[Behavioral and neurochemical study on the role of the brain cholecystokinin system in anxiety].
In order to elucidate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the author examined the effects of the selective non-peptide CCKB receptor antagonist LY288513 on freezing behavior induced by conditioned fear stress, an animal model of anxiety. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03-0.3 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide, blocked the expression of conditioned fear, but only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide, failed to do so. Subcutaneous administration of LY288513 (3 mg/kg) enhanced the conditioned fear-induced in 3, 4-dihydroxy-phenylacetic acid (DOPAC) contents in the medial prefrontal cortex, which was assayed by high performance liquid chromatography with electrochemical detection. Thirty min of inescapable electric footshock decreased CCK8S contents in the amygdala, which was assayed by radioimmunoassay. These results suggest that the brain CCKB receptors are involved in the regulation of anxiety, and that the anxiolytic effects of CCKB receptor antagonists are mediated by increasing dopamine activity in the medial prefrontal cortex. Furthermore, it is possible that the CCK neurons in the amygdala are also associated with anxiety.
Izumi
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Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.
D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002766:Cholecystokinin / Q000502:physiology*; D004195:Disease Models, Animal; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000502:physiology
D015306:Biogenic Monoamines; D006727:Hormone Antagonists; D011720:Pyrazoles; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C074681:1-(4-bromophenylaminocarbonyl)-4,5-diphenyl-3-pyrazolidinone; C053737:loxiglumide; D002766:Cholecystokinin; D011377:Proglumide; C048181:lorglumide