title: Several roles of CCKA and CCKB receptor subtypes in CCK-8-induced and LiCl-induced taste aversion conditioning.
abstract: Administration of a relatively large IP dose of sulfated cholecystokinin (26-33) (CCK-8; 1.0 mumol/kg) consistently induced moderate taste aversion conditioning (TAC) using a 20-min, one-bottle test in Long-Evans rats. Because CCK-8 has affinity for both CCKA and CCKB receptor subtypes, we wanted to determine the subtype involved in CCK-8-induced TAC. Pretreatment with the selective CCKA antagonist MK-329 (L-364, 718 or devazepide), at doses of 0.1, 1.0, or 10.0 mumol/kg, markedly antagonized (> 70%) CCK-8-induced TAC. Pretreatment with the selective CCKB antagonist L-365,260, at doses of 0.1 or 1.0 mumol/kg, partially antagonized (approximately 50%) CCK-8-induced TAC, although the highest dose of L-365,260. 10.0 mumol/kg, did not. These partial antagonistic effects of L-365,260 on CCK-8-induced TAC were replicated in our second study. In our third study, we observed that another CCKB antagonist, the dipeptoid CI-988, also partially antagonized CCK-8-induced TAC at a dose of 0.1, but not 1.0 or 10.0, mumol/kg. In our final study, pretreatments with a single dose (i.e., 10.0, but not 0.1 or 1.0, mumol/kg) of either MK-329 or L-365,260 were also shown to partially antagonize the formation of moderate TAC induced by treatment with LiCl at 708 mumol/kg. Marked antagonism of LiCl-induced TAC was also observed following pretreatment with the known anxiolytic chlordiazepoxide HCl at 7.4 mumol/kg. Considering the existing data on the induction of TAC by various CCK analogues, we consider an action of CCK-8 on peripheral CCKA, but not CCKB, receptors necessary for the induction of TAC. Our results of partial antagonism of CCK-8- and LiCl-induced TAC by L-365,260, CI-988, or MK-329 suggest, but do not prove, that both CCKA and CCKB mechanisms may be operative during TAC. Because the CCK antagonists affected TAC like chlordiazepoxide, blockade of CCKA and CCKB mechanisms may produce a mild anxiolytic effect.
authors: Department of Pharmacology, Glaxo-Wellcome Research Institute, Research Triangle Park, NC 27709, USA.
authors: J T
authors: JT
authors: Mosher
authors: M F
authors: MF
authors: Johnson
authors: L S
authors: LS
authors: Birkemo
authors: G N
authors: GN
authors: Ervin
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects*; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds; D051381:Rats; D011919:Rats, Inbred Strains; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000145:classification / Q000378:metabolism*; D012844:Sincalide / Q000494:pharmacology*; D013649:Taste / Q000187:drug effects*
chemical_list: D001570:Benzodiazepinones; D006727:Hormone Antagonists; D007211:Indoles; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C058121:L 365260; D008536:Meglumine; D002707:Chlordiazepoxide; D018021:Lithium Chloride; D020109:Devazepide; D012844:Sincalide