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)

Two new congeners, 4-(chloropropyl)-1-(2-quinolyl)piperazine- and 2-[3-[4-[2-(quinolyl)]-1-piperazinyl]propyl]-1,2,4-triazolo] 4,3-a]pyridin-3(2H)-one, of trazodone were synthesized and found to be potent and selective inhibitors of synaptosomal uptake of 5-hydroxytryptamine [5-HT, serotonin; IC50 = norepinephrine greater than 5 microM, 5-HT = 210-890 nM], with minimal effects in antagonizing (-)-apomorphine-induced climbing behavior and suppression of spontaneous locomotor activity in mice (ED50 greater than 50 mg/kg). The two compounds behaved like atypical antidepressants, since they weakly antagonized reserpine-induced hypothermia. The acute toxicity studies have shown that these compounds were less lethal when compared with imipramine or quipazine. Furthermore, chronic treatments (20 mg/kg, daily for 10 and 21 days) significantly decreased the isoprenaline-induced increase in cyclic AMP in the rat brain cortex, suggesting desensitization of beta-adrenoceptors. These findings point to the effects of these compounds as potential antidepressants dealing with specific serotonergic mechanisms.
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PMID:New hybrids of quipazine and trazodone as selective inhibitors of uptake of 5-hydroxytryptamine. 132 Jan 18

Caffeine and other methylxanthines induce a dose-dependent reduction in core body temperature in mice. These experiments investigated the effects of neurotransmitter and neuromodulator antagonists on caffeine-induced hypothermia. Pretreatment with the alpha 2-adrenoceptor antagonist, atipamezole; the beta-adrenoceptor antagonist, propranolol; the dopamine antagonist, haloperidol; or the benzodiazepine receptor antagonist, flumazenil had no intrinsic effects on core body temperature nor did they interact significantly with the hypothermic effects of caffeine. The alpha 1-adrenoceptor antagonist, prazosin and the 5-HT receptor antagonist, metergoline significantly enhanced the hypothermic effects of caffeine, probably involving a combined effect with their intrinsic hypothermic actions. Pretreatment with the opiate receptor antagonist, naloxone (3 mg/kg i.p.), had no intrinsic effect on core body temperature but attenuated the hypothermic effect of caffeine reflected in a parallel shift to the right in the caffeine dose-effect curve. The naloxone-induced attenuation of the hypothermic effects of caffeine was also seen to be dose-dependent. The results reveal that opiate receptors (but not adrenoceptors, 5-HT, dopamine or benzodiazepine receptors) may play a role in modulating the hypothermic action of caffeine and possibly other methylxanthines.
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PMID:Opioid receptor mediation of the hypothermic response to caffeine. 133 37

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.
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PMID:5-HT1A receptor-effector system responsivity in panic disorder. 134 19

Alcohol preference and manifestation of alcoholism are thought by many to be associated with serotonin (5-HT) dysfunction in the brain. Thus, experiments were performed to determine the effect of acute and subchronic administration of (+/-) 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine analog that stimulates 5-HT release, on alcohol preference in two strains of alcohol-preferring rats, the Fawn-Hooded (FH) and alcohol-preferring (P) rats. Rats were individually housed and provided free access to a solution of 10% ethanol, food, and water. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline for ethanol and water intake, each rat was injected SC with a dose of 5.0 mg/kg MDMA or an equal volume of saline for 1 or 3 consecutive days. Body temperature was recorded immediately before and 120, 240, and 360 min after MDMA treatment. Ethanol, food, and water intake were measured for the preceding 24 h. Further, to determine the effect of MDMA on alcohol metabolism rats were injected with 5.0 mg/kg MDMA or saline and 15 min later with 2.5 g/kg alcohol. Then, blood alcohol levels were determined at 1, 3, and 5 h after alcohol administration. Our results show that a single administration of 5.0 mg/kg MDMA significantly decreased ethanol intake in both FH and P rats and increased water intake. Subchronic administration of 5.0 mg/kg MDMA for 3 consecutive days significantly attenuated alcohol intake in both strains but only increased water intake in P rats. Administration of MDMA induced hyper- and hypothermia in FH and P rats, respectively. This drug failed to exert any significant effect on the pharmacokinetics of alcohol, indicating a central effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Attenuation of alcohol consumption by MDMA (ecstasy) in two strains of alcohol-preferring rats. 135 75

