Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated

Kennett, Guy A.; Trail, Brenda; Bright, Fiona

doi:10.1016/s0028-3908(98)00115-4

Cited by 82 publications

(56 citation statements)

References 23 publications

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“…These doses were based on both published and in-house data to likely be pharmacologically selective for each target receptor (Kehne et al 1996;Kennett et al 1997Kennett et al , 1998Reavill et al 1999;Higgins et al 2001). Within each experiment, all rats were tested under all six possible combinations of the antagonist and its vehicle, and cocaine and saline.…”

Section: Experiments 1a 1b and 1c Effects Of M100907 Sb215505 Amentioning

confidence: 99%

“…Our results are consistent with the latter finding and clearly suggest that 5-HT 2C rather than 5-HT 2B receptor blockade potentiates the effects of cocaine on locomotor activity since SB215,505 failed to alter cocaine-stimulated locomotion. The apparent lack of effectiveness of SB215,505 is unlikely to be due to inappropriate dose or route of administration since a previous report indicates that SB215,505 prevented the anxiolytic effect of the 5-HT 2B receptor agonist BW 723C86 (Kennett et al 1998). Thus, these results imply that 5-HT 2B receptor blockade may not influence cocaine-mediated hyperlocomotion.…”

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confidence: 94%

“…This profile of 5-HT 2A receptor antagonists appears opposite to that induced by 5-HT 2C receptor antagonists. Therefore an additional aim of these studies was to compare the effects of M100,907 with those of SB242,084 on the same behavioral effects of cocaine.To complete these investigations, we included the 5-HT 2B receptor preferring antagonist SB215,505 (Kennett et al 1998;Reavill et al 1999) in certain studies. Despite a developmental role in cardiac function (Nebigil et al 2000), the involvement of this receptor in central nervous system function is unclear (Barnes and Sharp 1999).…”

mentioning

confidence: 99%

“…Despite a developmental role in cardiac function (Nebigil et al 2000), the involvement of this receptor in central nervous system function is unclear (Barnes and Sharp 1999). Accordingly we examined SB215,505 at a pharmacologically active dose (Kennett et al 1998) against cocaine-induced hyperlocomotion. …”

mentioning

confidence: 99%

“…To complete these investigations, we included the 5-HT 2B receptor preferring antagonist SB215,505 (Kennett et al 1998;Reavill et al 1999) in certain studies. Despite a developmental role in cardiac function (Nebigil et al 2000), the involvement of this receptor in central nervous system function is unclear (Barnes and Sharp 1999).…”

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confidence: 99%

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Differential Effects of the 5-HT2A Receptor Antagonist M100,907 and the 5-HT2C Receptor Antagonist SB242,084 on Cocaine-induced Locomotor Activity, Cocaine Self-administration and Cocaine-induced Reinstatement of Responding

Fletcher

Grottick

Higgins

2002

Neuropsychopharmacology

161

254

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These studies investigated the effects of antagonists selective for the 5-HT 2A , 5-HT 2B , or 5-HT 2C receptor subtypes on behaviors elicited or maintained by cocaine. The selective 5-HT 2A receptor antagonist M100,907 (0.5 mg/kg, SC) attenuated the locomotor activity elicited by 10 mg/kg cocaine, whereas the selective 5-HT 2C receptor antagonist SB242,084 (0.5 mg/kg IP) potentiated the locomotor stimulant effect of 10 mg/kg cocaine. The selective 5-HT 2B antagonist SB215,505 (3 mg/kg PO) did not alter cocaineinduced locomotor activity. In a second series of experiments, the effects of M100,907 and SB242,084 were examined in rats self-administering cocaine intravenously according to a progressive ratio schedule. M100,907 (0.5-2 The behavioral effects of cocaine are mediated in part by increased activity of the mesolimbic dopamine (DA) system. Cocaine binds to a site on the DA transporter (McElvain and Schenk 1992) and inhibits re-uptake of released DA into presynaptic terminals. Cocaine elevates extracellular levels of DA (Di Ciano et al. 1995;Pettit and Justice 1991) and this is critical for the behavFrom the Section of Biopsychology, Centre for Addiction and Mental Health, Toronto, Ontario, Canada, and Departments of Psychiatry and Psychology, University of Toronto (PJF), and PRPN-B, Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland (AJG, GAH).Address correspondence to: P.J. Fletcher, CAMH, 250 College St., Toronto, Ontario, Canada, M5T 1R8. Tel.: (416) Fax: (416) 979-6942; E-mail: Paul_Fletcher@camh.net Received October 31, 2001; revised March 12, 2002; accepted April 1, 2002. Online publication: 4/3/02 at www.acnp.org/citations/ Npp040302276. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 5-HT 2A and 5-HT 2C Antagonists and Cocaine-mediated Behaviors 577 ioral effects of cocaine. Thus, the locomotor activating effect of cocaine is abolished in rats with 6-OHDA lesions of the mesolimbic pathway (Kelly and Iversen 1976), and similar lesions abolish self-administration of cocaine (Roberts et al. 1977;Pettit et al. 1984). DA receptor antagonists injected into the nucleus accumbens also block cocaine-induced hyperactivity (Neisewander et al. 1995), and disrupt cocaine self-administration (Maldonado et al. 1993). Although much of the work directed at understanding the neurochemical bases of the behavioral effects of cocaine has focused on DA, other neurotransmitters are likely involved. Cocaine inhibits the 5-hydroxytryptamine (5-HT, serotonin) transporter (Koe 1976) leading to enhanced levels of extracellular 5-HT (Bradberry et al. 1993), and cocaine self-administration is affected by treatments which alter 5-HT function. Increasing 5-HT availability, either by blocking re-uptake (Carroll et al. 1990;Richardson and Roberts 1991) or by administration of the 5-HT precursor L-tryptophan (McGregor et al. 1993) reduces responding for cocaine, whereas 5-HT depletion increases responding for cocaine (Loh and Roberts 1990;Roberts et al. 1994). One issue that is unresolved by previo...

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Section: Experiments 1a 1b and 1c Effects Of M100907 Sb215505 Amentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Differential Effects of the 5-HT2A Receptor Antagonist M100,907 and the 5-HT2C Receptor Antagonist SB242,084 on Cocaine-induced Locomotor Activity, Cocaine Self-administration and Cocaine-induced Reinstatement of Responding

Fletcher

Grottick

Higgins

2002

Neuropsychopharmacology

161

254

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Antianxiety Agents

Currie

2003

Burger's Medicinal Chemistry and Drug Discovery

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Anxiety is a complex and prevalent cluster of psychiatric disorders consisting of generalized anxiety disorder, panic disorder, social phobia, obsessive‐compulsive disorder, posttraumatic stress disorder, and specific phobias. These conditions are most commonly treated with benzodiazepines, buspirone, and serotonin reuptake inhibitors, all of which fall some way short of the ideal anxiolytic. The clinical applications, side effects, and drug metabolism of these medications are discussed. A multitude of neurotransmitter systems are implicated to a greater or lesser degree in the complex underlying neurobiology and physiology of anxiety, including GABA, serotonin, norepinephrine, glutamate, as well as neuropeptides such as CCK, CRF, and NPY. The increasing understanding of the roles of each neurobiological pathway provides a platform for medicinal chemistry efforts in anxiolytic research. The structure‐activity relationships of current medications and newer, investigational compounds interacting with these systems are discussed, as well as the future prospects for the development of improved anxiolytics.

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