Characterisation of the 5-HT receptor potentiating neurotransmission in rabbit bladder

Barras, Martine; Graaf, Pieter H. Van der; Angel, Itzchak

doi:10.1016/s0014-2999(96)00895-3

Cited by 21 publications

(20 citation statements)

References 8 publications

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“…5-HT receptors on parasympathetic efferent nerves also modulate detrusor smooth muscle contraction (Barras et al, 1996;Sellers et al, 2000), and evidence supports a role for 5-HT 3 receptors in the lower urinary tract. In the rabbit, for example, excitatory effects of 5-HT on the detrusor smooth muscle have been attributed to presynaptic 5-HT 3 receptors on parasympathetic efferents (Chen, 1990;Barras et al, 1996).…”

Section: Discussionmentioning

confidence: 93%

“…In the enteric nervous system, 5-HT 3 receptors also regulate gut motility and peristalsis (Galligan, 2002). Within the lower urinary tract, presynaptic 5-HT 3 receptors have been implicated in parasympathetic transmission to the urinary bladder through neuronal acetylcholine (ACh) release and smooth muscle contraction (Chen, 1990;Barras et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3AReceptor Subunit

Bhattacharya¹,

Dang²,

Zhu³

et al. 2004

J. Neurosci.

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Mutant mice with a hypersensitive serotonin (5-HT) 3A receptor were generated through targeted exon replacement. A valine to serine mutation (V13ЈS) in the channel-lining M2 domain of the 5-HT 3A receptor subunit rendered the 5-HT 3 receptor ϳ70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT 3B subunit. Mice homozygous for the mutant allele (5-HT 3A vs/vs ) had decreased levels of 5-HT 3A mRNA. Measurements on sympathetic ganglion cells in these mice showed that whole-cell serotonin responses were reduced, and that the remaining 5-HT 3 receptors were hypersensitive. Male 5-HT 3A vs/vs mice died at 2-3 months of age, and heterozygous (5-HT 3A vs/ϩ ) males and homozygous mutant females died at 4 -6 months of age from an obstructive uropathy. Both male and female 5-HT 3A mutant mice had urinary bladder mucosal and smooth muscle hyperplasia and hypertrophy, whereas male mutant mice had additional prostatic smooth muscle and urethral hyperplasia. 5-HT 3A mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT 3A vs/vs mice failed to contract to neurogenic stimulation, despite overall normal responses to a cholinergic agonist, suggestive of altered neuronal signaling in mutant mouse bladders. Consistent with this hypothesis, decreased nerve fiber immunoreactivity was observed in the urinary bladders of 5-HT 3A vs/vs compared with 5-HT 3A wild-type (5-HT 3A ϩ/ϩ ) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT 3A receptor in vivo may lead to excitotoxic neuronal cell death and functional changes in the urinary bladder, resulting in bladder hyperdistension, urinary retention, and overflow incontinence.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3AReceptor Subunit

Bhattacharya¹,

Dang²,

Zhu³

et al. 2004

J. Neurosci.

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“…Activation of 5-HT 3 receptors causes contractions mediated by stimulation of the receptor located on excitatory neurons in the bladder PHARMACOLOGY OF THE LOWER URINARY TRACT of cats (Saxena et al, 1985), mice (Holt et al, 1986), guinea pigs (Messori et al, 1995), rabbits (Chen, 1990;Barras et al, 1996), pigs (Sellers et al, 2000), and humans (Corsi et al, 1991;Tonini et al, 1994). The 5-HT 4 receptor has been suggested to be located on the excitatory bladder neurons, and its activation facilitates cholinergic transmission in pigs (Sellers et al, 2000) and humans (Tonini et al, 1994;Candura et al, 1996).…”

Section: Peripheral Targetsmentioning

confidence: 99%

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

Andersson

Wein²

2004

Pharmacol Rev

454

364

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“…At variance, peripherally 5-HT induces neuromuscular excitatory effects that have been described in detrusor muscle strips of mouse (Clean et al, 1989), guinea pig (Messori et al, 1995), rabbit (Barras et al, 1996), pig (Sellers et al, 2000), and man (Tonini et al, 1994). Several in vitro studies have shown that the contractile effect of mammalian detrusor in response to 5-HT exposure is mediated by activation of 5-HT 2 , 5-HT 3 , and 5-HT 4 receptors (Yoshida et al, 2002).…”

mentioning

confidence: 97%

Characterization of Prejunctional Serotonin Receptors Modulating [³H]Acetylcholine Release in the Human Detrusor

D׳Agostino¹,

Condino²,

Gallinari³

et al. 2005

J Pharmacol Exp Ther

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Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites. In this study, we demonstrated the presence of three distinct 5-HT receptors localized at parasympathetic nerve terminals of the human bladder by measuring electrically evoked tritiated acetylcholine release in isolated detrusor strips. These prejunctional receptors, involved in both positive and negative feedback mechanisms regulating cholinergic transmission, have been characterized by means of three highly selective 5-HT antagonists for 5-HT 4 , 5-HT 7 , and 5-HT 1A receptors,. Under these conditions, we confirmed the facilitatory role of 5-HT 4 heteroreceptors on acetylcholine release and revealed for the first time the occurrence of 5-HT 7 and 5-HT 1A heteroreceptors with a facilitatory and an inhibitory action, respectively. Our findings strengthen the novel concept for the use of recently patented selective 5-HT agonists and antagonists for the control of OAB dysfunctions associated with inflammatory conditions, although their therapeutic efficacy needs to be explored in the clinical setting.

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Characterisation of the 5-HT receptor potentiating neurotransmission in rabbit bladder

Cited by 21 publications

References 8 publications

Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3AReceptor Subunit

Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3AReceptor Subunit

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

Characterization of Prejunctional Serotonin Receptors Modulating [³H]Acetylcholine Release in the Human Detrusor

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Characterisation of the 5-HT receptor potentiating neurotransmission in rabbit bladder

Cited by 21 publications

References 8 publications

Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT3AReceptor Subunit

Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT3AReceptor Subunit

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

Characterization of Prejunctional Serotonin Receptors Modulating [3H]Acetylcholine Release in the Human Detrusor

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Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3AReceptor Subunit

Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3AReceptor Subunit

Characterization of Prejunctional Serotonin Receptors Modulating [³H]Acetylcholine Release in the Human Detrusor