Modulation of 5-HT2A receptor-mediated head-twitch behaviour in the rat by 5-HT2C receptor agonists

Vickers, Steven P.; Easton, Neil; Malcolm, Craig S.; Allen, N.H.P.; Porter, Richard H.; Bickerdike, M J; Kennett, Guy A.

doi:10.1016/s0091-3057(01)00552-4

Cited by 109 publications

(115 citation statements)

References 25 publications

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“…As mentioned in preceding text, the ''prototypical, 5-HT 2C agonist, Ro60,0175, behaved as an agonist at native, cerebral 5-HT 2A receptors, confirming previous studies of calcium fluxes triggered by cloned, human 5-HT 2A receptors where its potencies were very close (pEC 50 values of 6.4 and 6.8) to that seen herein for (upstream) engagement of Gq/11 (Porter et al, 1999;Vickers et al, 2001). These observations provide a cellular substrate for agonist properties of Ro60,0175 at 5-HT 2A receptors in functional paradigms.…”

Section: Role Of 5-ht 2a Receptors In Mediating Recruitment Of Gq/11 supporting

confidence: 87%

“…Further, motor actions of Ro60,0075 similar to those of 5-HT 2A receptor agonists were seen in mice genetically lacking 5-HT 2C receptors (Dalton et al, 2004) while, in the presence of 5-HT 2C receptor antagonists, Ro60,0175 elicited headtwitches, a prototypical response to recruitment of fronto-cortical 5-HT 2A receptors which was abolished by MDL100,907 (Schreiber et al, 1995;Vickers et al, 2001;Willins et al, 1998). Though the potency of Ro60,0176 at 5-HT 2A receptors is lower than at their 5-HT 2C counterparts (Cussac et al, 2002a,b;Porter et al, 1999;Vickers et al, 2001), it is important to systematically control for potential 5-HT 2A receptor-mediated effects of Ro60,0175 in in vivo studies of its functional actions.…”

Section: Role Of 5-ht 2a Receptors In Mediating Recruitment Of Gq/11 mentioning

confidence: 99%

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An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine

Cour

Chaput

Touzard

et al. 2008

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Though transduction mechanisms recruited by heterologously expressed 5-HT 2A receptors have been extensively studied, their interaction with specific subtypes of G-protein remains to be directly evaluated in cerebral tissue. Herein, as shown by an immunocapture/scintillation proximity analysis, 5-HT, the prototypical 5-HT 2A agonist, DOI, and Ro60,0175 all enhanced [ 35 S]GTPgS binding to Gaq/11 in rat cortex with pEC 50 values of 6.22, 7.24 and 6.35, respectively. No activation of Go or Gs/olf was seen at equivalent concentrations of DOI. Stimulation of Gaq/11 by 5-HT (30 lM) and DOI (30 lM) was abolished by the selective 5-HT 2A vs. 5-HT 2C /5-HT 2B antagonists, ketanserin (pK B values of 9.11 and 8.88, respectively) and MDL100,907 (9.82 and 9.68). By contrast, 5-HT-induced [ 35 S]GTPgS binding to Gaq/11 was only weakly inhibited by the preferential 5-HT 2C receptor antagonists, RS102,221 (6.94) and SB242,084 (7.39), and the preferential 5-HT 2B receptor antagonist, LY266,097 (6.66). The antipsychotic, clozapine, which had marked affinity for 5-HT 2A receptors, blocked the recruitment of Gaq/11 by 5-HT and DOI with pK B values of 8.54 and 8.14, respectively. Its actions were mimicked by the ''atypical'' antidepressant and 5-HT 2A receptor antagonist, mirtazapine, which likewise blocked 5-HT and DOI-induced Gaq/ 11 protein activation with pK B values of 7.90 and 7.76, respectively. In conclusion, by use of an immunocapture/scintillation proximity strategy, this study shows that native 5-HT 2A receptors in rat frontal cortex specifically recruit Gaq/11 and that this action is blocked by clozapine and mirtazapine. Quantification of 5-HT 2A receptor-mediated Gaq/11 activation in frontal cortex should prove instructive in characterizing the actions of diverse classes of psychotropic agent.