The mixed 5-hydroxytryptamine1A (5-HT1A) receptor agonist/antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol-[4.5]- decane-7,9-dione (BMY 7378) (5 mg/kg) did not significantly depress body temperature, but pretreatment with BMY 7378 blocked hypothermia induced by the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In contrast, another partial 5-HT1A agonist, pindolol (10 mg/kg), slightly but significantly depressed body temperature by itself but did not attenuate hypothermia elicited by 8-OH-DPAT. Attempts to identify the synaptic locus of the receptor were unsuccessful because depletion of central serotonin (5-HT) by treatment with para-chlorophenylalanine (PCPA; 3 x 150 mg/kg) did not alter the hypothermic response to 8-OH-DPAT. Partial, irreversible 5-HT1A receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (1 mg/kg) reduced the maximal hypothermic effect of 8-OH-DPAT (to 53% of control) without altering its ED50 (0.96 mg/kg). Analysis of the data indicated a linear relationship between 5-HT1A receptor occupancy and hypothermic response, that is, absence of receptor reserve. When groups of mice were treated with each of five different doses of 8-OH-DPAT (0.04, 0.16, 0.63, 2.5, and 10 mg/kg) 48 h apart, there was a significant reduction in hypothermic response after the second injection, but only at the three highest doses. The results demonstrate that 8-OH-DPAT-induced hypothermia in mice is mediated by a 5-HT1A receptor whose synaptic localization is uncertain but that has no receptor reserve. In addition, tolerance is observed after only a single agonist treatment.
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PMID:Serotonin 5-HT1A receptor-mediated hypothermia in mice: absence of spare receptors and rapid induction of tolerance. 135 73

The administration of TCP (15 mg/kg, i.p.) to rats pretreated with either intraperitoneal RbCl (3 mmol/kg, twice daily for 5 days) or dietary RbCl (30 mmol/kg diet, for 14 days), resulted in the complete 5-HT behavioural syndrome. Pretreatment with p-chlorophenylalanine (i.p. 300 mg/kg x2) or (-)-propranolol (20 mg/kg, i.p.), pindolol (4 mg/kg, i.p.) and ritanserin (0.4 mg/kg, s.c.) prevented the occurrence of the 5-HT syndrome, produced by dietary RbCl plus TCP. Intraperitoneal administration of RbCl had no effect upon the 5-HT behavioural syndrome, produced by 8-OH-DPAT (0.5 mg/kg, s.c.) or 5-MeODMT (2 mg/kg, i.p.) but enhanced the 5-HT syndrome produced by quipazine (20 mg/kg, i.p.), DOI (8 mg/kg, s.c.), p-chloramphetamine (4 mg/kg, i.p.) or by TCP plus L-tryptophan (50 mg/kg, i.p.) in rats. Dietary administration of RbCl resulted in the enhancement of the 5-HT2-mediated head-twitches in the mouse and the attenuation of hypothermia in the mouse, induced by 8-OH-DPAT (0.5 mg/kg, s.c.). The accumulation of 5-HT (after inhibition of monoamine oxidase) and the rate of synthesis of 5-HT in the whole brain (minus cerebellum) were enhanced by dietary and intraperitoneal administration of RbCl, respectively. The effects of lithium and rubidium, respectively, on 5HT function in brain are compared.
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PMID:The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse--1. Rubidium. 138 43

To study the regulation of 5-HT1A receptors in the brainstem, the region most relevant to the serotonin syndrome and to serotonin-responsive human myoclonic disorders, we chronically treated rats with various 5-HT1A agonists and labeled 5-HT1A sites with [3H]8-OH-DPAT. Daily injection for 30 consecutive days of 10 mg/kg ip 8-OH-DPAT (pre- and post-synaptic 5-HT1A agonist) significantly decreased 8-OH-DPAT-evoked flat body posture, forelimb myoclonus, and hypothermia compared to chronic vehicle injection. There was no cross tolerance to 8-OH-DPAT in rats chronically injected with ipsapirone or buspirone (presynaptic 5-HT1A agonists). However, none of the 5HT1A agonists significantly altered Bmax of brainstem 5-HT1A binding sites. Chronic injection with other drugs such as 1-propranolol, (+/-) pindolol and spiperone (5-HT1A and 5-HT2 antagonists), methysergide (5-HT1 and 5-HT2 antagonist), and agonists and antagonists at various other 5-HT receptors also had no effect on binding parameters. These data demonstrate lack of cross-tolerance between pre- and post-synaptically acting 5-HT1A agonists and absence of down-regulation of presynaptic 5-HT1A sites at doses which induced tolerance of 5-HT1A-mediated behaviors of the serotonin syndrome. They suggest changes in the post-synaptic cell rather than the receptor recognition site as the mechanism of tolerance.
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PMID:Brainstem 5-hydroxytrytamine1A binding sites are not down-regulated by agonists which induce tolerance in the rat: myoclonus and other serotonergic behaviors. 138 64

