The CCKB receptor antagonist, L-365,260, elicits antidepressant-type effects in the forced-swim test in mice

Eur J Pharmacol. 1994 Aug 22;261(3):257-63. doi: 10.1016/0014-2999(94)90115-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antidepressive Agents / pharmacology*
  • Benzodiazepinones / pharmacology*
  • Cholecystokinin / analogs & derivatives
  • Cholecystokinin / antagonists & inhibitors
  • Cholecystokinin / pharmacology
  • Depression / psychology*
  • Devazepide
  • Dopamine Antagonists / pharmacology
  • Male
  • Mice
  • Molecular Sequence Data
  • Motor Activity / drug effects
  • Nomifensine / pharmacology
  • Peptide Fragments / pharmacology
  • Phenylurea Compounds*
  • Receptors, Cholecystokinin / antagonists & inhibitors*
  • Sincalide / pharmacology
  • Swimming


  • Antidepressive Agents
  • BC 264
  • Benzodiazepinones
  • Dopamine Antagonists
  • Peptide Fragments
  • Phenylurea Compounds
  • Receptors, Cholecystokinin
  • Nomifensine
  • L 365260
  • Cholecystokinin
  • Devazepide
  • Sincalide