Neuropharmacology of 5-HT3 Receptor Ligands

Costall, B.; Naylor, R.J.

doi:10.1007/978-3-642-60921-3_16

Cited by 18 publications

(21 citation statements)

References 159 publications

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“…41 Indeed, 5-HT 3 receptor antagonists facilitate cognitive processes 1 and seem to have procognitive effects during ageing. 7,42,43 The inhibitory effects of neuroleptics at 5-HT 3 receptors might contribute to the antipsychotic potential of these compounds, as 5-HT 3 receptor antagonists reduce dopaminergic neurotransmission (see, for review, Costall et al ). Indeed, first clinical investigations suggested an anxiolytic and antipsychotic potency of specific 5-HT 3 receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

“…3 Postsynaptic 5-HT 3 receptors are present on g-aminobutyric acid (GABA) ergic interneurons, mediating fast synaptic neurotransmission in the CNS, 4,5 while presynaptic 5-HT 3 receptors modulate the release of several neurotransmitters in various brain regions. 2,6-10 Since 5-HT 3 receptors are highly expressed in the caudate nucleus, putamen, hippocampal and amygdala regions, 1,7 it has been suggested that selective 5-HT 3 receptor antagonists may have psychotropic effects. 11 Early animal studies suggest that 5-HT 3 receptor antagonists, in addition to their well-recognized antiemetic use, might be clinically useful for the treatment of anxiety, schizophrenia, drug and alcohol abuse, depression, cognitive disturbances, Alzheimer's disease, cerebellar tremor, Parkinson's disease treatment-related psychosis, treatment of inflammatory pain and appetite disorders.…”

Section: Introductionmentioning

confidence: 99%

“…11 Early animal studies suggest that 5-HT 3 receptor antagonists, in addition to their well-recognized antiemetic use, might be clinically useful for the treatment of anxiety, schizophrenia, drug and alcohol abuse, depression, cognitive disturbances, Alzheimer's disease, cerebellar tremor, Parkinson's disease treatment-related psychosis, treatment of inflammatory pain and appetite disorders. 1,7,11 The dopamine hypothesis of schizophrenia suggests an enhanced mesolimbic activity of dopaminergic neurotransmission. 12 Behavioural, neurochemical and electrophysiological investigations indicate that 5-HT 3 receptors modulate dopaminergic activity in mesolimbic and nigrostriatal pathways.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 This profile suggests that 5-HT 3 receptor antagonists mimic certain inhibitory effects of neuroleptic drugs on the dopaminergic system and prompted their use in schizophrenia. 7,19 However, clinical trials with specific 5-HT 3 receptor antagonists as a monotherapy were not encouraging so far. 20 Most neuroleptic drugs are antagonists at dopamine type 2 (D 2 ) and type 4 (D 4 ) receptors.…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

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The serotonin type 3 (5-HT 3 ) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT 3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT 2 ) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT 3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na þ -inward currents through 5-HT 3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT 3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca 2 þ influx, measured as a change in intracellular Ca 2 þ concentrations ([Ca 2 þ ] i ). All neuroleptic drugs, but not risperidone, antagonized Na þ -and Ca 2 þ -inward currents evoked by 5-HT (10 lM for 2 s and 1 lM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC 50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT 3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na þ and Ca 2 þ currents. Since 5-HT 3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT 3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

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“…Biochemical and anatomical studies have shown a functional interaction between serotonergic and cholinergic systems (Maura et al, 1992;Cassel and Jeltsch, 1995) and therefore, serotonergic receptors could modulate the activity of the cholinergic system to cooperate in the regulation of cognitive processes (Barnes et al, 1989;Cassel and Jeltsch, 1995). In particular, the involvement of 5-HT 3 receptors in learning and memory has been repeatedly suggested and 5-HT 3 receptor antagonists, such as ondansetron, have been described as potential cognitive enhancers in the treatment of dementia (Costall and Naylor, 1997;Meneses, 1998). In addition to the effects on cognition, 5-HT 3 receptor antagonists have also been shown to be useful in the treatment of non-cognitive disorders, such as anxiety (Ye et al, 2001), that occur frequently in AD.…”

Section: Introductionmentioning

confidence: 99%

Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation

Gil-Bea

2004

Neuropharmacology

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We have studied the effects of concomitant blockade of 5-HT 3 and GABA A receptors on acetylcholine (ACh) release in the frontal cortex of rats with a selective cholinergic lesion. Lesions were performed by microinjection of the cholinergic toxin 192 IgG-saporin into the nucleus basalis magnocellularis. Single treatment with either the 5-HT 3 receptor antagonist ondansetron, 0.1 lg/kg, or the GABA A receptor benzodiazepine site antagonist flumazenil, 10 mg/kg, did not affect ACh release. However, the combined ondansetron þ flumazenil administration significantly increased ACh release to a similar extent as a depolarising stimulus with K + , 100 mM, at both 7 and 30 days post-lesion. Cortical perfusion with the combined ondansetron þ flumazenil treatment also increased [ 3 H]ACh efflux ''in vitro'' 30 days after lesion, suggesting that local events within the frontal cortex may participate in the interaction of ondansetron with GABAergic neurons, modulating ACh release in situations of cholinergic hypoactivity. No differences in the expression of 5-HT 3 and GABA A receptors in the frontal cortex were found after the cholinergic lesion. These results suggest that a combined ondansetron þ flumazenil treatment would contribute to restoring a diminished cholinergic function and may provide a basis for using this treatment in the therapy of cognitive disorders associated with degeneration of the cholinergic system. #

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Tests for Anxiolytic Activity

Kallman¹

2017

Drug Discovery and Evaluation: Pharmacological Assays

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Neuropharmacology of 5-HT3 Receptor Ligands

Cited by 18 publications

References 159 publications

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation

Tests for Anxiolytic Activity

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