The influence of 5-hydroxytryptamine re-uptake blockade on CCK receptor antagonist effects in the rat elevated zero-maze.
In this study, the elevated zero-maze model of anxiety was used to investigate CCK receptor antagonist effects on the behaviour of male Lister-hooded rats and to demonstrate, by administering antagonists in the presence or absence of selective 5-hydroxytryptamine (5-HT) re-uptake inhibitors, the involvement of 5-HT in the mediation of these effects. Devazepide, a selective CCKA receptor antagonist, L-365,260 (3R(+)-N-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 3-yl-N1- (3-methyl-phenyl)urea) or CI-988 (4-([2-[[3-(1H-indol-3-yl)-2-methyl-1- oxo-2-[[(tricyclo[3.3.1.1.(3.7)]-dec-2-yloxy)-carbonyl]-amin o]- propyl]-amino]-1-phenylethyl]-amino)-4-oxo-[R-(R*,R*)]-butanoate- N-methyl-D-glucamine), both selective CCKB receptor antagonists, were administered 30 min prior to testing. Behavioural analysis during testing included measures of risk-assessment behaviours (e.g. stretched-attend posture) in addition to time spent on the open quadrants. Devazepide induced significant anxiolytic effects, whereas CI-988 produced inconsistent results and L-365,260 was ineffective. When administered simultaneously with the 5-HT re-uptake inhibitors zimelidine or Wy 27587 (N-[[[1-[(6- fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino] carbonyl]-3-pyridine carboxamide methyl sulphonate salt), the significant anxiolytic effect induced by devazepide was dose-dependently and significantly attenuated. Zimelidine and Wy27587 had little effect alone on zero-maze behaviour at the lower of two doses given. These data show that the elevated zero-maze, in conjunction with the analysis of 'risk-assessment' behaviours, is an anxiety model which is sensitive to the anxiolytic effects of CCK receptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Bickerdike
M J
MJ
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham, UK.
Marsden
C A
CA
Dourish
C T
CT
Fletcher
A
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D020109:Devazepide; D003975:Diazepam / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008536:Meglumine / Q000031:analogs & derivatives / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015031:Zimeldine / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D020109:Devazepide; D003975:Diazepam; D007211:Indoles; D008536:Meglumine; D009536:Niacinamide; D010671:Phenylurea Compounds; D010879:Piperazines; D010880:Piperidines; D011949:Receptors, Cholecystokinin; D017367:Selective Serotonin Reuptake Inhibitors; D015031:Zimeldine; C058897:WY 27587; C065599:PD 134308; C058121:L 365260; C015068:1-(3-chlorophenyl)piperazine