response showed that 5-HT occupied only 70% of the receptors to give a maximum response, whereas a linear relationship between percentage of occupancy and response was found for TFMPP. These differences had functional consequences as demonstrated in studies of regulation of the 5-HT1c receptor. Chronic administration of the 5-HT agonist quipazine produced a 32% loss of 5-HT1c binding sites in the choroid plexus, with no change in the 5-HT-induced phosphoinositide hydrolysis response. This dissociation between binding and function is likely explained by the receptor reserve that exists for the 5-HT1c receptors. Consistent with this interpretation, the TFMPP-induced phosphoinositide hydrolysis signal was reduced to the same extent as the loss of binding sites. These results show that the 5-HT1c receptor in the choroid plexus adapts predictably to chronic receptor activation and suggest the possibility that the paradoxical regulation that has been described for other 5-HT receptors might be explained partially by the unrecognized existence of receptor reserve.
Sanders-Bush
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Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Breeding
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D000818:Animals; D001665:Binding Sites; D002831:Choroid Plexus / Q000187:drug effects / Q000378:metabolism*; D008238:Lysergic Acid Diethylamide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008803:Mianserin / Q000378:metabolism; D010643:Phenoxybenzamine / Q000494:pharmacology; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011814:Quipazine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*
D010879:Piperazines; D011804:Quinolines; D011985:Receptors, Serotonin; D010643:Phenoxybenzamine; D008803:Mianserin; C018406:1-(3-trifluoromethylphenyl)piperazine; D011814:Quipazine; D008238:Lysergic Acid Diethylamide