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

Abstract

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.

Imaging Brain Phospholipase A2 Activation in Awake Rats in Response to the 5-HT2A/2C Agonist (±)2,5-Dimethoxy-4-Iodophenyl-2-Aminopropane (DOI)

“…These increments are consistent with the reported marked behavioral (5-HT 2 syndrome) and neuroendocrine responses provoked by this dose (Johnson et al, 1998;Pranzatelli, 1990;Van de Kar et al, 2001;Wettstein et al, 1999). The increments in k* could be completely blocked by chronic pretreatment with mianserin, a 5-HT 2 receptor agonist that has been reported to block the 5-HT 2 syndrome and the hyperthermia produced by DOI (Berendsen and Broekkamp, 1991;Mazzola-Pomietto et al, 1997).…”

Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse

“…Similarly, pilot experiments with the structurally similar direct 5-HT 2 agonist 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI) in the mouse also induced a head twitch response that was insensitive to p-CPA treatment (Fantegrossi et al 2004b) but failed to induce locomotor stimulation or hyperthermia at doses up to 30 times higher than those required to elicit significant head twitch behavior (unpublished results). Although 5-HT 2A/2C agonists have previously been shown to induce hyperthermia in the rat (Mazzola-Pomieto et al 1997), this lack of effects on core temperature may be a property of direct 5-HT 2 agonists in mice.…”

Imaging Brain Phospholipase A2-Mediated Signal Transduction in Response to Acute Fluoxetine Administration in Unanesthetized Rats

“…Increased tracer incorporation likely arises because fluoxetine indirectly increases binding of 5-HT to PLA 2 -coupled 5-HT 2A/2C receptors. Identifying the exact mechanisms of fluoxetine's acute action will entail using specific receptor antagonists with it (Hayakawa et al, 2001;Mazzola-Pomietto et al, 1997;Rabiner et al, 2002), or studying 5-HT 2A or 5-HT 2C knockout mice (Lira et al, 2001).…”