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Section: Role Of 5-ht 2a Receptors In Mediating Recruitment Of Gq/11 supporting

confidence: 87%

Section: Role Of 5-ht 2a Receptors In Mediating Recruitment Of Gq/11 mentioning

confidence: 99%

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine

Cour

Chaput

Touzard

et al. 2008

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“…In this study, however, the numbers of head shakes were counted in response to the doses ranging from the non-toxic to toxic and to lethal injections. The behavioral expression of shaking activity was very similar to that of (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a hallucinogenic drug (Dursun and Handley, 1996;Vickers et al, 2001). To date the relationship between hallucination and DOI-induced shaking behavior is not fully understood.…”

Section: Discussionmentioning

confidence: 90%

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Ma¹,

Zhang²,

Jenney³

et al. 2008

European Journal of Pharmacology

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Patients are at high risk of developing serotonin-toxicity syndrome (toxidrome) when they take multiple serotonergic drugs, particularly co-administered with monoamine oxidase inhibitors or 5-hydroxytryptamine (5-HT) reuptake blockers. The toxidrome can vary from mild to severe. The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5-hydroxy-L-tryptophan (5-HTP) in clorgylinized rats. The severity was obtained by scoring behavioral signs including head shakes, penile erection, forepaw treading, hind limb abduction, Straub tail and tremor. It was found that 5-HTP produced a dosedependent increase in degrees of the toxidrome. Furthermore, correlation between the toxidrome and changes in body-core temperature (claudqcT cor ) was determined. There was hypothermia in the mild toxidrome (claudqcT cor < −1 °C), high hyperthermia in the severe toxidrome (claudqcT cor > +2 °C) and a small change in T cor in the moderate toxidrome (−1 °C < claudqcT cor < +2 °C). Thus, claudqcT cor in response to drugs can be used to estimate the severity of the toxidrome. The second attempt was to identify the receptors mediating those changes. 5-HT 1A receptors were involved in the hypothermic response while 5-HT 2A and NMDA receptors mediated head shakes, hyperthermia, forepaw treading and Straub tail. Lastly, antidotal effect of cyproheptadine and (+)-MK-801 was examined. Both drugs blocked hyperthermia and death. However, the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced. These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5-HT toxidrome.

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“…Opposing effects exist for 5-HT 2A and 5-HT 2C receptors in modulating hyperlocomotion induced in mice by noncompetitive Nmethyl-d-aspartate (NMDA) antagonists (Martin et al, 1997). A recent study has found clear evidence supporting opposing effects of 5-HT 2A and 5-HT 2C receptors in modulating head shakes in rats (Vickers et al, 2001). Activation of 5-HT 2A and 5-HT 2C receptors also leads to opposing effects on sexual function in rodents (Berendsen et al, 1990), in a manner suggesting that activation of 5-HT 2A receptors could be responsible for the sexual side effects of SSRIs.…”

Section: Interactions Between 5-ht 2a and 5-ht 1a Receptorsmentioning

confidence: 99%

Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders

Marek

Carpenter

McDougle

et al. 2002

Neuropsychopharmacol

240

120

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Recently, the addition of drugs with prominent 5-HT 2 receptor antagonist properties (risperidone, olanzapine, mirtazapine, and mianserin) to selective serotonin reuptake inhibitors (SSRIs) has been shown to enhance therapeutic responses in patients with major depression and treatment-refractory obsessive-compulsive disorder (OCD). These 5-HT 2 antagonists may also be effective in ameliorating some symptoms associated with autism and other pervasive developmental disorders (PDDs). At the doses used, these drugs would be expected to saturate 5-HT 2A receptors. These findings suggest that the simultaneous blockade of 5-HT 2A

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Modulation of 5-HT2A receptor-mediated head-twitch behaviour in the rat by 5-HT2C receptor agonists

Cited by 109 publications

References 25 publications

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders

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Modulation of 5-HT2A receptor-mediated head-twitch behaviour in the rat by 5-HT2C receptor agonists

Cited by 109 publications

References 25 publications

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)2A receptors in rat cortex: Blockade by clozapine and mirtazapine

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)2A receptors in rat cortex: Blockade by clozapine and mirtazapine

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders

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An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine

An immunocapture/scintillation proximity analysis of Gαq/11 activation by native serotonin (5‐HT)_2A receptors in rat cortex: Blockade by clozapine and mirtazapine