Attenuation of CCK-induced aversion in rats on the elevated x-Maze by the selective 5-HT 1A receptor antagonists (+)WAY100135 and WAY100635

Abstract

The present study determined the effect of pretreatment with “silent” selective 5-HT 1A receptor antagonists on cholecystokinin(CCK)-mediated effects on rat behaviour in the elevated x-maze model of anxiety. In the absence of 5-HT 1A receptor antagonists, non-sulphated cholecystokinin-octapeptide (CCK-8ns; 10 and 50 μg/kg, i.p.; 30 min prior to testing) produced an anxiogenic profile of behaviour on the x-maze, reducing the number of open arm entries and the number of exploratory head dips, while increasing the level of risk-assessment as measured by the number of stretched-attend postures. CCK-8ns did not, however, alter ambulatory activity. Two 5-HT 1A receptor antagonists were employed in these experiments: ( + )WAY100135 (the active enantiomer of N-tert-butyl-3-(4-(2-rnethoxyphenyl)piperzin-1-yl)-2-phenylpropronamide) and WAY 10063 5 ( N-[2-[4(2-methoxyphenyl)-1 -piperazinyIJethyl]-7 V-2-pyridinyl)cyclohexanecarbonate trihydrochloride). When administered 10 min prior to CCK-8ns, ( + )WAY100135 (1.0 mg/kg s.c.) or WAY100635 (0.03 and 0.3 mg/kg s.c.) significantly attenuated the anxiogenic profile of CCK-8ns. ( + )WAY100135 was also demonstrated to significantly inhibit postsynaptic 5-HT 1A receptor-mediated 8-OH-DPAT (8-hydroxy-2-(di-,/-Vpropylamino) tetralin)-induced 5-HT syndrome at the same dose used in the x-maze experiment. Neither ( + )WAY100135 nor WAY100635 had any effects on ambulatory activity. These results support a CCK/5-HT 1A receptor interaction in the modulation of aversion in rats exposed to the elevated x-maze.