Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows that s.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.
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PMID:Differential serotoninergic and dopaminergic activities of the (R)- and the (S)-enantiomers of 2-(di-n-propylamino)tetralin. 881 61

Bromocriptine, a potent dopamine D2 receptor agonist, appears to have neuroprotective actions. In order to investigate the effect of bromocriptine on axotomy-induced cell death, we have examined the survival of spinal motor neurons after sciatic nerve transection in the neonatal rats. Newborn rats were anesthetized with hypothermia. Sciatic nerve was transected near the obturator tendon in the left thigh. Animals were then treated daily with bromocriptine for 14 days with intraperitoneal injections. Control animals received PBS in the same fashion. After the treatment, the number of spinal motor neurons in the L4-6 was counted. There is approximately a 50% loss of spinal motor neurons in the PBS treated group. By contrast, bromocriptine prevents spinal motor neuron death after axotomy. The motor neuron diameter on the lesioned side is significantly larger in the bromocriptine-treated group. These results are consistent with the possible role of bromocriptine as a survival factor for developing spinal motor neurons.
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PMID:Bromocriptine prevents spinal motor neuron death following sciatic nerve transection in neonatal rats. 887 3

The present study was designed to examine a possible interaction between dopamine D1 and D2/3 receptors involved in thermoregulation in rats. The dose-dependent hypothermia produced by the dopamine D1 receptor agonist A 68930 (0.9-15.0 micromol kg-1, s.c.), was augmented in an additive manner by pretreatment with the dopamine D2/3 receptor agonist 7-OH-DPAT (0.06 micromol kg-1, s.c.). The dose-dependent hypothermia produced by 7-OH-DPAT (0.06-1.00 micromol kg-1 s.c.) was also augmented in an additive manner by pretreatment with A 68930 (0.9 micromol kg-1 s.c.). In contrast to these observations, locomotor activity measurements disclosed a marked interaction between the dopamine D1 and D2/3 receptor agonists. Thus, A 68930 (0.9-15.0 micromol kg-1, s.c.) produced a dose-dependent suppression of open-field locomotor activity. The addition of 7-OH-DPAT (1.00 micromol kg-1, s.c.), which by itself produced a weak suppression of locomotor activity, resulted in a gradual reversal of the A 68930-induced suppression of the locomotor activity. Thus, the present results provides strong support for an independent role of dopamine D1 receptors in rat thermoregulatory mechanisms, distinct from effects mediated via the dopamine D2 receptor family.
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PMID:Independent roles of dopamine D1 and D2/3 receptors in rat thermoregulation. 950 18

Ro4-1284 (2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2H-benzo[a] quinolizin-2-ol hydrochloride), a benzoquinolizine, is a potent dopamine depletion agent whose acute and chronic administration results in a (1) deterioration of learning in the Morris Water Maze and passive avoidance tasks, (2) decrease in locomotion and rearing, (3) intense hypothermia, and (4) decrease in the percentage of polyunsaturated fatty acids and an increase in the level of cholesterol in neuronal membranes. Pretreatment with a specific mixture of free polyunsaturated fatty acids prevents most of the behavioral, physiological, and biochemical effects of Ro4-1284 except for rearing. We propose that the dopamine-mediated functions tested in this study are dependent on the interaction of intact dopamine D1 and D2 receptors. Rearing, which is controlled only by dopamine D1 receptors, remained, therefore, unaffected. Our hypothesis is that SR-3 exerts its beneficial effects by normalizing the structure and function of the neuronal membrane and by restoring dopamine D2 receptor functions.
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PMID:Treatment with a polyunsaturated fatty acid prevents deleterious effects of Ro4-1284. 998 19

The atypical antipsychotic olanzapine (2.5-20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5-20 mg/kg) was blocked by the selective dopamine D2 receptor antagonist pimozide (0.5 and 1 mg/kg) but not by the dopamine D1 receptor antagonist SCH 23390 (0.5 and 1 mg/kg). The dopamine D1/D2 receptor agonist apomorphine (3 mg/kg) and the selective dopamine D2 receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D2 receptor populations involved in thermoregulation in the rat.
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PMID:Antagonism by pimozide of olanzapine-induced hypothermia. 1052 Jul 26

Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake.
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PMID:A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy expenditure. 1128 60

While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED50 = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)1A, 5HT2C, and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D2 receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out.
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PMID:Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems. 1156 Oct 96

The tetrahydrobenzindole, 2a-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl)-2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one (DR4004) has been described as a highly selective antagonist for the 5-hydroxytryptamine(7) (5-HT(7)) receptor [J. Med. Chem. 42 (1999) 533]. Consistent with original data, DR4004 bound to rat hypothalamic membranes with an affinity of 7.3+/-0.2 (pK(i)+/-S.E.M.) for the 5-HT(7) receptor. However, competition binding studies showed that DR4004 had poor receptor selectivity with the following affinity profile; dopamine D2 receptor, alpha(1)-adrenoceptor > or =5-HT(7) receptor>histamine H(1) receptor, alpha(2)-adrenoceptor>dopamine D1 receptor>beta-adrenoceptor, muscarinic and 5-HT(2A/C) receptors. In conscious rats DR4004 (1, 5 or 10 mg/kg i.p.) produced a dose-dependent hyperglycaemia and hypothermia, but the former was reduced by the dopamine D2 receptor antagonist raclopride. Another 5-HT(7) receptor antagonist, (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) produced hypothermia but no hyperglycaemia. This study confirms that DR4004 has high affinity for the 5-HT(7) receptor but suggests that dopamine D2 receptor activity contributes to some of the in vivo effects.
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PMID:DR4004, a putative 5-HT(7) receptor antagonist, also has functional activity at the dopamine D2 receptor. 1216 13

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') administration to rats produces hyperthermia if they are housed in normal or warm ambient room temperature (Ta) conditions (>or=20 degrees C), but hypothermia when in cool conditions (Ta<or=17 degrees C). We have now investigated some of the mechanisms involved. MDMA (5 mg kg(-1) i.p.) produced a rapid decrease in rectal temperature in rats at Ta 15 degrees C. This response was blocked by pretreatment with the dopamine D2 receptor antagonist remoxipride (10 mg kg(-1) i.p.), but unaltered by pretreatment with the D1 antagonist SCH23390 (1.1 mg kg(-1) i.p). MDMA (5 mg kg(-1)) did not alter the tail temperature of rats at Ta 15 degrees C, but decreased the tail temperature of rats at Ta 30 degrees C. A neurotoxic dose of MDMA (three doses of 5 mg kg(-1) given 3 h apart) decreased cortical and hippocampal 5-HT content by approximately 30% 7 days later. This lesion did not influence the rise in tail temperature when rats were moved from Ta 20 degrees C to 30 degrees C compared to nonlesioned controls, but did result in a lower tail temperature than that of controls when they were returned to Ta 24 degrees C. Acute administration of MDMA (5 mg kg(-1)) to MDMA-lesioned rats produced a sustained decrease in tail temperature in rats housed at Ta 30 degrees C compared to nonlesioned controls. These data suggest that the thermoregulatory problems previously observed in MDMA-lesioned rats housed at Ta 30 degrees C result, partially, from their inability to lose heat by vasodilation of the tail, a major heat-loss organ in this species.
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PMID:Studies on the effect of MDMA ('ecstasy') on the body temperature of rats housed at different ambient room temperatures. 1599 30

Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct- and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole.
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PMID:Food restriction alters N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: evidence for sensitization of dopamine D2 receptor-mediated effects. 1830 18


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