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

doi:10.1016/0014-2999(94)90115-5

European Journal of Pharmacology

Volume 261, Issue 3, 22 August 1994, Pages 257-263

https://doi.org/10.1016/0014-2999(94)90115-5 Get rights and content

Abstract

Selective CCK_A and CCK_B 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 CCK_B 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 CCK_A 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 CCK_B 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 CCK_B receptors could result in an increase of extracellular dopamine contents in some brain areas involved in depression and suggest a potential use of CCK_B receptor antagonists, alone or combined with antidepressants, in the treatment of depressive syndromes.

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Depression is the second leading cause of disability in the world population, for which currently available pharmacological therapies either have poor efficacy or have some adverse effects. Accumulating evidence from clinical and preclinical studies demonstrates that the amygdala is critically implicated in depressive disorders, though the underlying pathogenesis mechanism needs further investigation. In this literature review, we overviewed depression and the key role of Gamma-aminobutyric acid (GABA) and Glutamate neurotransmission in depression. Notably, we discussed a new cholecystokinin-dependent plastic changes mechanism under stress and a possible antidepressant response of cholecystokinin B receptor (CCKBR) antagonist. Moreover, we discussed the fundamental role of the amygdala in depression, to discuss and understand the pathophysiology of depression and the inclusive role of the amygdala in this devastating disorder.
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Depression is one of the most prevalent forms of mental disorders and is the most common cause of disability in the Western world. Besides, the harmful effects of stress-related mood disorders on the patients themselves, they challenge the health care system with enormous social and economic impacts. Due to the high proportion of patients not responding to existing drugs, finding new treatment strategies has become an important topic in neurobiology, and there is much evidence that neuropeptides are not only involved in the physiology of stress but may also be clinically important. Based on preclinical trial data, new neuropharmaceutical candidates may target neuropeptides and their receptors and are expected to be essential and valuable tools in the treatment of psychiatric disorders. In the current article, we have summarized data obtained from animal models of depressive disorder and transgenic mouse models. We also focus on previously published research data of clinical studies on corticotropin-releasing hormone (CRH), galanin (GAL), neuropeptide Y (NPY), neuropeptide S (NPS), Oxytocin (OXT), vasopressin (VP), cholecystokinin (CCK), and melanin-concentrating hormone (MCH) stress research fields.
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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.
Endoproteases in the secretory pathway process pro-cholecystokinin (CCK) into the biologically active forms found in the tissues that express CCK mRNA. Thus far, the endoproteases involved in CCK processing include cathepsin L and the prohormone convertases (PC) 1, 2, and 5. This study finds that PC7 is also critical for normal production of CCK in specific areas of the brain. Loss of PC7 results in decreased levels of CCK in more brain regions than any other endoprotease studied to date. Substantial decreases in brain levels of CCK are found in the prefrontal, frontal, parietal-insular-pyriform, and temporal cortex, caudate-putamen, basal forebrain, thalamus, hippocampus, septum, and medulla of PC7 knock-out (KO) mice. A tissue-specific sexual dimorphism of PC7 activity was also identified. This is the first report that loss of PC7 alters levels of a neuropeptide in the brain. This loss of PC7 and CCK may independently contribute to the decrease in Brain Derived Neurotrophic Factor production and be partially responsible for the learning and memory defects observed in mice that lack PC7.
Neuropeptide Y attenuates anxiety- and depression-like effects of cholecystokinin-4 in mice
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Citation Excerpt :
This observation is in accordance with the earlier report (Derrien et al., 1994), wherein CCK-B receptor antagonist showed antidepressant effect in the FST model in mice. CCK-B receptor agonist BC 264, increased depression-like response in mice following inescapable electric shocks and the same were prevented by the selective CCK-B receptor antagonist L-365260 (Hernando et al., 1994). Moreover, panic patients showed a significant association with the CCK-B receptor gene polymorphism (Kennedy et al., 1999).
