title: The CCKB receptor antagonist, L-365,260, elicits antidepressant-type effects in the forced-swim test in mice.
abstract: Selective CCKA and CCKB receptor agonists and antagonists were used to study the involvement of endogenous cholecystokinin in the behavioural changes that occur in mice in the forced-swimming test (Porsolt's test). The CCKB receptor antagonist, L-365,260 ((3R)-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-3-methylphenylurea), but not the CCKA receptor antagonist, devazepide ((3S)-(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)- 1H-indole-2-carboxamide), elicited an antidepressant-type response (a decrease in the duration of immobility) that was suppressed by previous treatment with either CCK-8 (H-Asp-Tyr(OSO3H)-Met-Gly- Trp-Met-Asp-Phe-NH2) or the selective CCKB receptor agonist BC-264 (Boc-Tyr(SO3H)-gNle-mGly-Trp-N(Me)-Nle-Asp-Phe- NH2). The L-365,260 effect was also prevented by the dopamine receptor antagonist, SCH-23,390 (a dopamine D1-selective receptor antagonist: R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine) and sulpiride (a dopamine D2-selective receptor antagonist: (-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-2-metoxybenzamide). On the other hand, co-administration of subthreshold doses of L-365,260 and nomifensine (an atypical antidepressant that selectively blocks dopamine re-uptake mechanisms, 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinamine) led to a potent antidepressant-type response. These results indicate that blocking of CCKB receptors could result in an increase of extracellular dopamine contents in some brain areas involved in depression and suggest a potential use of CCKB receptor antagonists, alone or combined with antidepressants, in the treatment of depressive syndromes.
authors: Department of Pharmacology, School of Pharmacy, Universidad Complutense de Madrid, Spain.
authors: F
authors: F
authors: Hernando
authors: J A
authors: JA
authors: Fuentes
authors: B P
authors: BP
authors: Roques
authors: M
authors: M
authors: Ruiz-Gayo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D002766:Cholecystokinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003863:Depression / Q000523:psychology*; D020109:Devazepide; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D009627:Nomifensine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012844:Sincalide / Q000494:pharmacology; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; C084553:BC 264; D001570:Benzodiazepinones; D018492:Dopamine Antagonists; D010446:Peptide Fragments; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D009627:Nomifensine; C058121:L 365260; D002766:Cholecystokinin; D020109:Devazepide; D012844:Sincalide