In vitro and in vivo profile of SB 206553, a potent 5‐HT2C/5‐HT2B receptor antagonist with anxiolytic‐like properties

Kennett, Guy A.; Wood, Martyn; Bright, Fiona; Cilia, Jackie; Piper, D.C.; Gager, Tracey; Thomas, David R.; Baxter, G.S.; Forbes, Ian J.; Ham, P. J.; Blackburn, Thomas P.

doi:10.1111/j.1476-5381.1996.tb15208.x

Cited by 238 publications

(195 citation statements)

References 31 publications

(42 reference statements)

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“…The progressive ratio procedure is used to assess the motivational value of a reinforcer: If a drug increases the reinforcing value of the Ensure solution, the mice respond at higher breakpoint values; if a drug decreases the reinforcing value of the Ensure solution, the mice respond at lower breakpoint values. For example, the 5-HT 1B/2C receptor agonist mCPP, which produces hypophagia in many assays (e.g., Kennett and Curzon 1988;Kennett et al 1996), significantly decreased the breakpoint value for Ensure solution (Fig. 4) without altering response rates in the progressive ratio assay, as previously reported (Ward et al 2008).…”

Section: Discussionsupporting

confidence: 79%

“…Any dose of drug that produced changes in the autoshaping-operant procedure was also examined in the progressive ratio procedure. In addition, m-chlorophenylpiperazine (mCPP), a serotonin agonist that produces hypophagia in many assays (e.g., Kennett and Curzon 1988;Kennett et al 1996) and decreases the breakpoint value for Ensure in mice (Ward et al 2008), was tested as a positive control of a compound that decreases breakpoint responding.…”

mentioning

confidence: 99%

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Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

2008

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Rationale-The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date.Objective-We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory.Materials and methods-In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session.Results-Methotrexate (1.0-32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering responserates or motivation to respond as measured by progressive ratio responding. Conclusion-Takentogether, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.

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Section: Discussionsupporting

confidence: 79%

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confidence: 99%

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

2008

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“…Abercrombie et al, 1989;Thierry et al, 1976). 5-HT2C receptors have also been implicated in anxiety (Kennett et al, 1996(Kennett et al, , 1997. Thus, it is increasingly important to understand the role of 5-HT/DA interactions in depression, anxiety, and their treatments.…”

Section: Depression/anxietymentioning

confidence: 99%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

526

311

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The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

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“…Although drugs interacting acutely with alpha-adrenergic receptors or dopaminergic receptors modulate 8-OH-DPAT-induced hypothermia in mice (Bill et al 1991;Durcan et al 1991), this has been shown not to be the case for 8-OH-DPAT-induced hypothermia in rats (Millan et al 1997). However, if mianserin or ketanserin treatment had modified 8-OH-DPATinduced hypothermia or forepaw treading in the current study, it would have been necessary to address the potential involvement of alpha-adrenergic receptors or 5-HT 2C receptors by investigating the effect of chronic administration of the alpha-1 antagonist prazosin or the selective 5-HT 2C receptor antagonist SB 206553 (Kennett et al 1996) on these 5-HT 1A receptor mediated behaviors. In the absence of an effect of either ketanserin or mianserin on 8-OH-DPAT-induced hypothermia or forepaw treading, we did not investigate this further.…”

Section: Discussionmentioning

confidence: 84%

Effect of Chronic Serotonin-2 Receptor Agonist or Antagonist Administration on Serotonin-1A Receptor Sensitivity

Hensler

Truett

1998

Neuropsychopharmacology

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We have investigated the effect of 5-HT 2 receptor agonist or antagonist administration on postsynaptic 5-HT 1A receptor sensitivity assessed by two behavioral measures, reciprocal forepaw treading or hypothermia induced by acute injection of the 5-HT 1A receptor agonist 8-OH-DPAT. The effectiveness of these drug treatments to downregulate 5-HT 2A receptors was confirmed by measuring the binding of [ 3 H]-ketanserin in cortical homogenates, because all of these drug treatments have been shown to result in the downregulation of 5-HTOf some 14 subtypes of receptor for the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) (see Hoyer et al. 1994), a tremendous amount of attention has been focused on the serotonin 1A (5-HT 1A ) receptor subtype. Drugs that act as agonists at this receptor have proved useful clinically as antidepressants (see Murphy et al. 1995) and anxiolytics (Coplan et al. 1995). The unique distribution of this serotonin receptor subtype in brain is consistent with its potential involvement in cognitive or integrative functions, as well as in emotional states. In terminal field areas of serotonergic innervation, the 5-HT 1A receptor is located postsynaptically and is present in high density in cortical and limbic structures (i.e., hippocampus, entorhinal cortex, septum, amygdala, frontal cortex) (Vergé et al. 1986;Hensler et al. 1991;Khawaja 1995). The 5-HT 1A receptor is also found in high density in serotonin cell body areas, such as the dorsal and median raphé, where it is believed to function as the somatodendritic autoreceptor modulating the activity of serotonergic neurons (see Aghajanian et al. 1990).The sensitivity of behavioral (Goodwin et al. 1987;Hensler et al. 1991;Wieland et al. 1993;Maj et al. 1996) and electrophysiological (Blier and deMontigny 1983, Received June 16, 1997; revised December 15, 1997; accepted February 16, 1998. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 5 Modulation of 5-HT 1A Receptor Sensitivity 355 1985 responses mediated by the 5-HT 1A receptor is decreased after chronic administration of 5-HT 1A receptor agonists or antidepressants drugs. The desensitization of 5-HT 1A receptor-mediated responses has also been reported to occur after acute or short-term agonist administration (Kennett et al. 1987;Larsson et al. 1990). Although some investigators have reported changes in 5-HT 1A receptor number following agonist or antidepressant treatments (Welner et al. 1989;Fanelli and McMonagle-Strucko 1992), in many cases desensitization of 5-HT 1A receptor-mediated responses has not been found to be accompanied by a decrease 5-HT 1A receptor number (Larsson et al. 1990;Schecter et al. 1990;Hensler et al. 1991;Wieland et al. 1993). Changes in 5-HT 1A receptor second messenger function have not been consistently reported to follow administration of antidepressants or 5-HT 1A receptor agonists (Sleight et al. 1988;Varrault et al. 1991;Newman et al. 1992).Interactions between serotonin receptor subtypes have been observed in behavioral studies. For example, 5...

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In vitro and in vivo profile of SB 206553, a potent 5‐HT_2C/5‐HT_2B receptor antagonist with anxiolytic‐like properties

Cited by 238 publications

References 31 publications

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Effect of Chronic Serotonin-2 Receptor Agonist or Antagonist Administration on Serotonin-1A Receptor Sensitivity

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