It has been shown that caesium, which shares properties with quinine as a K(+)-channel blocker, enhanced 5-HT-mediated behaviour in both rats and mice. It was therefore of interest to investigate the effects of quinine on 5-HT-mediated behaviour in the rat and mouse. Quinine, dose-dependently (ED50 = 5 mg/kg), produced the 5-HT behavioural syndrome in rats pre-treated with tranylcypromine (TCP) (15 mg/kg, i.p.). p-Chlorophenylalanine (i.p., 300 mg/kg x2) or (-)-propranolol (20 mg/kg, i.p.), pindolol (4 mg/kg, i.p.) and ritanserin (0.4 mg/kg, s.c.), all prevented the behavioural syndrome induced by quinine (72 mg/kg, i.p.) plus TCP. The administration of quinine (72 mg/kg, i.p.) enhanced the 5-HT syndrome elicited by p-chloramphetamine (4 mg/kg, i.p.) and the 5-HT agonists, 8-OH-DPAT (0.5 mg/kg, s.c.), 5-MeODMT (2 mg/kg, i.p.), DOI (8 mg/kg, s.c.) and quipazine (25 mg/kg, i.p.) in rats. Pretreatment with quinine also potentiated the 5-HT2-mediated head-twitch in the mouse but had no effect on the hypothermia in the mouse, induced by 8-OH-DPAT (0.5 mg/kg, s.c.). Quinine also enhanced the rate of synthesis of 5-HT in the brain of the rat. On the basis of these findings, together with those in the preceding two papers, it is suggested that the effects of rubidium, caesium and quinine, to enhance differentially various aspects of 5-HT function are mediated by actions on 5-HT-modulated K(+)-channels. This conclusion is also discussed in relation to the actions of lithium and electroconvulsive shock on 5-HT function in brain and the treatment of manic-depressive disease.
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PMID:The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse--3. Quinine. 138 54

L-Methionine-D,L-sulfoximine (MSO) intraperitoneally or intracerebroventricularly (third ventricle) injected at convulsant doses induced a hypothermia, primarily associated with a syndrome of ataxia, in the restrained rat maintained at an ambient temperature of 23 degrees C. Depletion of brain serotonin (5-HT) by pretreatment with p-chlorophenylalanine (PCPA), p-chloroamphetamine (PCA), and d-fenfluramine (FFA) did not significantly modify the time course and magnitude of MSO-induced developing hypothermia but it enhanced abnormal motor behavior. Enhancement of 5-HT synthesis in MSO-submitted rats pretreated with 5-hydroxytryptophan (5-HTP) (200 mg/kg, IP) alone or 5-HTP (100 mg/kg, IP) preassociated with carbidopa (10 mg/kg, IP) suppressed significantly hypothermia, but it did not greatly modify motor disturbances. In conclusion, the neurocytochemical processes initiating hypothermia following administration of MSO to the rat appear to be linked to a slowdown of the rate of brain 5-HT turnover, maybe at the level of the midbrain raphe nuclei.
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PMID:Possible link between brain serotonin metabolism and methionine sulfoximine-induced hypothermia and associated behavior in the rat. 140 1

Rats and mice were given either CsCl (3 mmol/kg, s.c.) or saline (as control), twice daily for 3 days. The administration of tranylcypromine (TCP) (15 mg/kg, i.p.) to rats pretreated with CsCl produced the 5-HT behavioural syndrome. Pretreatment with CsCl also enhanced the syndrome induced by p-chloroamphetamine (3 mg/kg, i.p.) or by TCP (15 mg/kg, i.p.) plus L-tryptophan (50 mg/kg, i.p.). p-Chlorophenylalanine (300 mg/kg, i.p., daily on 2 consecutive days) or (-)-propranolol (20 mg/kg, i.p.), pindolol (4 mg/kg, i.p.) and ritanserin (0.4 mg/kg, s.c.), all prevented the behavioural syndrome induced by CsCl and TCP in rats. Pretreatment of rats with CsCl potentiated the 5-HT syndrome, elicited by the 5-HT agonists, 8-OH-DPAT (0.5 mg/kg, s.c.), 5-MeODMT (2 mg/kg, s.c.) and quipazine (25 mg/kg, i.p.). Pretreatment with CsCl potentiated the 5-HT2-mediated head-twitches in the mouse but had no effects on hypothermia in the mouse induced by 8-OH-DPAT (0.5 mg/kg, s.c.). The rate of synthesis of 5-HT in the whole brain (excluding cerebellum) was enhanced by pretreatment with CsCl. The enhancement of 5-HT neuronal function by caesium may be related to its ability to block K(+)-channels in neuronal membranes.
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PMID:The effects of rubidium, caesium and quinine on 5-HT-mediated behaviour in rat and mouse--2. Caesium. 152 94


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