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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA(B) receptor agonists produce hypothermia and motor incoordination. Two GABA(B(1)) receptor subunit isoforms exist, but because of lack of specific molecular or pharmacological tools, the relevance of these isoforms in controlling basal body temperature, locomotor activity, or in vivo responses to GABA(B) receptor agonists has been unknown. Here, we used mice deficient in the GABA(B(1a)) and GABA(B(1b)) subunit isoforms to examine the influence of these isoforms on both baseline motor behavior and body temperature and on the motor-incoordinating and hypothermic responses to the GABA(B) receptor agonists l-baclofen and gamma-hydroxybutyrate (GHB). GABA(B(1b))(-/-) mice were hyperactive in a novel environment and showed slower habituation than either GABA(B(1a))(-/-) or wild-type mice. GABA(B(1b))(-/-) mice were hyperactive throughout the circadian dark phase. Hypothermia in response to l-baclofen (6 and 12 mg/kg) or GHB (1 g/kg), baclofen-induced ataxia as determined on the fixed-speed Rotarod, and GHB-induced hypolocomotion were significantly, but for the most part similarly, attenuated in both GABA(B(1a))(-/-) and GABA(B(1b))(-/-) mice. We conclude that l-baclofen and GHB are nonselective for either GABA(B(1)) receptor isoform in terms of in vivo responses. However, GABA(B(1)) receptor isoforms have distinct and different roles in mediating locomotor behavioral responses to a novel environment. Therefore, GABA(B(1a)) and GABA(B(1b)) isoforms are functionally relevant molecular variants of the GABA(B(1)) receptor subunit, which are differentially involved in specific neurophysiological processes and behaviors.
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PMID:GABAB1 receptor subunit isoforms exert a differential influence on baseline but not GABAB receptor agonist-induced changes in mice. 1699 May 8

The stress-induced hyperthermia procedure, in which effects of drugs on basal (T(1)) and stress-induced body temperature (T(2)) are measured, predicts anxiolytic drug effect. Serotonergic drugs alter these responses and here, we studied the role of 5-HT(1A) receptors in stress-induced hyperthermia by using 5-HT(1A) receptor knockout mice. Three strains (129/Sv, Swiss Webster and C57Bl6) were used because genetic background can significantly modulate the null phenotype. We found that GABA-ergic drugs with an anxiolytic profile and stimulate alpha(2) subunit containing GABA(A) receptors, including diazepam and L838,417, result in reduced DeltaT (DeltaT=T(2)-T(1)). The alpha(1) subunit containing GABA(A) receptor was found to be primarily involved in regulation of basal body temperature T(1) and its stimulation can induce hypothermia. In addition, stimulation of 5-HT(1A) receptors by buspirone results in a reduced DeltaT, while stimulation of 5-HT(7) receptors primarily results in hypothermia. The null mutation of 5-HT(1A) receptors resulted in differences in drug-sensitivity that was further modulated by the genetic background. In particular, the null mutation on the SW and C57Bl6 backgrounds resulted in differential diazepam/L838,417 and 5-CT responses respectively. This indicates an interaction between the 5-HT(1A) receptor and genetic background and demonstrates the importance of selecting the background strain in a receptor knockout model.
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PMID:Effects of genetic background and null mutation of 5-HT1A receptors on basal and stress-induced body temperature: modulation by serotonergic and GABAA-ergic drugs. 1702 70

The use of general anaesthetics has facilitated great advantages in surgery within the last 150 years. General anaesthesia is composed of several components including analgesia, amnesia, hypnosis and immobility. To achieve these components, general anaesthetics have to act via multiple molecular targets at different anatomical sites in the central nervous system. Much of our current understanding of how anaesthetics work has been obtained within the last few years on the basis of genetic approaches, in particular knock-out or knock-in mice. Anaesthetic drugs can be grouped into volatile and intravenous anaesthetics according to their route of administration. Common volatile anaesthetics induce immobility via molecular targets in the spinal cord, including glycine receptors, GABA(A) receptors, glutamate receptors, and TREK-1 potassium channels. In contrast, intravenous anaesthetics cause immobility almost exclusively via GABA(A) receptors harbouring beta3 subunits. Hypnosis is predominantly mediated by beta3-subunit containing GABA(A) receptors in the brain, whereas beta2 subunit containing receptors, which make up more than 50% of all GABA(A) receptors in the central nervous system, mediate sedation. At clinically relevant concentrations, ketamine and nitrous oxide block NMDA receptors. Unlike all other anaesthetics in clinical use they produce analgesia. Not only desired actions of anaesthetics, but also undesired side effects are linked to certain receptors. Respiratory depression involves beta3 containing GABA(A) receptors whereas hypothermia is largely mediated by GABA(A) receptors containing beta2 subunits. These recent insights into the clinically desired and undesired actions of anaesthetic agents provide new avenues for the design of drugs with an improved side-effect profile. Such agents would be especially beneficial for the treatment of newborn children, elderly patients and patients undergoing ambulatory surgery.
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PMID:Anaesthetic drugs: linking molecular actions to clinical effects. 1707 66

