Distribution of 5-HT4 receptor mRNA in the rat brain

Ullmer, Christoph; Engels, Peter; Abdel'Al, Samir; Lübbert, Hermann

doi:10.1007/bf00178723

Cited by 32 publications

(12 citation statements)

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“…Recently, the distribution of h5-HT 4a and h5-HT 4b mRNAs has been determined with reverse transcriptase polymerase chain reaction in human and monkey brain and the same expression pattern for both splice variants has been found in frontal cortex, hippocampus, and striatum (Vilaró et al, 1998). The distribution pattern of 5-HT 4 receptor mRNA in the human brain described in the present study parallels the findings in previous studies performed in the rat brain (Ullmer et al, 1996;Vilaró et al 1996). The highest levels of expression were also found in the basal ganglia and the hippocampal formation.…”

Section: Discussionsupporting

confidence: 92%

Mapping of serotonin 5-HT4 receptor mRNA and ligand binding sites in the post-mortem human brain

Bonaventure

Hall

Gommeren

et al. 2000

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The anatomical localization of 5-HT(4) receptor mRNA and 5-HT(4) receptor protein was examined in sections of post-mortem human brain by in situ hybridization histochemistry and radioligand receptor autoradiography. In the in situ hybridization study, the highest levels of 5-HT(4) receptor mRNA were found in caudate nucleus, putamen, nucleus accumbens, and in the hippocampal formation. No 5-HT(4) receptor mRNA was detected in globus pallidus and substantia nigra. For receptor autoradiography, two new and highly selective radioligands were compared: [(3)H]prucalopride, which preferentially labels the G-protein coupled fraction of receptors, and [(3)H]R116712, which labels the entire receptor population at subnanomolar concentrations. [(3)H]Prucalopride and [(3)H]R116712 binding was performed on human brain hemisphere sections. The highest densities for both radioligands were found in the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus, substantia nigra). Moderate to low densities were detected in the hippocampal formation and in the cortical mantle. Mismatches between 5-HT(4) receptor mRNA and binding sites in the globus pallidus and the substantia nigra suggested that the binding sites may be localized on axonal projections originating from the striatum. To compare densities of binding sites, concentration binding curves with [(3)H]prucalopride, [(3)H]R116712 and [(3)H]GR113808 were performed on membranes from homogenates of several human brain regions. Comparison of B(max)-values obtained with [(3)H]prucalopride and [(3)H]R116712 indicated that the G-protein coupled fraction of 5-HT(4) receptors in the substantia nigra was exceptionally high (54%) in comparison with percentages (16-27%) found in the frontal cortex, the striatum and the hippocampus. Such a high percentage (40%) of [(3)H]prucalopride vs. [(3)H]R116712 binding was also observed in the substantia nigra in the receptor autoradiography experiments. The [(3)H]prucalopride binding was GppNHp-sensitive, whereas [(3)H]R116712 and [(3)H]GR113808 was not. These data indicate that in the substantia nigra 5-HT(4) receptors are more strongly coupled to their signal transduction pathway than in other brain regions.

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Section: Discussionsupporting

confidence: 92%

Mapping of serotonin 5-HT4 receptor mRNA and ligand binding sites in the post-mortem human brain

Bonaventure

Hall

Gommeren

et al. 2000

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“…Corresponding isoforms have been reported in rats and mice, where the isoforms originally referred to as 5-HT 4S and 5-HT 4L correspond to human 5-HT 4(a) and to 5-HT 4(b) , respectively (Claeysen et al, 1996(Claeysen et al, , 1997. Although the data currently available suggest a heterogeneous distribution of mRNA for the different isoforms in brain regions and peripheral tissues, none are purely central or peripheral, apart from the 5-HT 4(d) , which is limited to the intestine, and no brain region expresses only a single isoform (Gerald et al, 1995;Ullmer et al, 1996;Blondel et al, 1998;Claeysen et al, 1999;Bender et al, 2000;Medhurst et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

SL65.0155, A Novel 5-Hydroxytryptamine₄ Receptor Partial Agonist with Potent Cognition-Enhancing Properties

