Role of 5-HT2 receptors in the tryptamine-induced 5-HT syndrome in rats

Abstract

We distinguished the functions of the different 5-hydroxytryptamine-2 (5-HT(2)) receptor (5-HT(2)R) subtypes in the tryptamine-induced 5-HT syndrome in rats using (1) the 5-HT(2A)R antagonist R93274 (N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-amino-5-iodo-2-methoxybenzamide), the 5-HT(2A/C)R antagonist R99647 (2-(dimethylaminomethyl)2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine), the 5-HT(2B/C)R antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), and several 5-HT(2)R antagonists (ketanserin, risperidone, pipamperone and mianserin); and (2) chronic 5-HT(2)R activation by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast to SB-242084, the selective 5-HT(2A)R antagonist R93274 as well as the non-selective 5-HT(2A)R antagonists (R99647, ketanserin, risperidone, pipamperone and mianserin) significantly inhibited tryptamine-induced forepaw treading and tremors, and reversed peripherally mediated cyanosis into hyperaemia; only the 5-HT(2A/C)R antagonists R99647 and mianserin inhibited the tryptamine-induced hunched back. Intermittent DOM administration (intravenously every 48 h for 12 days) did not change the centrally mediated tryptamine-induced forepaw treading, tremors and hunched back at 1, 4 or 7 days after the last DOM pretreatment. The DOM-induced head twitch response, measured immediately after every DOM injection, was not affected. In contrast, peripherally mediated cyanosis was reversed into hyperaemia in 75, 11 and 20% of all pretreated rats at 1, 4 and 7 days, respectively, after the last DOM administration. Taken together, these finding suggest that central 5-HT(2A)Rs mediate tryptamine-induced forepaw treading and tremors, that peripheral 5-HT Rs mediate tryptamine-induced cyanosis, and that 5-HT(2A)Rs mediate tryptamine-induced hunched back. Peripheral 5-HT(2C)Rs are more sensitive to desensitization after intermittent treatment with an agonist than central 5-HT(2A)Rs.

Role of the serotonin 5-HT2A receptor in the hyperlocomotive and hyperthermic effects of (+)-3,4-methylenedioxymethamphetamine

“…However, the magnitude of 5-HT syndrome behaviors elicited by 32 mg/kg (+)-MDMA in mice could limit full expression of horizontal hyperactivity; inhibition of this behavioral syndrome by M100907 might enhance horizontal activity. This possibility is supported by reports indicating a role for the 5-HT 2A R in components of the 5-HT syndrome (Nisijima et al 2001;Van Oekelen et al 2002).…”

Pharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy

“…Notably, the 5-HT 7 receptor antagonist SB-269970 did not modify the 5-HTP-induced HTR but prevented both the AS19-and fluoxetine-stimulating effects. Interestingly, various drugs with 5-HT 7 antagonistic activity, including atypical antipsychotics olanzapine and risperidone, antagonize HTR induced by 5-HTP or tryptamine (Kitaichi et al, 1994;Fu et al, 2000;Van Oekelen et al, 2002).…”

Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

“…We also tested whether opioids that interact with one of these monoamine transporters induce transporter‐mediated monoamine release. Furthermore, activity at 5‐HT 1A , 5‐HT 2A and 5‐HT 2C receptors may be involved in animal models of the serotonin syndrome (Martin et al, ; Van Oekelen et al, ; Tao et al, ; Fox et al, ). Therefore, we determined the affinities of opioids to bind directly to these 5‐HT receptors.…”