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 inv estigate CCK receptor antagonist effects on the behaviour of male List er-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 nyl-1H-1 ,4-benzodiazepin-3-yl-N1-(3-methyl-phenyl) )urea) or CI-988 4-oxo-[R-( R,R*)]-butanoate-N-methyl-D-glucamine), both selective CCKB receptor antagonists, were administered 30 min prior to testing. Behavioural an alysis 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. Wh en administered simultaneously with the 5-HT re-uptake inhibitors zime lidine or Wy [(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]am carbon yl]3-pyridine carboxamide methyl sulphonate salt), the significant anx iolytic effect induced by devazepide was dose-dependently and signific antly attenuated. Zimelidine and Wy27587 had little effect alone on ze ro-maze behaviour at the lower of two doses given. These data show tha t the elevated zero-maze, in conjunction with the analysis of 'risk-as sessment' behaviours, is an anxiety model which is sensitive to the an xiolytic effects of CCK receptor antagonism. The efficacy of devazepid e, 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 C CKA receptor subtype is the more reliable mediator of anxiety state in this rat model. The reduction in CCK receptor antagonist-induced anxi olysis 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.