Moser¹,

Bergis²,

Jegham³

et al. 2002

J Pharmacol Exp Ther

102

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SL65.0155 [5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride] is a novel benzodioxanoxadiazolone compound with high affinity for human 5-hydroxytryptamine (5-HT) 4 receptors (K i of 0.6 nM) and good selectivity (greater than 100-fold for all other receptors tested). In cells expressing the 5-HT 4(b) and 5-HT 4(e) splice variants, SL65.0155 acted as a partial agonist, stimulating cAMP production with a maximal effect of 40 to 50% of serotonin. However, in the rat esophagus preparation, SL65.0155 acted as a 5-HT 4 antagonist with a pK b of 8.81. In addition, SL65.0155 potently improved performance in several tests of learning and memory. In the object recognition task, it improved retention at 24 h when administered i.p. or p.o. (0.001-0.1 mg/kg). This effect was antagonized by the 5-HT 4 antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT 4 agonism. SL65.0155 also reversed the cognitive deficits of aged rats in the linear maze task and the scopolamineinduced deficit of mice in the water maze task. Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT 4 receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia.Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline, debilitating behavioral impairment, and ultimately death. Neurofibrillary tangles and amyloid plaques are the pathological hallmarks of this disease, which is also characterized by a dramatic loss of cholinergic neurons in brain regions involved in higher cognitive functions. It is widely accepted that the loss of cholinergic markers is one of the major neurochemical deficits in AD and that this deficit correlates well with loss of cognitive abilities (Bierer et al., 1995;Palmer, 1996). Despite this, cholinergic therapies, such as inhibitors of acetylcholinesterase, have had only partial success (e.g., Volger, 1991), possibly due to the multifactorial nature of the deficits and poorly understood etiology of AD. Thus, there is a major need for novel therapeutic approaches that can alleviate the symptoms of the disease.In addition to the cholinergic deficit, loss of several other neurotransmitter systems has been reported in AD, including norepinephrine, dopamine (see Gottfries, 1990 for a review), and 5-hydroxytryptamine (5-HT) (Palmer, 1996; MeltArticle, publicat...

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“…The presence of 5-HT 4 receptor protein, but not its mRNA, has been reported in both the GP and the SN of different mammal species, with the highest densities in the latter area, thus supporting the idea of a localization of this receptor on striatopallidal and striatonigral terminals (Compan et al, 1996;Ullmer et al, 1996;Vilaro et al, 1996;Bonaventure et al, 2000). Moreover, 5-HT 4 receptor binding sites in the rat SN were confined to the pars lateralis, while in guinea pig brain, a wider distribution was observed in the same area, with most of the SNr being strongly labelled (Waeber et al, 1994;Vilaro et al, 2005); in human and monkey brain, the distribution pattern resembled that of guinea pig brain.…”

Section: Substantia Nigra and Globus Pallidusmentioning

confidence: 74%

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

Matteo

Pierucci

Esposito

et al. 2008

Progress in Brain Research

133

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Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.

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Distribution of 5-HT4 receptor mRNA in the rat brain

Cited by 32 publications

References 10 publications

Mapping of serotonin 5-HT4 receptor mRNA and ligand binding sites in the post-mortem human brain

Mapping of serotonin 5-HT4 receptor mRNA and ligand binding sites in the post-mortem human brain

SL65.0155, A Novel 5-Hydroxytryptamine₄ Receptor Partial Agonist with Potent Cognition-Enhancing Properties

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

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Distribution of 5-HT4 receptor mRNA in the rat brain

Cited by 32 publications

References 10 publications

Mapping of serotonin 5-HT4 receptor mRNA and ligand binding sites in the post-mortem human brain

Mapping of serotonin 5-HT4 receptor mRNA and ligand binding sites in the post-mortem human brain

SL65.0155, A Novel 5-Hydroxytryptamine4 Receptor Partial Agonist with Potent Cognition-Enhancing Properties

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

Contact Info

Product

Resources

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SL65.0155, A Novel 5-Hydroxytryptamine₄ Receptor Partial Agonist with Potent Cognition-Enhancing Properties