Targeted Invalidation of CCK2 Receptor Gene Induces Anxiolytic-like Action in Light-dark Exploration, but Not in Fear Conditioning Test

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2005 Apr 15

PMID 15830228

Citations 13

Authors

Sirli Raud

Jurgen Innos

Urho Abramov

Ain Reimets

Sulev Koks

Andres Soosaar

Toshimitsu Matsui

Eero Vasar

Affiliations

Soon will be listed here.

Abstract

Rationale: Evidence suggests that gamma-aminobutyric acid (GABA) and cholecystokinin (CCK) have opposite roles in the regulation of anxiety.

Objectives: The aim of our work was to study the behaviour of CCK(2) receptor deficient mice in light-dark exploration and fear conditioning tests. Moreover, the action of diazepam and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), having the opposite effect on GABA(A) receptors, was evaluated on the exploratory behaviour in these mice. Expression levels of GABA(A) receptor subunit genes were also measured.

Methods: Light-dark exploration and fear conditioning tests were used to determine changes in anxiety of mice. The action of diazepam (0.5-2 mg/kg i.p.) and DMCM (0.25-1 mg/kg i.p.) was studied in the light-dark box. The effect of DMCM was also evaluated in the motor activity test to demonstrate that its anti-exploratory action was not related to motor suppression. Expression levels of GABA(A) receptor subunit genes were determined by means of real-time polymerase chain reaction (qRT-PCR).

Results: Female mice lacking CCK(2) receptors displayed increased exploratory activity in the light-dark box compared to their wild-type (+/+) littermates. Locomotor activity in the motility boxes and the intensity of freezing did not differ in wild-type (+/+) and homozygous (-/-) mice. Treatment with diazepam (0.5 mg/kg) increased the number of transitions in wild-type (+/+) animals, whereas in homozygous (-/-) mice diazepam (0.5-2 mg/kg) reduced exploratory activity. Administration of DMCM (0.25-1 mg/kg) induced an anxiogenic-like effect in homozygous (-/-) mice, but did not change their locomotor activity. Gene expression analysis established a 1.6-fold increase in the expression of the alpha2 subunit of GABA(A) receptors in the frontal cortex of homozygous (-/-) mice.

Conclusion: Genetic invalidation of CCK(2) receptors induced an anxiolytic-like action in exploratory, but not in conditioned models of anxiety. The observed reduction in anxiety in homozygous (-/-) mice is probably related to an increased function of GABAergic system in the brain.

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References

Perez de la Mora M, Mendez-Franco J, Fuxe K . Cholecystokinin-8 increases K(+)-evoked [3H] gamma-aminobutyric acid release in slices from various brain areas. Eur J Pharmacol. 1993; 250(3):423-30. DOI: 10.1016/0014-2999(93)90029-h. View

Contet C, Rawlins J, Deacon R . A comparison of 129S2/SvHsd and C57BL/6JOlaHsd mice on a test battery assessing sensorimotor, affective and cognitive behaviours: implications for the study of genetically modified mice. Behav Brain Res. 2001; 124(1):33-46. DOI: 10.1016/s0166-4328(01)00231-5. View

Mohler H, Fritschy J, Rudolph U . A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2001; 300(1):2-8. DOI: 10.1124/jpet.300.1.2. View

Costall B, Domeney A, Hughes J, Kelly M, Naylor R, Woodruff G . Anxiolytic effects of CCK-B antagonists. Neuropeptides. 1991; 19 Suppl:65-73. DOI: 10.1016/0143-4179(91)90084-v. View

Rodgers R, Boullier E, Chatzimichalaki P, Cooper G, Shorten A . Contrasting phenotypes of C57BL/6JOlaHsd, 129S2/SvHsd and 129/SvEv mice in two exploration-based tests of anxiety-related behaviour. Physiol Behav. 2002; 77(2-3):301-10. DOI: 10.1016/s0031-9384(02)00856-9. View

