mdl-100907 and Fever

This study determined whether blockade of 5-hydroxytryptamine 2A (5-HT2A) receptors attenuated hyperthermia and tachycardia responses to psychological stress in mice. For this purpose, male mice (C57BL/6N) were pre-instrumented with a telemetric probe to measure core body temperature and heart rate prior to experimentation. Vehicle or 5-HT2A antagonist, eplivanserin hemifumarate (SR-46349B) ((1Z,2E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-2-propen-1-one O-[2-(dimethylamino) ethyl] oxime hemifumarate) (0.5, 1.0, 5.0 mg/kg), was injected intraperitoneally. To elicit psychological stress, an intruder male mouse confined to a small cage was introduced into the resident mouse's cage 30 min after administration of the injection. The application of this psychological stress increased body temperature by ~ 1.0 °C and heart rate by ~ 150 bpm in the vehicle group. In contrast, SR-46349B was shown to reduce this psychological stress-induced increase in body temperature in a dose-dependent manner (P < 0.05). However, the SR-46349B treatment groups had no influence on the intruder-elicited increase in heart rate. This study, therefore, suggests that 5-HT2A receptors play a significant role in mediating hyperthermia, but not tachycardia, during intruder-elicited psychological stress.

Topics: Animals; Fever; Fluorobenzenes; Heart Rate; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phenols; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological

The antidepressive drug agomelatine combines the properties of an agonist of melatonergic receptors 1 and 2 with an antagonist of the 5-HT2C receptor. We analyzed the effects of agomelatine in psychosocially stressed male tree shrews, an established preclinical model of depression. Tree shrews experienced daily social stress for a period of 5 weeks and were concomitantly treated with different drugs daily for 4 weeks. The effects of agomelatine (40 mg/kg/day) were compared with those of the agonist melatonin (40 mg/kg/day), the inverse 5-HT2C antagonist S32006 (10mg/kg/day), and the SSRI fluoxetine (15 mg/kg/day). Nocturnal core body temperature (CBT) was recorded by telemetry, and urinary norepinephrine and cortisol concentrations were measured. Chronic social stress induced nocturnal hyperthermia. Agomelatine normalized the CBT in the fourth week of the treatment (T4), whereas the other drugs did not significantly counteract the stress-induced hyperthermia. Agomelatine also reversed the stress-induced reduction in locomotor activity. Norepinephrine concentration was elevated by the stress indicating sympathetic hyperactivity, and was normalized in the stressed animals treated with agomelatine or fluoxetine but not in those treated with melatonin or S32006. Cortisol concentration was elevated by stress but returned to basal levels by T4 in all animals, irrespective of the treatment. These observations show that agomelatine has positive effects to counteract stress-induced physiological processes and to restore the normal rhythm of nocturnal CBT. The data underpin the antidepressant properties of agomelatine and are consistent with a distinctive profile compared to its constituent pharmacological components and other conventional agents.

Topics: Acetamides; Animals; Antidepressive Agents; Antidepressive Agents, Second-Generation; Body Temperature; Body Weight; Central Nervous System Depressants; Circadian Rhythm; Depressive Disorder; Fever; Fluoxetine; Hydrocortisone; Indoles; Male; Melatonin; Motor Activity; Norepinephrine; Pyridines; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological; Tupaiidae

The use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") as a recreational drug has spread worldwide. Fatal hyperthermia is a likely side effect of using MDMA in combination with monoamine oxidase inhibitors. However, most antidepressants do not pose a high risk of developing hyperthermia when used in conjunction with MDMA. Mirtazapine is a novel antidepressant and a potent 5-HT(2A) receptor antagonist. It remains to be elucidated whether mirtazapine is unlikely to have life-threatening implications in combination with MDMA. In the present study, we evaluated whether mirtazapine and fluoxetine influence MDMA-induced hyperthermia in rats. The rectal temperature of the rats increased to above 41°C following an injection of MDMA (10mg/kg). Pre- and post-treatment administration of mirtazapine (5mg/kg) significantly attenuated MDMA-induced hyperthermia. Administration of WAY100635 (1mg/kg), a 5-HT(1A) receptor antagonist, did not influence the ability of mirtazapine to decrease hyperthermia induced by MDMA. Although pretreatment administration of fluoxetine (10mg/kg) significantly attenuated MDMA-induced hyperthermia, post-treatment administration of the same drug had no effect. The differences in body temperature between the groups post-treated mirtazapine and the groups post-treated fluoxetine may be due to differing mechanisms of action of the two antidepressants. The present study indicates that mirtazapine is unlikely to induce fatal hyperthermia when used with MDMA, and it may be rather effective against MDMA-induced hyperthermia. Considering our previous study demonstrating that potent 5-HT(2A) antagonists completely inhibit MDMA-induced hyperthermia, the findings of the present study suggest that mirtazapine inhibits MDMA-induced hyperthermia mainly by blocking the activation of 5-HT(2A) receptors.

