Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system
3区 · 医学
作者: Hodges, H. ; Sowinski, P. ; Turner, J. J. ; Fletcher, A.
The effects of the 5-HT3 receptor antagonists. WAY-100,579 and ondansetron (both at doses of 0.001, 0.01 and 0.1 mg/kg s.c.) and the muscarinic receptor agonist arecoline (1.0 mg/kg s.c.), on spatial learning and memory in the water maze were examined in rats after combined S-AMPA lesions to the nucleus basalis and medial septal brain regions. Lesioned rats showed substantially increased latency to find the submerged platform, and spent less time searching in the correct quadrant, and more time circling the periphery of the pool, relative to controls. Lesioned rats treated with WAY-100,579, ondansetron and arecoline exhibited marked improvement in these parameters of learning relative to lesioned animals, with arecoline-treated animals showing the most substantial recovery. Linear dose-related trends of improvement were seen with both of the 5-HT3 antagonists. In probe trials, testing retention of the platform position 24 and 72 h after the end of training, control rats exhibited substantial superiority relative to lesioned rats in accuracy of search in the training quadrant and former platform area, matched by rats treated with arecoline on the first, and by rats treated with the two higher doses of WAY-100,579 and ondansetron on the second probe trial. These results are consistent with our previous studies which demonstrated that another selective 5-HT3 receptor antagonist. WAY-100,289, significantly reversed the cognitive deficits in water maze performance induced by ibotenic acid lesions of forebrain cholinergic projection system. Therefore, selective 5-HT3 receptor antagonists may provide a novel effective therapy for treating cognitive deficits associated with degeneration of central cholinergic neurones, such as Alzheimer's disease or age-associated memory impairment.
1996-03-01·Canadian Journal of Physiology and Pharmacology4区 · 医学
Mediation of altered motility in food protein induced intestinal anaphylaxis in Hooded-Lister rat
4区 · 医学
作者: Scott, R. B. ; Tan, D. T. M.
In the Hooded-Lister rat model, food protein induced intestinal anaphylaxis disrupts the migrating motor complex (MMC) and causes an increased frequency of migrating clusters of contractions (MCCs, including giant migrating contractions (GMCs)) and diarrhea. To determine whether mast cell mediators act on enteric neurons to initiate these alterations in motility, rats were sensitized by intraperitoneal injection of 10 micrograms egg albumin (antigen (Ag)). Seven days later two jejunal manometry catheters were implanted 2.5 cm apart. On day 14, motility was recorded in fasted rats before and after intraluminal challenge with 10 mg Ag in 0.5 mL saline, both without and after pretreatment by specific antagonists. Ag challenge of sensitized animals disrupted MMCs and caused an increase in total MCCs (including GMCs) and diarrhea. Atropine or hexamethonium abolished all intestinal motility, including Ag-induced MCCs, GMCs, and diarrhea. At higher doses, agents that inhibit mast cell degranulation, cromoglycate, doxantrazole, and quercetin, did inhibit Ag-induced MCCs, GMCs, and diarrhea, but at the expense of inhibiting normal intestinal motility. Cimetidine and diphenhydramine together inhibited normal cycling of the MMC, but did not abolish Ag-induced MCCs, GMCs, and diarrhea. Methysergide was ineffective, but cinanserin and WAY 100,289 significantly inhibited, and indomethacin most effectively blocked, the Ag-induced disruption of MMCs and the increase in MCCs, GMCs, and diarrhea. Thus, the altered motility and the diarrhea observed after food protein induced luminal challenge of sensitized rats is dependent upon myenteric neuronal circuitry. The mast cell stabilizers doxantrazole and quercetin block the response because of a nonspecific anticholinergic effect. Cinanserin and WAY 100,289 partially inhibit, and indomethacin most effectively blocks, the response, suggesting that activated mast cells release prostaglandins and perhaps 5-hydroxytryptamine, which stimulate the neuronal pathway.
1995-07-01·British Journal of Pharmacology2区 · 医学
The enantiomers of zacopride: an intra-species comparison of their potencies in functional and anxiolytic models
2区 · 医学
作者: Bill, David J. ; Coleman, James ; Hallett, Ian ; Middlefell, Vicki C. ; Rhodes, Keith F. ; Fletcher, Allan
1. The 5-HT3 receptor antagonist, zacopride, and its enantiomers, R(+)-zacopride and S(-)-zacopride, were examined in three pharmacological models: (i) 5-HT-induced depolarization of the mouse isolated vagus nerve preparation, (ii) the 5-HT-evoked von Bezold-Jarisch reflex in the mouse, and (iii) the mouse light:dark box model of anxiety. Other standard 5-HT3 receptor antagonists were also included for comparison in these studies. 2. Racemic zacopride, and both of the enantiomers, displayed potent 5-HT3 receptor antagonist activity in the isolated vagus nerve and in the von Bezold-Jarisch model. No 5-HT3 receptor agonist or partial agonist effects of these compounds were detected. 3. In the isolated vagus nerve, R(+)-zacopride and ondansetron were surmountable 5-HT3 receptor antagonists (pA2 values of 9.3 and 8.3, respectively), whereas racemic zacopride, S(-)-zacopride and tropisetron were insurmountable antagonists, markedly suppressing the maximum response to 5-HT. 4. In vivo, racemic zacopride, R(+)-zacopride, S(-)-zacopride and WAY100289 were potent antagonists of the 5-HT-evoked von Bezold-Jarisch reflex, with minimum effective doses (lowest dose required to reduce the reflex by > or = 85%; MED85) of 1.0, 3.0, 0.3 and 3.0 micrograms kg-1, s.c., respectively. 5. Racemic zacopride, R(+)-zacopride and S(-)-zacopride were active in the mouse light:dark box model of anxiety, with similar potencies (minimum effective dose 1 microgram kg-1, s.c.) and similar active dose-ranges (1-1000 micrograms kg-1, s.c.). 6. The doses of racemic zacopride, R( + )-zacopride and S(-)-zacopride required to block 5-HT3receptors in vivo correlated reasonably well with their potencies in an anxiety model within the same species. In these studies, there was no evidence of a marked difference between the anxiolytic potencies ofR( + )-zacopride and S(-)-zacopride.