THE INFLUENCE OF 5-HYDROXYTRYPTAMINE REUPTAKE 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]-amino]-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]am 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. The efficacy of devazepide, the less consistent efficacy of CI-988, and the inactivity of L-365,260, as anxiety-reducing agents in the model used, suggest that the CCKA receptor subtype is the more reliable mediator of anxiety state in this rat model. The reduction in CCK receptor antagonist-induced anxiolysis observed after zimelidine and Wy 27587 suggests that a CCK-5-HT interaction exists which may act as a mechanism for the modulation of anxiety.