Drug‐induced defaecation in rats: role of central 5‐HT_1A receptors

Abstract

We investigated the acute effects of 5‐hydroxytryptamine (5‐HT), and of the 5‐HT1A receptor agonists, 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), buspirone and SR 57746A, on rat faecal pellet output and water content. 5‐HT, 8‐OH‐DPAT, buspirone and SR 57746A, a new selective 5‐HT1A receptor agonist, displaced [3H]‐8‐OH‐DPAT from specific binding sites in rat hippocampus membranes (Ki, nM: 1.8, 1.2, 15, 3.1 respectively) and stimulated rat defaecation dose‐dependently. SR 57746A and buspirone induced 1 g dry weight of faeces at 1.3 and 6.1 mgkg−1, p.o. (ADO respectively. 8‐OH‐DPAT and 5‐HT stimulated defaecation after s.c. injection (ADl5 0.07 and 7.5mgkg−1, respectively). All these agents increased faecal water content. The putative 5‐HTlA receptor antagonist, pindolol, injected s.c. or i.c.v., significantly reduced the defaecation induced by systemically administered 8‐OH‐DPAT, buspirone or SR 57746A, but not 5‐HT. Pretreatment with p‐chlorophenylalanine (i.p.) or 5,7‐dihydroxytryptamine (i.c.v.), according to protocols designed to cause either generalized or CNS‐limited 5‐HT depletion respectively, also reduced the defaecation induced by buspirone or SR 57746A. No specific 5‐HT1A binding sites could be labelled by incubating rat colon membranes with [3H]‐8‐OH‐DPAT, and in vitro preparations of rat colon segments showed no response to 8‐OH‐DPAT or SR 57746A up to 5 μM. After eight days' repeated daily treatment, complete tolerance developed to the stimulant effects of SR 57746A and buspirone on faecal water content, but not on faecal pellet output. This suggests that faecal mass excretion and water exchange through the gut wall are affected by independent mechanisms. The present findings support the involvement of central 5‐HT1A receptors in intestinal propulsion and regulation of luminal fluid content, presumably accounting for the drug‐induced defaecation in rats.

Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart

“…The 5-HT 1A receptor is expressed on neurons and glial cells. Hence, xaliproden has been shown to enhance intestinal motility and luminal fluid content in rats [33]. However, these effects may be considered to reduce manifestations of radiation enteropathy in the rat, rather than aggravate them as we have observed in our studies.…”

Negative modulation of nitric oxide production by neurotensin as a putative mechanism of the diuretic action of SR 48692 in rats

“…treatment, rats were anaesthetized with pentobarbitone (40 mgkg −1 , i.p. ), placed in a Kopf ste‐reotaxic instrument and implanted with a polyethylene can‐nula in the right lateral ventricle according to a previously described method (Croci et al , 1995b).…”

The 5-HTlA receptor agonist flesinoxan increases aversion in a model of panic-like anxiety in rats

“…agonists by selective action in dorsal raphe is probably subdued by post-synaptic receptor activation necessarily occurring when compounds are given systemically, at least upon acute administration. Finally, the possibility cannot be excluded that peripheral effects of 5-HTIA receptor agonists such as cerebrovascular changes (McBean et al, 1991), reminiscent of those induced by CCK, a panic precipitating agent (Harro et al, 1993), or intestinal effects (Croci et al, 1995) may also contribute as indirect anxiogenic side-effects. It is interesting to note that the decreased threshold for fear responses recorded in rats following systemic flesinoxan was similar to that induced by the panic precipitating agent yohimbine.…”