Changes in sensitivity of 5-HT receptor mediated functional responses in the rat oesophagus, fundus and jejunum following chronic infusion with 5-hydroxytryptamine.

ABSTRACT

The effects of chronic infusion with 5-hydroxytryptamine (5-HT, 75 micrograms/kg per hour) for 5 or 10 days in vivo on the responses of rat oesophagus, fundus and jejunum to 5-HT and partial 5-HT receptor agonists in vitro were investigated. In the rat oesophagus, chronic treatment produced rightward shifts of the 5-HT4 receptor-mediated concentration-effect curves to 5-HT (dose-ratio = 3.8, day 5 and 2.8, day 10) and SC 53116 (1-S,8-S)-4-amino-5-chloro-N-[(hexahydro-1H-pyrrolizin-1-yl) methyl]-2-methoxy-benzamide hydrochloride, dose-ratio = 7.1, day 5 and 8.9, day 10) as compared to control tissues. The maximum effect of 5-HT and SC 53116 in rat oesophagus was reduced following the 10 day treatment. The 5-HT2B receptor-mediated contractile effect of 5-HT on rat fundus from treated animals responded with a significantly reduced potency (dose-ratio = 4.1, 5-day; 4.2, 10-day) compared to control tissues. The maximum response to 5-HT was reduced in tissues from animals treated for 10 days. The concentration-effect curve to the partial agonist 1-(3-chlorophenyl)-piperazine dihydrochloride (mCPP) was shifted to the right in fundic tissue from treated animals (dose-ratio = 2.5, 5-day; 2.8, 10-day) compared to control tissues. The maximum response to mCPP was also reduced in tissues from 5-HT treated animals. It has recently been shown in a preliminary characterisation that in rat jejunum, 5-HT produces a biphasic concentration-effect curve which is mediated by a putative 5-ht7 (first phase) and 5-HT3 (second phase) receptor mechanism. In the present study 5-HT produced a control biphasic concentration-effect curve in rat jejunum with a pEC50-1 value of 8.5 +/- 3.5 and a pEC50-2 value of 5.9 +/- 0.3 and maximum response values of 43.8 (32.5-55.0)% (Emax1) and 65.3 (41.7-88.9)% (Emax 2) of the response to acetylcholine. In jejunal tissues from treated animals, 5-HT produced its contractile effect in vitro with a 3.7 and 2.8 fold (5-day) and a 1.3 and 1.4 fold (10-day) rightward shift of the first and second phase respectively of the control concentration-effect curve to 5-HT. The maximum response produced by 5-HT in the first phase in jejunal tissues from animals treated for 10 days was significantly reduced by 49.1%. These findings represent the first report that chronic infusion of 5-HT produces a residual desensitisation of the 5-HT4, 5-HT2B, and putative 5-ht7/5-HT3 receptor-mediated responses in rat oesophagus, fundus and jejunum respectively when measured in vitro.