The differential activities of R(+)- and S(−)-zacopride as 5-HT3 receptor antagonists

Barnes, James L.; Barnes, Nicholas M.; Costall, B.; Domeney, A.M.; Johnson, D.; Kelly, M.E.; Munson, H. Randall; Naylor, R.J.; Young, Richard

doi:10.1016/0091-3057(90)90554-u

Cited by 56 publications

(22 citation statements)

References 21 publications

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“…Guy and Gardner 1985;Saldivar-Gonzales et al 1996;Chermat et al 1997;Hasenöhrl et al 1998), but Sprague-Dawley (SPRD) rats (e.g. Barnes et al 1990;Kennett et al 1997) and Lister rats (e.g. File et al 1993) are also utilised.…”

Section: Discussionmentioning

confidence: 99%

Anxiolytic-like profile in Wistar, but not Sprague?Dawley rats in the social interaction test

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Anxiolytic-like profile in Wistar, but not Sprague?Dawley rats in the social interaction test

et al. 2004

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“…A partial agonist action of S(-) zacopride would explain its anxiolytic action during withdrawal, since it would have an antagonist action under the conditions of increased 5-HT release. In contrast, the anxiolytic action of low doses of zacopride is likely to reside primarily in the activity of the R(+) enantiomer, which has potent anxiolytic activity in the rat and mouse (Barnes et al 1990;Young and Johnson 1992). It has been suggested that this anxiolytic action resides from activity at a novel binding site, at which other 5-HT 3 antagonists have little affinity (Kidd et al 1992) and that it is due to an inhibition of 5-HT release through an action at terminal receptors (Barnes et al 1992).…”

Section: Behavioural Studiesmentioning

confidence: 89%

“…The effects of zacopride were also changed by treatment with diazepam and low doses (1 gg/kg) were anxiolytic only in the withdrawal group, whereas at the highest dose tested (100 gg/kg) there was an anxiogenic effect only in the control-treated rats. Zacopride is a racemic mixture and anxiogenic effects of the S( -) enantiomer have been reported (Barnes et al 1990). We would attribute this to an agonist action at 5-HT 3 receptors.…”

Section: Behavioural Studiesmentioning

confidence: 99%

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence

Andrews

File

1993

Psychopharmacology

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This paper reviews the biochemical and behavioural evidence that the increased anxiety that occurs during benzodiazepine withdrawal is caused by increased 5-HT activity. In hippocampal slices taken from rats withdrawn for 24 h from chronic diazepam treatment (2 mg/kg/day for 21 days) there was a significant increase in K(+)-evoked release of [3H]5-HT and in 45Ca2+ uptake and both of these changes were reversed by the GABAB agonist, baclofen. Baclofen also reversed the anxiogenic response that is detected on withdrawal from chronic diazepam treatment. Other drugs that reduce 5-HT function (tianeptine which increases 5-HT uptake; buspirone, a 5-HT1A receptor agonist/partial agonist; zacopride, a 5-HT3 receptor antagonist) also reversed this anxiogenic response. Finally, we present data from a group of rats that did not develop tolerance to the anxiolytic effects of diazepam (2 mg/kg), even after 5 weeks treatment. This group failed to show an anxiogenic response on withdrawal from diazepam, nor was there an increase in hippocampal 5-HT release. We discuss the extent to which increased hippocampal 5-HT release can be causally linked to the increased anxiety during benzodiazepine withdrawal.

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“…While the (R)-isomer of zacopride has been reported to be more potent in exhibiting anxiolytic-like effects than the (S)-isomer (Barnes et al 1990a;Young and Johnson 1991), the (S)-isomer has been shown to be more potent at inhibiting [3H]zacopride binding ) and antagonizing dopamine-induced hyperactivity (Barnes et aI. 1990a).…”

Section: -Hg Antagonists and Behaviormentioning

confidence: 96%

“…These effects include a reduction in dopamineinduced hyperactivity (Costall et al 1987), alteration in ethanol consumption (Knapp and Pohorecky 1992) and the discriminative stimulus effects of ethanol (Grant and Barrett 1991), reduction in the severity of benzodiazepine withdrawal (Goudie and Leathley 1990), and improvement in performance on a variety of cognition tests (Barnes et al 1990b). 5-HT 3 antagonists exhibit anxiolytic-like effects in many behavioral models such as the primate reaction to human threat (Costall et al 1988;Jones et al 1988;Barnes et al 1990a), place aversion conditioning (Papp 1988;Acquas et al 1990), social interaction (Costall et al 1988;Johnston and File 1988;Jones et al 1988;Barnes et al 1990a;Cutler t990, t991;Cutler and Piper 1990;Dunn et al 1991;Higgins et al 1991), light/ dark exploratoration (Costall et al 1988(Costall et al , 1989Jones et al 1988;Kilfoil et al 1989;Onaivi and Martin 1989;Cutler, 1990;Young and Johnson 1991), the elevated plus-maze (Dunn et al 1991 ;Wright et al 1992), and the potentiated startle response (Glenn and Green 1989). As shown in Table 2, however, in many of these same models, 5-HT 3 antagonists have failed to show anxiolytic-like effects (File and Johnston 1989;Johnston and File 1988).…”

Section: -Hg Antagonists and Behaviormentioning

confidence: 99%

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

Barrett¹,

Vanover²

1993

Psychopharmacology

150

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The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT1C/2 and 5-HT3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

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The differential activities of R(+)- and S(−)-zacopride as 5-HT3 receptor antagonists

Cited by 56 publications

References 21 publications

Anxiolytic-like profile in Wistar, but not Sprague?Dawley rats in the social interaction test

Anxiolytic-like profile in Wistar, but not Sprague?Dawley rats in the social interaction test

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

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