Abramov U, Raud S, Koks S, Innos J, Kurrikoff K, Matsui T . Targeted mutation of CCK(2) receptor gene antagonises behavioural changes induced by social isolation in female, but not in male mice. Behav Brain Res. 2004; 155(1):1-11. DOI: 10.1016/j.bbr.2004.03.027. View

Farook J, Zhu Y, Wang H, Moochhala S, Lee L, Wong P . Strain differences in freezing behavior of PVG hooded and Sprague-Dawley rats: differential cortical expression of cholecystokinin2 receptors. Neuroreport. 2001; 12(12):2717-20. DOI: 10.1097/00001756-200108280-00025. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Koks S, Volke V, Veraksits A, Runkorg K, Sillat T, Abramov U . Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system. Psychopharmacology (Berl). 2001; 158(2):198-204. DOI: 10.1007/s002130100855. View

10.

Aguilar-Roblero R, Perez de la Mora M . Role of cholecystokinin-A and cholecystokinin-B receptors in anxiety. Amino Acids. 2002; 23(1-3):283-90. DOI: 10.1007/s00726-001-0139-x. View

11.

Harro J, Vasar E, Bradwejn J . CCK in animal and human research on anxiety. Trends Pharmacol Sci. 1993; 14(6):244-9. DOI: 10.1016/0165-6147(93)90020-k. View

12.

Low K, Crestani F, Keist R, Benke D, Brunig I, Benson J . Molecular and neuronal substrate for the selective attenuation of anxiety. Science. 2000; 290(5489):131-4. DOI: 10.1126/science.290.5489.131. View

13.

Bradwejn J, De Montigny C . Benzodiazepines antagonize cholecystokinin-induced activation of rat hippocampal neurones. Nature. 1984; 312(5992):363-4. DOI: 10.1038/312363a0. View

14.

Ferraro L, Beani L, Trist D, Reggiani A, Bianchi C . Effects of cholecystokinin peptides and GV 150013, a selective cholecystokininB receptor antagonist, on electrically evoked endogenous GABA release from rat cortical slices. J Neurochem. 1999; 73(5):1973-81. View

15.

Holmes A, Lit Q, Murphy D, Gold E, Crawley J . Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav. 2003; 2(6):365-80. DOI: 10.1046/j.1601-1848.2003.00050.x. View

16.

Koks S, Vasar E, Soosaar A, Lang A, Volke V, Voikar V . Relation of exploratory behavior of rats in elevated plus-maze to brain receptor binding properties and serum growth hormone levels. Eur Neuropsychopharmacol. 1998; 7(4):289-94. DOI: 10.1016/s0924-977x(97)00034-5. View

17.

Sebret A, Lena I, Crete D, Matsui T, Roques B, Dauge V . Rat hippocampal neurons are critically involved in physiological improvement of memory processes induced by cholecystokinin-B receptor stimulation. J Neurosci. 1999; 19(16):7230-7. PMC: 6782842. View

18.

Miyasaka K, Kobayashi S, Ohta M, Kanai S, Yoshida Y, Nagata A . Anxiety-related behaviors in cholecystokinin-A, B, and AB receptor gene knockout mice in the plus-maze. Neurosci Lett. 2002; 335(2):115-8. DOI: 10.1016/s0304-3940(02)01176-x. View

19.

Singh L, Field M, Vass C, Hughes J, Woodruff G . The antagonism of benzodiazepine withdrawal effects by the selective cholecystokininB receptor antagonist CI-988. Br J Pharmacol. 1992; 105(1):8-10. PMC: 1908629. DOI: 10.1111/j.1476-5381.1992.tb14201.x. View

20.

Raud S, Runkorg K, Veraksits A, Reimets A, Nelovkov A, Abramov U . Targeted mutation of CCK2 receptor gene modifies the behavioural effects of diazepam in female mice. Psychopharmacology (Berl). 2003; 168(4):417-25. DOI: 10.1007/s00213-003-1453-7. View