Long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in Fawn-Hooded rats

Aulakh, Charanjit S.; Mazzola-Pomietto, Pascale; Murphy, Dennis L.

doi:10.1016/0014-2999(95)00279-t

Cited by 24 publications

(3 citation statements)

References 33 publications

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“…The animals were challenged 1, 2, 3, 4 or 6 days later with a 2.5 mg/kg dose of either m-CPP or DOI. The selection of the 2.5 mg/kg dose of m-CPP and DOI was based on our previous work (Aulakh et al 1995b;Mazzola-Pomietto et al 1995).…”

Section: Methodsmentioning

confidence: 99%

Functional subsensitivity of 5-HT 2A and 5-HT 2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT 2A/2C receptor antagonists

et al. 1997

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In the present study, we investigated the duration of attenuation of the temperature increases produced by (±) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) which followed pretreatment with four serotonin (5-HT) antagonists; metergoline, mesulergine, mianserin and ritanserin. The duration of attenuation of m-CPP-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for the 5 mg/kg doses of both mianserin and metergoline and more than 2 days for the 5 mg/kg dose of mesulergine. The duration of attenuation of DOI-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for mianserin, more than 2 days for the 5 mg/kg dose of metergoline and more than 4 days for mesulergine. Daily administration of a low (1.0 mg/kg per day) dose of ritanserin for 14 days led to an attenuation of the temperature increases produced by m-CPP given 24 h after the last dose of ritanserin, but did not cause a similar desensitization of DOI-induced hyperthermia. On the other hand, daily administration of both low (1.0 mg/kg per day) and high (5.0 mg/kg per day) doses of mianserin for 14 days caused desensitization of DOI-induced hyperthermia but did not cause desensitization of m-CPP-induced hyperthermia when these agonists were administered 48 h after the last dose of mianserin. These findings demonstrate functional subsensitivity of both 5-HT 2A and 5-HT 2C receptors mediating hyperthermia following both acute and chronic administration of 5-HT 2A /5-HT 2C receptor antagonists; some differences in time course and in responses to individual antagonists at 5-HT 2A versus 5-HT 2C sites were also observed.

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Section: Methodsmentioning

confidence: 99%

Functional subsensitivity of 5-HT 2A and 5-HT 2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT 2A/2C receptor antagonists

et al. 1997

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“…For example, 8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (8‐OH‐DPAT) is normally hypothermic in both rats and mice (Goodwin and Green, 1985; Goodwin et al ., 1985; Hjorth, 1985), although the effect is probably pre‐synaptic in mice (Goodwin et al ., 1985), but post‐synaptic in rats (Bill et al ., 1991). In contrast, 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI), a selective 5‐HT 2A agonist, and m ‐chlorophenylpiperazine ( m ‐CPP) and 6‐chloro‐2(1‐piperazinyl)‐pyrazine (MK‐212), selective agonists of 5‐HT 2C receptors, induce hyperthermia (Gudelsky et al ., 1986; Aulakh et al ., 1995; Mazzola‐Pomietto et al ., 1997). While there have been several studies that have attempted to dissect the receptors responsible for inducing the temperature changes following MDMA, absolute conclusions are difficult due to the lack of total receptor subtype selectivity of any antagonist used.…”

Section: Role Of 5‐ht In the Acute Mdma‐induced Hyperthermic Responsementioning

confidence: 99%

The role of monoamines in the changes in body temperature induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives

