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

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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-1 H-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-1 H-1,4-benzodiazepin-3-yl)-1 H-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-1 H-3-benzazepine) and sulpiride (a dopamine D2-selective receptor antagonist: (-)-5-(aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]2- metoxybenzamide). O 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.

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Cited by (57)

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    CCK was found to mediate its action by binding to its receptors, named CCK1 and CCK2. Animal studies have shown that CCK2 antagonists produce antidepressive effects in the mouse FST, while CCK1 receptor antagonists have no effect (Hernando et al., 1994). Interestingly, the CCK2 receptor antagonist, CI-988 normalizes immobility in the rat force swim test.

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    In the mammalian brain, CCK is one of the most abundant neuropeptides [5–7]. CCK's role in the brain is not completely clear, but there is compelling evidence to suggest that it is an essential component of processes underlying anxiety [8–11]; memory retention and learning [12], mood disorders such as depression [13–16] via the alteration of dopamine release [15,16], schizophrenia [17,18], and pain perception [19–23]. CCK is one of the neuropeptides in which the same primary translation product is processed into different molecular forms in different tissues.

  • Neuropeptide Y attenuates anxiety- and depression-like effects of cholecystokinin-4 in mice

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    Several preclinical and clinical studies reported panicogenic and anxiogenic responses following the administration of CCK-4 (Singh et al., 1991; Bradwejn et al., 1994; Rex et al., 1994; van Megen et al., 1996; Holy and Wisniewski, 1998). In addition, treatment with CCK-B receptor antagonist elicited anxiolytic- (Singh et al., 1991; Derrien et al., 1994) and antidepressant-like responses (Hernando et al., 1994; Becker et al., 2008). CCK-B receptors are localized on neuropeptide Y (NPY) containing neurons (Bi et al., 2004; Chen et al., 2006; Chee and Colmers, 2008); the peptide is an established orexigenic agent in the brain (Beck, 2006).

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    In addition, the reduction of rat brain CCK content following intracerebroventricular administration of antisense oligonucleotides to CCK mRNA converted non-responder rats into responder rats (Tang et al., 1997). Blockade of CCK-2 receptors might result in antidepressant-like effects (Hernando et al., 1994). Chronic imipramine prevents changes such as hyperactivity of hypothalamic-pituitary-adrenal axis, increased immobility time in the forced swimming test, decrease of body weight and of sweet water consumption and reduction of hippocampal volume associated with a decreased cell proliferation in the dentate gyrus, which are taken as correlates of depressive symptoms in humans, and is associated in the increase in cortical CCK release (Becker et al., 2008).

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