Topics: Animals; Antidepressive Agents, Tricyclic; Disease Models, Animal; Fever; Fluoxetine; Male; Mianserin; Mirtazapine; N-Methyl-3,4-methylenedioxyamphetamine; Rats; Rats, Wistar; Serotonin 5-HT2 Receptor Antagonists; Serotonin Agents

Chronic stress precipitates drug seeking behavior and alters the effects of drugs of abuse. Although it is known that chronic stress potentiates acute neurochemical and hyperthermic responses to the drug of abuse methamphetamine, no studies have investigated if and how chronic stress alters other physiological responses to methamphetamine. Therefore the objective of these studies was to determine if 10 days of chronic unpredictable stress modulates corticosterone (CORT) responses to methamphetamine and furthermore how chronic stress may modulate methamphetamine-induced increases in hyperthermia and CORT. As chronic stress potentiates hyperthermic responses to serotonin 2 (5-HT2) stimulation and 5-HT2 receptors are important in mediating both hyperthermic and CORT responses, we also investigated if 5-HT2 antagonism would block hyperthermia and CORT secretion by the serial exposure to stress and methamphetamine (stress/methamphetamine). The results of these studies illustrate that stress potentiates methamphetamine-induced increases in body temperature and CORT secretion and that these increases are blocked by the 5-HT2 antagonist ketanserin. Furthermore, the combination of stress and methamphetamine depletes 5-HT content in the hippocampus 7 days after methamphetamine administration which is blocked by the 5-HT2 antagonist ketanserin. Overall, these results indicate a pharmacological mechanism for the depletion of hippocampal 5-HT by the serial exposure to stress and methamphetamine and further illustrate the deleterious interactions between chronic stress and methamphetamine use.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Body Temperature Regulation; Central Nervous System Stimulants; Corticosterone; Drug Administration Schedule; Fever; Hippocampus; Ketanserin; Male; Methamphetamine; Periodicity; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological

The aim of this study was to determine whether 5-HT2A receptors mediate cardiovascular and thermogenic responses to acute psychological stresses. For this purpose, adult male Wistar hooded rats instrumented for telemetric recordings of either electrocardiogram (ECG) (n=12) or arterial pressure (n=12) were subjected, on different days, to four 15-min episodes of social defeat. Prior to stress, animals received s.c. injection of the selective 5-HT2A receptor antagonist SR-46349B (trans-4-((3Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate) (at doses of 0.3, 1.0 and 3.0 mg/kg) or vehicle. The drug had no effect on basal heart rate or heart rate variability indexes, arterial pressure, and core body temperature. Social defeat elicited significant and substantial tachycardic (347+/-7 to 500+/-7 bpm), pressor (77+/-4 to 97+/-4 mm Hg) and hyperthermic (37.0+/-0.3 to 38.5+/-0.1 degrees C) responses. Blockade of 5-HT2A receptors, at all doses of the antagonist, completely prevented stress-induced hyperthermia. In contrast, stress-induced cardiovascular responses were not affected by the blockade (except small reduction of tachycardia by the highest dose of the drug). We conclude that in rats, 5-HT2A receptors mediate stress-induced hyperthermic responses, but are not involved in the genesis of stress-induced rises in heart rate or arterial pressure, and do not participate in cardiovascular control at rest.

