Effects of cholecystokinin tetrapeptide and sulfated cholecystokinin octapeptide in rat models of anxiety

doi:10.1016/0304-3940(94)90681-5

Neuroscience Letters

Volume 172, Issues 1–2, 19 May 1994, Pages 139-142

https://doi.org/10.1016/0304-3940(94)90681-5 Get rights and content

Abstract

The effects of the acutely administered cholecystokinin (CCK) agonists CCK tetrapeptide (BOC-CCK-4) and sulfated CCK octapeptide (CCK-8S) were examined in four animal models of anxiety in rats. In the elevated plus maze, BOC-CCK-4 reduced the time spent in the open arms and the number of entries into the open arms. BOC-CCK-4 but not the anorectic acting CCK-8S increased the suppression of feeding in a conflict paradigm based on novelty suppressed feeding in hungry rats. In the two-compartment black-and-white box, BOC-CCK-4 decreased the time spent and locomotor activity in the white compartment. In the ultrasound vocalization test, using rat pups separated from the mother, BOC-CCK-4 increased the number of distress calls. No evidence was found for inducing anxiety-like behaviour by CCK-8S.

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Cholecystokinin (CCK) is a neuropeptide modulating digestion, glucose levels, neurotransmitters and memory. Recent studies suggest that CCK exhibits neuroprotective effects in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Thus, we review the physiological function and therapeutic potential of CCK. The neuropeptide facilitates hippocampal glutamate release and gates GABAergic basket cell activity, which improves declarative memory acquisition, but inhibits consolidation. Cortical CCK alters recognition memory and enhances audio-visual processing. By stimulating CCK-1 receptors (CCK-1Rs), sulphated CCK-8 elicits dopamine release in the substantia nigra and striatum. In the mesolimbic pathway, CCK release is triggered by dopamine and terminates reward responses via CCK-2Rs. Importantly, activation of hippocampal and nigral CCK-2Rs is neuroprotective by evoking AMPK activation, expression of mitochondrial fusion modulators and autophagy. Other benefits include vagus nerve/CCK-1R-mediated expression of brain-derived neurotrophic factor, intestinal protection and suppression of inflammation. We also discuss caveats and the therapeutic combination of CCK with other peptide hormones.
BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents
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This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC₈₀ agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments.
Neuropeptide Y attenuates anxiety- and depression-like effects of cholecystokinin-4 in mice
2014, Neuroscience
Citation Excerpt :
CCK knock-down mice showed anxiolytic- and antidepressant-like effects (Del Boca et al., 2012). 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).
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.
Anxiogenic effect of CCK8s in the ventral hippocampus of rats: Possible involvement of GABA<inf>A</inf> receptors
2012, Pharmacological Reports
Citation Excerpt :
Bilateral injection of CCK8s into the ventral hippocampus, decreased %OAT and %OAE without affecting locomotor activity indicating a pure anxiogenic effect. The present finding is consistent with the results of previous studies in which anxiogenic responses following intraperitoneal [39, 48], intracerebroventricular [12], intra-central nucleus of amygdala [20], intra-periaqueductal grey [31] and intra-dorsal hippocampus [40] administration of CCK analogues have been reported. Moreover, the results of Pérez de la Mora et al. [34] showed that injection of either CCK4 or CCK8s into the rostrolateral amygdala promoted anxiogenic-like effects in the elevated plus-maze.
Cholecystokinin (CCK) as an important neuropeptide in the brain has been implicated in the modulation of anxiety. The effects of this neurotransmitter on anxiety-like behavior in the ventral hippocampus have not been evaluated yet. Moreover, some evidences show a functional interaction between GABA and CCK in the nervous system. Bilateral injections of three doses of CCK8s (0.01, 0.05 and 0.1 μg/rat) into the ventral hippocampus decreased percentage of open arm time (%OAT) and open arm entries (%OAE) that are representative of anxiogenic-like behavior in the elevated plus-maze test of anxiety. Bilateral injections of LY225910, a selective CCK₂ receptor antagonist, at the doses of 0.01, 0.1 and 0.5 μg/rat did not change anxiety-related parameters. Administration of muscimol, a selective GABA_A receptor agonist, at the doses of 0.001, 0.005 and 0.01 μg/rat produced dose dependent increase in %OAT and %OAE indicating an anxiolytic-like effect, while administration of bicuculline, a selective GABA_A receptor antagonist, at the doses of 0.1, 0.2 and 0.5 μg/rat decreased %OAT and %OAE showing that this drug promoted anxious behavior of the rats. Co-administration of bicuculline (0.2 μg/rat) with CCK8s decreased the anxiogenic effects of CCK8s. Furthermore, co-administration of LY225910 (0.5 μg/rat) with muscimol increased the anxiolytic effect of muscimol at the dose of 0.001 μg/rat. The results of this study suggest that both CCK and GABAergic system have important and opposite roles in the modulation of anxiety-like behavior in the ventral hippocampus of rats and they may have a complex interaction in the ventral hippocampus to modulate anxiety-related behavior.
CCK as a modulator of cardiovascular function
2009, Journal of Chemical Neuroanatomy
The gut-brain peptide cholecystokinin (CCK) has been implicated in a wide range of physiological processes including digestion, satiety, anxiety, nociception and lordosis. In addition, it is becoming clear that CCK is involved in regulating certain aspects of cardiovascular function. This article reviews the cardiovascular effects elicited by CCK via its actions at both central and peripheral sites and considers the physiological role of the peptide with respect to the cardiovascular function in different physiological and pathophysiological states. In the periphery CCK released from entoeroendocrine cells in the gut wall in response to a meal triggers a local postprandial hyperaemia in the gut that could promote digestion by facilitating intestinal motility and secretory processes. In addition, activation of CCK receptors on abdominal vagal afferents elicits a reflexly evoked hyperaemia that potentiates these effects and is also gasroprotective. In the brain CCK appears to act as a neuromodulator rather than a direct mediator within cardiovascular control circuits. In particular, it facilitates activity in amygdalar, hypothalamic and midbrain circuits that are involved in mediating acute cardiovascular and behavioural responses to an extreme physical or psychologically stressful challenge. Whilst in the short term activation of the CCK system appears to be beneficial to the organism, chronic stimulation of the system may be maladaptive, laying the foundation for the development of pathophysiological conditions such as panic disorder and chronic pain, both of which are states characterised by significant autonomic activation.
Stress and pain responses in rats lacking CCK<inf>1</inf> receptors
2006, Peptides
CCK involvement in stress- and pain-responsiveness was examined by studying the behavior of infant (11–12-days-old) and adult OLETF rats that do not express CCK₁ receptors. Infant odor- and texture-preferences were also assessed. We hypothesized that OLETF rats will show behavioral patterns similar to those previously observed after CCK₁ antagonist administration. Rate of separation-induced ultrasonic vocalization was significantly greater in OLETF compared to controls, in two separate studies. Infant pups of the two strains did not differ in odor- and texture-preference tests. OLETF rats showed consistently longer hot-plate paw-lift (as infants, in two separate studies) and paw-lick (as adults) latencies. Summary: OLETF pups vocalized in isolation more than controls and showed relative hypoalgesic responses, evident also in adulthood, in concordance with the pharmacological literature.

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Effects of cholecystokinin tetrapeptide and sulfated cholecystokinin octapeptide in rat models of anxiety

Abstract

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Neuropeptides

J. Pharmacol. Methods

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

J. Neurosci. Methods

TIPS

Prog. Neuropsychopharmacol. Biol. Psychiatry