The potential anxiolytic activity of GR38032F, a 5‐HT<sub>3</sub>‐receptor antagonist

Jones, Brian; Costall, B.; Domeney, A.M.; Kelly, M.E.; Naylor, R.J.; Oakley, N.R.; Tyers, M.B.

doi:10.1111/j.1476-5381.1988.tb11489.x

Cited by 328 publications

(94 citation statements)

References 16 publications

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“…Moreover, locomotor activity by both genotypes decreased as a function of time in the open-field environment (F time (5,150) ¼ 13.55, po0.001), which indicates normal habituation to the environment. This finding is consistent with our previous report (Kelley et al, 2003) and supports pharmacological evidence, which indicates that 5-HT 3 receptor antagonists have no effects on locomotor behavior (Jones et al, 1988).…”

Section: Locomotor Activitysupporting

confidence: 94%

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

Hodge

Kelley

Bratt³

et al. 2004

Neuropsychopharmacol

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The ionotropic serotonin subtype-3 (5-HT 3 ) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT 3A receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT 3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle homecage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT 3A receptor subunit gene. 5-HT 3A -null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT 3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose þ 10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT 3 antagonism is dependent on the presence of 5-HT 3A -containing receptors.

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Section: Locomotor Activitysupporting

confidence: 94%

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

Hodge

Kelley

Bratt³

et al. 2004

Neuropsychopharmacol

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“…Evidence from radioligand binding studies (Kilpatrick et al, 1987;Peroutka & Hamik, 1988;Waeber et al, 1989) and behavioural tests (Costall et al, 1987;Jones et al, 1988) have shown that 5-HT3 receptors exist not only in the periphery but also in the central nervous system. 5-HT3 receptors appear most promising as targets for novel drugs.…”

Section: Discussionmentioning

confidence: 99%

“…In general, it seems that stimulation of the 5-HT system results in an anxiogenic effect, while a reduction in inappropriately elevated 5-HT neuronal activity leads to anxiolysis. Accordingly anxiolytic activity has recently been reported for 5-HT3 receptor antagonists (Jones et al, 1988;Lecrubier et al, 1990). Administration of cholecystokinin (CCK), a major neuropeptide in the central nervous system (Vanderhaeghen et al, 1975;Dockray, 1976) has been found to induce anxiety both in the experimental animal and in man and CCK receptor antagonists have been shown to display anxiolytic activity (see review by Ravard & Dourish, 1990, and references therein).…”

Section: Introductionmentioning

confidence: 99%

Cholecystokinin release mediated by 5‐HT₃ receptors in rat cerebral cortex and nucleus accumbens

Paudice

Raiteri

1991

British J Pharmacology

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1 The effects of 5-hydroxytryptamine (5-HT) on the release of cholecystokinin-like immunoreactivity (CCK-LI) were examined in synaptosomes prepared from rat cerebral cortex and nucleus accumbens and depolarized by superfusion with 15 mM KCl. 2 In both areas 5-HT, tested between 0.1 and 100 nm, increased the calcium-dependent, depolarizationevoked CCK-LI release in a concentration-related manner. The concentration-response curves did not differ significantly between the two brain areas (EC50: 0.4 + 0.045 nm and 0.48 + 0.053 nm, respectively, in cortical and n. accumbens synaptosomes; maximal effect: about 60% at 10 nm 5-HT).3 The 5-HT,/5-HT2 receptor antagonist methiothepin (300 nM) did not affect the CCK-LI release elicited by 10nm 5-HT. However, the effects of 10nm 5-HT were antagonized in a concentration-dependent manner by the 5-HT3 receptor antagonists (3a-tropanyl)-lH-indole-3-carboxylic acid ester 0.1-100 nM; IC50: 3.56 + 0.42 nm in the cortex and 3.90 + 0.50 nm in the n. accumbens) and ondasetron (IC50: 8.15 + 0.73nm in the cerebral cortex). 5-HT (10nM) was also strongly antagonized by l00nM laH, 3a5aH-tropan-3-yl-3,5-dichlorobenzoate (MDL 72222) another blocker of the 5-HT3 receptor. Moreover, the 5-HT3 receptor agonist 1-phenylbiguanide (tested in the cerebral cortex between 0.1 and 100nM) enhanced CCK-LI release in a manner almost identical to that of 5-HT (EC5o = 0.64 + 0.071 nM).4 It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs.

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“…social phobia, particularly as the 5-HT3 receptor antagonist, ondansetron, which has anxiolytic-like effects in the test (Jones et al, 1988;Blackburn et al, 1993), but not in the GellerSeifter procedure (Tyers et al, 1987;Piper et al, 1988), has recently been reported to be effective in clinical trials (Bell & DeVeaugh-Geiss, 1994).…”

Section: Effectsmentioning

confidence: 99%

Effects of the 5‐HT_2B receptor agonist, BW 723C86, on three rat models of anxiety

Kennett

Bright

Trail

et al. 1996

British J Pharmacology

106

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1 BW 723C86 (3 and 10 mg kg-', s.c. 30 min pretest), a 5-HT2B receptor agonist, increased total interaction, but not locomotion in a rat social interaction test, a profile consistent with anxiolysis. 2 The effect of BW 723C86 in the social interaction test is likely to be 5-HT2B receptor-mediated as it was prevented by pretreatment with the 5-HT2C,2B receptor antagonist, SB 200646A, (1 and 2 mg kg-', p.o., 1 h pretest) which did not affect basal levels of social interaction at the doses used. 3 An anxiolytic-like action was also observed in the rat Geller-Seifter conflict test, where BW 723C86 (0.5-50 mg kg-', s.c. 30 min pretest) modestly, but significantly increased punished, but not unpublished responding. 4 In a rat 5 min elevated x-maze test, BW 723C86 (1-10 mg kg-', s.c.) had no significant effect. 5 The maximal anxiolytic-like effect of BW 723C86 approached that of the benzodiazepine anxiolytic, chloradiazepoxide (5 mg kg-', s.c. 30 min pretest) in the social interaction test, but was markedly less in the Geller-Seifter test. The effect of BW 723C86 was also clearly less than chlordiazepoxide in the elevated x-maze procedure where it had no significant effect. 6 In conclusion, BW 723C86 exerted an appreciable anxiolytic-like profile in a rat social interaction test, but had a weaker effect in the Geller-Siefter and was ineffective in the elevated x-maze test used. These effects are likely to be 5-HT2B receptor-mediated.

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The potential anxiolytic activity of GR38032F, a 5‐HT₃‐receptor antagonist

Cited by 328 publications

References 16 publications

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

Cholecystokinin release mediated by 5‐HT₃ receptors in rat cerebral cortex and nucleus accumbens

Effects of the 5‐HT_2B receptor agonist, BW 723C86, on three rat models of anxiety

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The potential anxiolytic activity of GR38032F, a 5‐HT3‐receptor antagonist

Cited by 328 publications

References 16 publications

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

Cholecystokinin release mediated by 5‐HT3 receptors in rat cerebral cortex and nucleus accumbens

Effects of the 5‐HT2B receptor agonist, BW 723C86, on three rat models of anxiety

Contact Info

Product

Resources

About

The potential anxiolytic activity of GR38032F, a 5‐HT₃‐receptor antagonist

Cholecystokinin release mediated by 5‐HT₃ receptors in rat cerebral cortex and nucleus accumbens

Effects of the 5‐HT_2B receptor agonist, BW 723C86, on three rat models of anxiety