Topics: Analysis of Variance; Animals; Blood Pressure; Body Temperature; Cardiovascular System; Electrocardiography; Fever; Fluorobenzenes; Heart Rate; Male; Phenols; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Social Dominance; Stress, Psychological; Tachycardia

Contradictory evidence exists regarding the role of the 5-HT(2A) receptor (5-HT(2A)R) in hyperactivity and hyperthermia elicited by the substituted amphetamine (+)-3,4-methylenedioxymethamphetamine.. The present studies examined the ability of the selective 5-HT(2A)R antagonist M100907 to block hyperactivity and hyperthermia produced across the (+)-MDMA dose-effect curve.. Male rats were pretreated with M100907 (0, 0.25, 0.5, 1, and 2 mg/kg) followed by treatment with (+)-MDMA (0-12 mg/kg); activity was recorded for 90 min followed by determination of rectal temperature. Additionally, we investigated the ability of M100907 (0 and 0.5 mg/kg) to reverse hyperthermia elicited by (+)-MDMA (12 mg/kg).. The first study demonstrated that M100907 attenuated hyperactivity in the periphery of the monitor and eliminated rearing induced by (+)-MDMA (3 mg/kg) with no effect on basal activity. In two subsequent studies, (+)-MDMA (0-12 mg/kg) dose-dependently increased peripheral activity and rearing and produced hyperthermia. Pretreatment with M100907 decreased peripheral activity evoked by (+)-MDMA, right-shifted the dose-effect curve for rearing, and blocked (+)-MDMA-induced hyperthermia, while having no effect when administered alone. A final study demonstrated the ability of M100907 (0.5 mg/kg) to reverse hyperthermia produced by (+)-MDMA (12 mg/kg).. These results suggest that the 5-HT(2A)R contributes to the generation of peripheral hyperactivity and rearing and, especially, the hyperthermia evoked by (+)-MDMA and that 5-HT(2A)R antagonists should be further investigated as treatments for the psychological and hyperthermic effects of (+/-)-MDMA.

Topics: Animals; Dose-Response Relationship, Drug; Drug Antagonism; Drug Therapy, Combination; Fever; Fluorobenzenes; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Time Factors

No selective antagonists for the effects of MDMA have yet been identified. The structurally-similar, naturally-occurring plant alkaloid nantenine (9,10-methylenedioxy-1,2 dimethoxyaporphine) may represent such a compound.. To investigate the capacity of nantenine to block and/or reverse MDMA-induced hyperthermia, lethality, locomotor stimulation, and head twitches in mice, and to compare these actions with those of the selective alpha1 antagonist prazosin and the selective 5-HT2A antagonist M100907.. Pretreatments of either 10 mg/kg nantenine or 1 mg/kg prazosin were administered 15 min before 32 mg/kg MDMA; core temperature and locomotor stimulation were then monitored via radiotelemetry for at least 3 h. In further hyperthermia studies, 32 mg/kg MDMA was administered first and temperature was allowed to rise for 30 min; 10 mg/kg nantenine, 1 mg/kg prazosin, or 1 mg/kg M100907 was then administered in an attempt to reverse MDMA-induced hyperthermia. In lethality assays, percent lethality was quantified 2 h after MDMA injection in two distinct housing conditions, one or 12 mice per cage, with or without 15 min pretreatments of 10 mg/kg nantenine or 1 mg/kg prazosin. Drug elicited head twitches were quantified for 10 min following administration of either MDMA enantiomer, with and without pretreatments of 1 mg/kg nantenine, 0.1 mg/kg prazosin, or 0.001 mg/kg M100907.. Nantenine blocked and rapidly reversed MDMA-induced hyperthermia, attenuated lethality in both housing conditions, and reduced MDMA-induced locomotor stimulation and head twitches in mice. Prazosin blocked, but did not reverse, MDMA-induced hyperthermia, attenuated lethality (more effectively in singly-housed animals), and reduced MDMA-induced locomotor stimulation and head twitches. M100907 did not reverse MDMA-induced hyperthermia, but effectively blocked drug-elicited head twitches.. Nantenine functions as an effective antagonist against a wide range of MDMA-induced effects in mice. The antagonist actions of this compound at serotonin and adrenergic receptors may be differentially implicated across endpoints.

Topics: Adrenergic alpha-Antagonists; Animals; Aporphines; Behavior, Animal; Crowding; Dose-Response Relationship, Drug; Fever; Fluorobenzenes; Male; Mice; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Piperidines; Prazosin; Serotonin Agents; Serotonin Antagonists; Stereoisomerism