The Panicogenic Effects of Cholecystokinin-Tetrapeptide Are Antagonized by L-365,260, a Central Cholecystokinin Receptor Antagonist, in Patients With Panic Disorder

Griebel

European Journal of Pharmacology

2003

258

159

The Mouse Defense Test Battery was developed from tests of defensive behaviors in rats, reflecting earlier studies of both acute and chronic responses of laboratory and wild rodents to threatening stimuli and situations. It measures flight, freezing, defensive threat and attack, and risk assessment in response to an unconditioned predator stimulus, as well as pretest activity and postthreat (conditioned) defensiveness to the test context. Factor analyses of these indicate four factors relating to cognitive and emotional aspects of defense, flight, and defensiveness to the test context. In the Mouse Defense Test Battery, GABA A -benzodiazepine anxiolytics produce consistent reductions in defensive threat/attack and risk assessment, while panicolytic and panicogenic drugs selectively reduce and enhance, respectively, flight. Effects of GABA A -benzodiazepine, serotonin, and neuropeptide ligands in the Mouse Defense Test Battery are reviewed. This review suggests that the Mouse Defense Test Battery is a sensitive and appropriate tool for preclinical evaluation of drugs potentially effective against defense-related disorders such as anxiety and panic. D

Section: Effects Of Cck Receptor Antagonists In the Mouse Defense Tesmentioning

confidence: 99%

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

Griebel

European Journal of Pharmacology

2003

258

159

“…Cholecystokinin (CCK) is one of the most widespread peptide system in the brain. It is involved in many brain physiological or pathological conditions, including anxiety, panic, and depression (Guimarães et al, 1992;Hernandez-Gomez et al, 2002;Bradwejn et al, 1992Bradwejn et al, , 1994Rehfeld, 2000). CCK-immunoreactive fibers and a high concentration of CCK exist in the PAG (De Belleroche et al, 1990;Liu et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Anxiogenic Effect of Cholecystokinin in the Dorsal Periaqueductal Gray

Netto¹,

Guimarães²

2003

Neuropsychopharmacol

Systemic administration of cholecystokinin (CCK) fragments produces anxiogenic effects. The dorsal periaqueductal gray (dPAG) has been related to anxiety and panic reactions. The objective of this study was to investigate a possible anxiogenic effect of CCK-8 microinjected into the dPAG. At 10 min after the last microinjection (0.5 ml) into the dPAG male Wistar rats (N ¼ 7-17) were tested in the elevated plus-maze, an animal model of anxiety. The following treatments were tested alone or in combination: sulfated CCK-8 (CCK-8s, 0.5-1 mg), PD 135,158 (N-methyl-D-glucamine, 0.1 mg), a CCK-2 receptor antagonist, lorglumide (0.1-0.3 mg), a CCK-1 receptor antagonist. In addition, Fos immunohistochemistry was performed in rats (n ¼ 3-4) treated with CCK-8s (1 mg) alone or in combination with PD 135,158 (0.1 mg). CCK-8s produced anxiogenic-like effect, decreasing the percentage of time spent in open arm (saline ¼ 30.3 7 6.6, CCK 0.5 mg ¼ 15.2 7 1.8; CCK 1 mg ¼ 14.6 7 2.1). This effect was prevented by pretreatment with PD 135,158, but not by lorglumide. CCK-8s injected into the dPAG induced Fos immunoreactivity in several brain areas related to defensive behavior, including the PAG, median, and dorsal raphe nuclei, superior colliculus, lateral septal nuclei, medial hypothalamus, and medial amygdala. This effect was also prevented by pretreatment with PD 135,158. These results suggest that CCK-8s, acting on CCK-2 receptors, may modulate anxiety reactions in the dPAG.

“…18 Likewise, agonists to the CCK-B receptor differentially induce panic in those with panic disorder when compared to controls. 19 Antagonists to this receptor have a more variable effect, with one study showing that such an agent could attenuate CCK-4-provoked panic attacks, 20 while other studies showed that such an antagonist was not efficacious in reducing panic attacks. [21][22][23] Further, antipanic agents like imipramine, fluvoxamine, and citalopram suppress CCK-4-mediated panic attacks.…”

Section: Introductionmentioning

confidence: 99%

No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder

et al. 2000

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise nonsignificant. The results reported here provide little support for the role of these polymorphisms in panic disorder. Molecular Psychiatry (2001) 6, 59-65.