Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin (5-HT) and 5-HT(1A) receptors have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, particularly in the case of selective serotonin reuptake inhibitors (SSRIs). In the rat learned helplessness (LH) paradigm, a valid animal model of human depression, repeated treatment with the 5-HT(1A) receptor agonist 8-OH-DPAT (0.125 and 0.5mg/kg) and several classes of antidepressants such as the tricyclic agent desipramine (30 and 60mg/kg), the monoamine oxidase inhibitor (MAOI) pargyline (60mg/kg) and the SSRIs fluoxetine (15 and 30mg/kg), paroxetine (15 and 30mg/kg) and sertraline (30mg/kg) improved behavioural deficit in helpless rats. The involvement of serotonergic mechanisms in the antidepressant-like effect of these agents was investigated using the selective 5-HT(1A) receptor antagonist WAY 100,635 and the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). Pretreatment with WAY 100,635 blocked the 8-OH-DPAT-induced reduction in escape failures, but did not counteract the antidepressant effect of fluoxetine and paroxetine. PCPA given alone did not modify helpless behaviour nor did it affect the behavioural effect of 8-OH-DPAT, fluoxetine and paroxetine. Adaptive changes in 5-HT(1A) receptor function were studied by measuring 8-OH-DPAT-mediated hypothermia and lower lip retraction (LLR) in the animals 24h after LH test session. Fluoxetine and paroxetine treatments caused a marked reduction in agonist-induced responses, an effect completely prevented by WAY 100,635 and PCPA. In conclusion, whereas direct agonist activity at postsynaptic 5-HT(1A) receptors attenuated helpless behaviour, the antidepressant-like effect of SSRIs was found to be independent of their actions on either 5-HT(1A) receptor function or extracellular 5-HT.
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PMID:Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability. 1714 11

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') produces acute hyperthermia which increases the severity of the selective serotoninergic neurotoxicity produced by the drug in rats. Heat shock protein 70 (Hsp70) is a major inducible cellular protein expressed in stress conditions and which is thought to exert protective functions. MDMA (12.5 mg/kg, i.p.), given to rats housed at 22 degrees C, produced an immediate hyperthermia and increased Hsp70 in frontal cortex between 3 h and 7 days after administration. MDMA, given to rats housed at low ambient temperature (4 degrees C) produced transient hypothermia followed by mild hyperthermia but no increase in Hsp70 expression, while rats treated at elevated room temperature (30 degrees C) showed enhanced hyperthermia and similar expression of Hsp70 to that seen in rats housed at 22 degrees C. Fluoxetine-induced inhibition of 5-HT release and hydroxyl radical formation did not modify MDMA-induced Hsp70 expression 3 h later. Four- or 8-day heat shock (elevation of basal rectal temperature by 1.5 degrees C for 1 h) or geldanamycin pre-treatment induced Hsp70 expression and protected against MDMA-induced serotoninergic neurotoxicity without affecting drug-induced hyperthermia. Thus, MDMA-induced Hsp70 expression depends on the drug-induced hyperthermic response and not on 5-HT release or hydroxyl radical formation and pre-induction of Hsp70 protects against the long-term serotoninergic damage produced by MDMA.
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PMID:Evidence for a role of Hsp70 in the neuroprotection induced by heat shock pre-treatment against 3,4-methylenedioxymethamphetamine toxicity in rat brain. 1732 12

Numerous studies support a role for the endogenous 5-hydroxytryptamine (5-HT) system in the hypothermic effect of capsaicin. None of those studies, however, selectively delineate a role for 5-HT reuptake or 5-HT receptors in this regard. In the present investigation, we determined if the blockade of 5-HT reuptake or the activation of 5-HT(1A) or 5-HT(2) receptors modulates capsaicin-evoked hypothermia. The administration of capsaicin (0.2-1mg/kg, i.m.) produced dose-related hypothermia. Fluoxetine (10mg/kg, i.p.), a selective serotonin reuptake inhibitor (SSRI), did not affect body temperature. For combined administration, pretreatment with fluoxetine (10mg/kg, i.p.) significantly attenuated the hypothermia caused by capsaicin (0.5 and 1mg/kg, i.m.). For the 5-HT receptor experiments, we pretreated rats with either WAY 100635, a 5-HT(1A) receptor antagonist, or mianserin, a 5-HT(2) receptor antagonist, and then administered a fixed, hypothermic dose of capsaicin (1mg/kg, i.m.). WAY 100635 (1mg/kg, s.c.) administration did not affect capsaicin-evoked hypothermia. This indicates that 5-HT(1A) receptor activation does not play a major role in the hypothermic effect of capsaicin. In contrast, pretreatment with mianserin (10mg/kg, i.p.) enhanced the hypothermic effect of capsaicin (1mg/kg, i.m.). The present data reveal that capsaicin-evoked hypothermia in rats is attenuated by the blockade of 5-HT reuptake and enhanced by the antagonism of 5-HT(2) receptors.
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PMID:5-HT reuptake and 5-HT2 receptors modulate capsaicin-evoked hypothermia in rats. 1815 35

Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT(1A)) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT(1A) autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT(1A) autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle- and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.
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PMID:Functional status of somatodendritic serotonin 1A autoreceptor after long-term treatment with fluoxetine in a mouse model of anxiety/depression based on repeated corticosterone administration. 2203 71


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