This experiment examined the effects of the GABA-B agonist baclofen on flash-evoked potentials (FEPs) recorded from both the visual cortex (VC) and superior colliculus (SC) of chronically implanted male Long-Evans rats. FEPs were recorded at 5, 25, 45, and 65 min following intraperitoneal injections of saline, and of 1.25, 2.5, 5.0, and 10.0 mg/kg baclofen on separate days. In the VC, the amplitude of components P(23), P(37), N(55), N(150), and P(242) increased, while the amplitude of components N(31) and P(48) decreased following baclofen administration. P(88) was unchanged. In the SC, components P(28), N(49), N(55), and N(59) were reduced in amplitude, while P(39) was unaffected by baclofen. These effects on amplitudes were dose- and time-dependent. Many peak latencies in the VC and SC were altered by baclofen, although there was no obvious pattern of change, with some decreasing, a few increasing, and others unchanged. Body temperature was recorded in a separate group of animals, with both the 5.0 and 10.0 mg/kg doses of baclofen producing significant hypothermia. The 10.0 mg/kg dose of baclofen resulted in a significant decrease in movement during the recording sessions, but not in subsequent open field observations. The results show the involvement of GABA-B receptors in the production/modulation of the various components of FEPs.
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PMID:Baclofen alters flash-evoked potentials in Long-Evans rats. 1740 91

The endogenous brain constituent, gamma-hydroxybutyric acid (GHB), as well as its prodrug, gamma-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the gamma-aminobutyric acid(B) (GABA(B)) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABA(B) receptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABA(B)-receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation/hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABA(B)-receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation /hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABA(B) receptor.
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PMID:Gamma-aminobutyric acidB (GABAB)-receptor mediation of different in vivo effects of gamma-butyrolactone. 1827 Apr 75

Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safety-feasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6h therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials. This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized.
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PMID:Neuroprotection for ischemic stroke: past, present and future. 1830 47

There is a growing body of data to support the notion that GABA(B) receptors may be a therapeutic target for anxiety disorders. However, the application of GABA(B) receptor agonists in anxiety research and psychiatry is hampered by side effects that include motor in-coordination and hypothermia. Recently the GABA(B) receptor positive modulator GS39783 was shown to be anxiolytic in rodent models, but was devoid of accompanying side effects characteristic of full agonists. However, it is important to test whether such anxiolytic effects generalise to another chemical class of GABA(B) receptor positive modulators. We therefore aimed to investigate the anxiolytic and side-effect profile of CGP7930, the first-reported GABA(B) receptor positive modulator, in rodent models of anxiety, motor coordination and hypothermia. CGP7930 (3-300 mg/kg) showed a modest, compared to the benzodiazepine chlordiazepoxide (10mg/kg), dose-dependent anxiolytic profile in the mouse stress-induced hyperthermia (100mg/kg), staircase (100 and 300 mg/kg) and elevated zero maze tests (3-100mg/kg), but did not have any anxiolytic effects in the rat elevated plus maze. Similar to GS39783, CGP7930 also demonstrated a greatly reduced side-effect profile in comparison to the GABA(B) receptor full agonist baclofen in the mouse rotarod and traction wire tests and did not induce hypothermia. Although the effects of CGP7930 were modest, these results represent a second, structurally distinct, class of GABA(B) positive modulators showing anxiolytic activity. As such, these data support the premise that GABA(B) receptor positive modulation represents a novel therapeutic strategy for the development of anxiolytic drugs with a superior side-effect profile. The generation of more potent compounds is now warranted.
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PMID:Evaluation of the anxiolytic-like profile of the GABAB receptor positive modulator CGP7930 in rodents. 1832 7

