Review
Cholecystokinin-2 (CCK2) receptor-mediated anxiety-like behaviors in rats

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Abstract

Cholecystokinin (CCK) is a neurotransmitter in the brain closely related to anxiety. Of the two CCK receptor subtypes, CCK2 receptors are most implicated in the control of anxiety-related behavior. CCK2 receptor activation causes anxiogenic effects while the blockade of this receptor has anxiolytic effects. This review focuses on the molecular mechanisms of CCK2 receptors underlying anxiety-related behaviors of PVG hooded and Spraque–Dawley (SD) rats in two anxiety models (elevated plus-maze [EPM] and cat exposure test). PVG hooded rats showed prolonged freezing behavior in the cat exposure test while SD rats showed very low levels of freezing. A CCK2 receptor antagonist (LY225910) attenuated freezing behavior in PVG hooded rats while a CCK2 receptor agonist (CCK-4) increased freezing behavior in SD rats. In contrast, the two strains behaved similarly on the EPM. CCK-4 caused a pronounced anxiogenic effect in PVG hooded rats but only a slight effect in SD rats. CCK2 antagonists also showed more pronounced anxiolytic effects in PVG hooded rats than in SD rats. CCK2 receptor expression was greater in PVG hooded than in SD rats in the cortex and hippocampus. Genetic studies also demonstrated four differences in the DNA sequence of the CCK2 receptor gene between the two rat strains.

Section snippets

Discovery of CCK and its molecular forms

Cholecystokinin (CCK) was first identified (initially characterized as a 33-amino-acid long peptide) in the gastrointestinal tract (Ivy and Janecek, 1959) where it acts as a hormone with a major role in the regulation of gut motility, pancreatic secretion, and gall bladder contractions. It was later found to be one of the most widely distributed peptides in the brain (Vanderhaeghen et al., 1975) where it acts as a neurotransmitter (Rehfeld, 1985). It is now known that CCK exists in a variety of

Characterization of two CCK receptor subtypes: CCK1 and CCK2

CCK receptors exist as two major subtypes: CCK1 and CCK2, which differ in terms of molecular structure, distribution, and affinity for the natural ligands CCK and gastrin, which share the same COOH-terminal pentapeptide amide sequence but differ in sulfation at the sixth (gastrin) or seventh (CCK) tyrosyl residue. Previously, these two subtypes were known as CCK-A (alimentary) and CCK-B (brain) (Noble et al., 1999). A nomenclature committee of the International Union of Pharmacology (IUPHAR)

Evidence from CCK receptor agonists and antagonists

Fekete et al. (1981) were the first to demonstrate that injection of CCK-8 into the central nucleus of the amygdala enhances behavioral arousal and fear in rats. Since that report, evidence from different animal models of anxiety has accumulated to suggest that CCK peptides are anxiogenic after peripheral or intracerebral administration. BOC-CCK-4 (Boc-Trp-Met-Asp-Phe-NH2) injected i.p. produced anxiogenic effects in Wistar and Lister rats in a conflict test, EPM, light/dark test and ultrasonic

The expression of CCK2 receptor in animal models of anxiety

To date, the molecular mechanisms involved in CCK2 receptor mediation of anxiety in terms of the expression of CCK2 receptor has been studied in two animal models of anxiety: the elevated plus maze and cat exposure test.

Interaction between CCK and other neurotransmitter systems in anxiety

Although the precise mechanism of CCK-induced anxiety remains to be elucidated, evidence has accumulated that other neurotransmitter systems, e.g. corticotropin-releasing factor (CRF), serotonin (5-hydroxytryptamine, 5-HT), GABA and dopamine neuronal systems, may modulate CCK actions.

Recently, in a preliminary study to investigate the interaction between the CCK and CRF systems in anxiety and fear formation, we tested the effects of the CCK analog CCK-4, human/ rat corticotropin-releasing

Conclusions

It is well demonstrated by our results and by an extensive literature that the CCK system is involved in anxiety-like behaviors. CCK-4 increased the anxiety level of SD rats during cat exposure and in PVG hooded rats in the EPM, while CCK2 antagonists showed pronounced anxiolytic effects in these two animal models. Increased CCK2 receptor expression and decreased CCK2 receptor activation have been observed in anxiogenic and anxiolytic state, respectively. Physiological functions of the CCK

Acknowledgements

The current study was mainly supported by research grants from National Medical Research Council of Singapore (NMRC/0754/2003), Singapore Defense Science Organization (R-184-000-060-123/232) and National University of Singapore. Y.Z. Zhu was awarded a Lee Kuan Yew Research Fellowship.

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