We investigated the involvement of neuropeptide Y (NPY) in the modulation of cholecystokinin-4 (CCK-4)-evoked anxiety and depression. Adult male mice were injected with vehicle, CCK-4, NPY, NPY Y1 receptor agonist [Leu³¹, Pro³⁴]-NPY or antagonist BIBP3226, via intracerebroventricular route, and subjected to social interaction or forced swim test (FST) for the evaluation of anxiety- and depression-like phenotypes, respectively. To assess the interactions between the two systems, if any, NPYergic agents were administered prior to CCK-4 and the animals were subjected to these behavioral tests. Treatment with CCK-4 or BIBP3226 dose-dependently reduced social interaction time, while NPY or [Leu³¹, Pro³⁴]-NPY produced opposite effect. CCK-4 treatment increased immobility time in FST. This effect was reversed by NPY and [Leu³¹, Pro³⁴]-NPY, although BIBP3226 per se did not alter the immobility time. In a combination study, the anxiogenic or depressive effects of CCK-4 were attenuated by NPY or [Leu³¹, Pro³⁴]-NPY and potentiated by BIBP3226. The brains of CCK-4 treated rats were processed for NPY immunohistochemistry. Following CCK-4 treatment, the nucleus accumbens shell (AcbSh), ventral part of lateral division of the bed nucleus of stria terminalis (BSTLV), hypothalamic paraventricular nucleus and locus coeruleus showed a reduction in NPY-immunoreactive fibers. Population of NPY-immunopositive cells was also decreased in the AcbSh, BSTLV, prefrontal cortex and hypothalamic arcuate nucleus (ARC). However, NPY-immunoreaction in the fibers of the ARC and cells of the central nucleus of amygdala was unchanged. We conclude that, inhibition of NPY signaling in the brain by CCK-4 might be causal to anxiety- and depression-like behaviors.
Amitriptyline converts non-responders into responders to low-frequency electroacupuncture-induced analgesia in rats
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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).
The purpose of this study was to examine whether the use of intraperitoneal or intrathecal amitriptyline combined with electroacupuncture modifies the tail-flick reflex and incision pain in rats that normally do not have analgesia to electroacupuncture in the tail-flick test (non-responder rats).
Changes in the nociceptive threshold of intraperitoneal or intrathecal saline- or amitriptyline-treated non-responder rats were evaluated using the tail-flick or incision pain tests before, during and after a 20-min period of electroacupuncture, applied at 2 Hz to the Zusanli and Sanynjiao acupoints. Amitriptyline was used at doses of 0.8 mg/kg or 30 μg/kg by intraperitoneal or intrathecal route, respectively. At these doses, amitriptyline has no effect against thermal or incision pain in rats.
Rats selected as non-responders to the analgesic effect of electroacupuncture 2 Hz in tail-flick and incision pain tests become responders after an intraperitoneal or intrathecal injection of amitriptyline.
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In recent years, studies have advocated neuropeptide systems as modulators for the behavioral states found in mood disorders such as depression and anxiety disorders. Neuropeptides have been tested in traditional animal models and screening procedures that have been validated by known antidepressants and anxiolytics. However, it has become clear that although these tests are very useful, neuropeptides have distinct behavioral effects and dose-dependent characteristics, and therefore, use of these tests with neuropeptides must be done with an understanding of their unique characteristics. This review will focus on the behavioral actions of neuropeptides and their synthetic analogs, particularly in studies utilizing various preclinical tests of depression and anxiety. Specifically, the following neuropeptide systems will be reviewed: corticotropin-releasing factor (CRF), urocortin (Ucn), teneurin C-terminal associated peptide (TCAP), neuropeptide Y (NPY), arginine vasopressin (AVP), oxytocin, the Tyr-MIF-1 family, cholecystokinin (CCK), galanin, and substance P. These neuropeptide systems each have a unique role in the regulation of stress-like behavior, and therefore provide intriguing therapeutic targets for mood disorder treatment.

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

Abstract

Brain Res.

Pain

Eur. J. Pharmacol.

Neuroscience

Peptides

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Brain Res.

Neuropharmacology

Brain Res.

Peptides

Eur. J. Pharmacol.

Brain Res.

Trend. Pharmacol. Sci.

Peptide

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Peptides

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Peptides

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