Attenuation of CCK-induced aversion in rats on the elevated x-maze by the selective 5-HT1A receptor antagonists (+) WAY100135 and WAY100635.
The present study determined the effect of pretreatment with "silent" selective 5-HT1A receptor antagonists on cholecystokinin (CCK)-mediated effects on rat behaviour in the elevated x-maze model of anxiety. In the absence of 5-HT1A receptor antagonists, non-sulphated cholecystokinin-octapeptide (CCK-8ns; 10 and 50 micrograms/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-HT1A receptor antagonists were employed in these experiments: (+)WAY100135 (the active enantiomer of N-tert-butyl-3-(4-(2-methoxyphenyl)piperzin-1-yl)- 2-phenylpropronamine) [sequence: see text] and WAY100635 (N-[2-[4(2-methoxyphenyl)-1-piperazinyl-1-piperazinyl]-N-2- pyridinyl)cyclohexanecarbonate [sequence: see text] trihydrochloride). When administered 10 min prior to CCK-8ns, (+) WAY100135 and 0.3 mg/kg s.c.) significantly attenuated profile of CCK-8ns. (+)WAY100135 was also demonstrated to significantly inhibit postsynaptic 5-HT1A receptor-mediated 8-OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin)-induced 5-HT syndrome at the same dose used in the x-maze experiment. Neither (+)WAY100135 nor WAY100635 had any affects on ambulatory activity. These results support a CCK/5-HT1A receptor interaction in the modulation of aversion in rats exposed to the elevated x-maze.
Department of Physiology & Pharmacology, Medical School, Queen's Medical Centre, Nottingham, U.K.
M J
MJ
Bickerdike
A
A
Fletcher
C A
CA
Marsden
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal; D002766:Cholecystokinin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012844:Sincalide / Q000494:pharmacology*; D013997:Time Factors
D010446:Peptide Fragments; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; C081293:WAY 100135; C050803:cholecystokinin 10 C-terminal fragment; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002766:Cholecystokinin; D012844:Sincalide