Morbidity and mortality of subarachnoid hemorrhage (SAH) are correlated with the severity of the patient's acute neurological deficit. This initial presentation has been attributed to cerebral hypoperfusion in the acute phase, and we investigated the impact of moderate hypothermia on the early changes in perfusion and metabolism following massive experimental SAH. SAH was induced in 61 anesthetized rats by rapid injection of 0.5 mL of arterial blood into the cisterna magna. In normothermia (NT), animals were kept at 37 degrees C, while in the primary hypothermia (pHT) group, temperature was lowered to 32 degrees C prior to SAH, and in the secondary hypothermia (sHT) group, cooling was started immediately after SAH. From 30 min prior to 180 min after SAH, Laser-Doppler-flowmetry (LDF) probes allowed online recording of cerebral blood flow (CBF) while parenchymal dialysate was collected by microdialysis probes within the frontoparietal cortex. In NT, the acute phase was characterized by impaired autoregulation and prolonged hypoperfusion. In pHT and sHT, autoregulation was preserved and acute hypoperfusion rapidly improved. SAH also caused a highly significant reduction in glucose in NT only. pHT significantly reduced accumulation of lactate, glutamate, and aspartate. Comparable trends were present for histidine, GABA, and taurine, while glutamine consumption was ameliorated. Early perfusion deficits caused by acute hypoperfusion and disruption of cerebral autoregulation can be ameliorated by hypothermia. Also, the acute phase of experimental SAH is characterized by glucose depletion, lactate accumulation, and release of excitatory amino acids, which can be influenced favorably by hypothermia.
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PMID:Hypothermia reduces early hypoperfusion and metabolic alterations during the acute phase of massive subarachnoid hemorrhage: a laser-Doppler-flowmetry and microdialysis study in rats. 1835 24

This experiment examined the separate and combined effects of baclofen (5.0 mg/kg, i.p.), a GABA B receptor agonist, and ethanol (2.0 g/kg, i.p.) on flash-evoked potentials (FEPs) recorded from both the visual cortex and superior colliculus (SC) of chronically implanted male Long-Evans rats. In the visual cortex, ethanol significantly decreased the amplitude of positive component P87, but increased P37 and P47. Other component amplitudes were not significantly altered. In contrast, baclofen reduced the amplitude of negative component N31 to such an extent that it became positive. Although P47 was also reduced by baclofen, the amplitude of most other components was increased. Only P24 and P87 were unchanged by baclofen. The combination of baclofen and ethanol resulted in amplitudes very similar to ethanol alone for secondary components P47, N62, and P87, but very similar to baclofen alone for primary component N31 and late components N147 and P230. In the SC, component amplitudes were generally decreased by ethanol, baclofen, and the combination treatment. Latencies of most components in both structures were increased by the drug treatments. Each drug treatment produced significant hypothermia. Locomotor behavior was also altered. These results demonstrate: (1) pharmacological differences between the primary and late components versus the secondary components of the cortical FEP, (2) that baclofen does not counteract significant effects of ethanol on cortical or collicular component amplitudes, and (3) that baclofen enhances N147-P230 amplitude, suggesting reduced cortical arousal.
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PMID:Baclofen does not counteract the acute effects of ethanol on flash-evoked potentials in Long-Evans rats. 1885 34

gamma-Hydroxybutyrate (GHB) is a euphoric, prosocial and sleep inducing drug that binds with high affinity to its own GHB receptor site and also more weakly to GABA(B) receptors. GHB is efficacious in the treatment of narcolepsy and alcoholism, but heavy use can lead to dependence and withdrawal. Many effects of GHB (sedation, hypothermia, catalepsy) are mimicked by GABA(B) receptor agonists (e.g. baclofen). However other effects (euphoric and prosocial effects and a therapeutic effect in narcolepsy) are not. The present study used Fos immunohistochemistry to assess the neural activation produced in rat brain by medium to high doses of GHB (250, 500 and 1000 mg/kg) and a high dose of baclofen (10 mg/kg) that produced similar sedation to 500 mg/kg GHB. Results showed many common regions of activation with these two drugs including the supraoptic, paraventricular, median preoptic and ventral premammillary nuclei of the hypothalamus, the central nucleus of the amygdala, Edinger-Westphal nucleus, lateral parabrachial nucleus, locus coeruleus, and nucleus of the solitary tract. GHB (500 mg/kg), but not baclofen (10 mg/kg), induced significant Fos expression in the median raphe nucleus and lateral habenula, while a higher dose of GHB (1000 mg/kg) induced additional Fos expression in the islands of Calleja, dentate gyrus (polymorphic layer) and arcuate nucleus, and in various regions implicated in rapid and non-rapid eye movement sleep (laterodorsal tegmental nucleus, tuberomammillary nucleus and the ventrolateral and anterodorsal preoptic nuclei). Surprisingly, Fos immunoreactivity was not observed with either GHB or baclofen in reward-relevant regions such as the nucleus accumbens, striatum and ventral tegmental area. Overall these results indicate a distinctive signature of brain activation with GHB that may be only partly due to GABA(B) receptor effects. This confirms a unique neuropharmacological profile for GHB and indicates key neural substrates that may underlie its characteristic influence on sleep, body temperature, sociability and endocrine function.
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PMID:The distribution of gamma-hydroxybutyrate-induced Fos expression in rat brain: comparison with baclofen. 1899 47


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