Docherty

2010

British J Pharmacology

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Hyperthermia is probably the most widely known acute adverse event that can follow ingestion of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) by recreational users. The effect of MDMA on body temperature is complex because the drug has actions on all three major monoamine neurotransmitters [5-hydroxytryptamine (5-HT), dopamine and noradrenaline], both by amine release and by direct receptor activation. Hyperthermia and hypothermia can be induced in laboratory animals by MDMA, depending on the ambient temperature, and involve both central thermoregulation and peripheral changes in blood flow and thermogenesis. Acute 5-HT release is not directly responsible for hyperthermia, but 5-HT receptors are involved in modulating the hyperthermic response. Impairing 5-HT function with a neurotoxic dose of MDMA or p-chlorophenylalanine alters the subsequent MDMA-induced hyperthermic response. MDMA also releases dopamine, and evidence suggests that this transmitter is involved in both the hyperthermic and hypothermic effects of MDMA in rats. The noradrenergic system is also involved in the hyperthermic response to MDMA. MDMA activates central a2A-adrenoceptors and peripheral a1-adrenoceptors to produce cutaneous vasoconstriction to restrict heat loss, and b3-adrenoceptors in brown adipose tissue to increase heat generation. The hyperthermia occurring in recreational users of MDMA can be fatal, but data reviewed here indicate that it is unlikely that any single pharmaceutical agent will be effective in reversing the hyperthermia, so careful body cooling remains the principal clinical approach. Crucially, educating recreational users about the potential dangers of hyperthermia and the control of ambient temperature should remain key approaches to prevent this potentially fatal problem.

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“…Supporting this hypothesis, it has been demonstrated that chronic corticosetrone treatment induces depression-like behavioural manifestations in rodents with decreased 5-HT 1A and increased 5HT 2A receptor binding [83]. Chronic antidepressant treatment alters 5-HT 2A (and 5-HT 2C ) mediated hyperthermia in Fawn-Hooded rats (genetic model of depression) [13]. Antisense oligonucleotide induced 5-HT 2A receptor down-regulation is sufficient to achieve antidepressant-like effects in mice and enhances psychomotor activity.…”

Section: -Ht2a Receptormentioning

confidence: 99%

Assessing the Neuronal Serotonergic Target-based Antidepressant Stratagem: Impact of In Vivo Interaction Studies and Knockout Models

Rajkumar

Mahesh²

2008

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Depression remains a challenge in the field of affective neuroscience, despite a steady research progress. Six out of nine basic antidepressant mechanisms rely on serotonin neurotransmitter system. Preclinical studies have demonstrated the significance of serotonin receptors (5-HT1-3,6,7), its signal transduction pathways and classical down stream targets (including neurotrophins, neurokinins, other peptides and their receptors) in antidepressant drug action. Serotonergic control of depression embraces the recent molecular requirements such as influence on proliferation, neurogenesis, plasticity, synaptic (re)modeling and transmission in the central nervous system. The present progress report analyses the credibility of each protein as therapeutically relevant target of depression. In vivo interaction studies and knockout models which identified these targets are foreseen to unearth new ligands and help them transform to drug candidates. The importance of the antidepressant assay selection at the preclinical level using salient animal models/assay systems is discussed. Such test batteries would definitely provide antidepressants with faster onset, efficacy in resistant (and co-morbid) types and with least adverse effects. Apart from the selective ligands, only those molecules which bring an overall harmony, by virtue of their affinities to various receptor subtypes, could qualify as effective antidepressants. Synchronised modulation of various serotonergic sub-pathways is the basis for a unique and balanced antidepressant profile, as that of fluoxetine (most exploited antidepressant) and such a profile may be considered as a template for the upcoming antidepressants. In conclusion, 5-HT based multi-targeted antidepressant drug discovery supported by in vivo interaction studies and knockout models is advocated as a strategy to provide classic molecules for clinical trials.

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Long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in Fawn-Hooded rats

Cited by 24 publications

References 33 publications

Functional subsensitivity of 5-HT 2A and 5-HT 2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT 2A/2C receptor antagonists

Functional subsensitivity of 5-HT 2A and 5-HT 2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT 2A/2C receptor antagonists

The role of monoamines in the changes in body temperature induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and its derivatives

Assessing the Neuronal Serotonergic Target-based Antidepressant Stratagem: Impact of In Vivo Interaction Studies and Knockout Models

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