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PubMed1999

Opening of potassium channels: the common cardioprotective link between preconditioning and natural hibernation?

BACKGROUND: The tolerance of hibernating mammals to cold hypoxia is related to a factor similar to agonists of delta-opioid receptors. This study was designed to assess whether activation of these receptors could reproduce the protection conferred by ischemic preconditioning and whether such cardioprotection was similarly mediated by an opening of ATP-sensitive potassium (KATP) channels. METHODS AND RESULTS: Thirty-two isolated rat hearts were arrested with and stored in Celsior at 4 degrees C for 5 hours before being reperfused for 2 hours. They were divided into 4 equal groups. Group 1 hearts served as controls. In group 2, ischemic preconditioning was elicited by two 5-minute global ischemia periods interspersed with 5 minutes of reperfusion before arrest. In group 3, hearts were pharmacologically preconditioned with a 15-minute infusion of the delta-opioid receptor agonist D-Ala2-D-Leu5-enkephalin (DADLE; 200 micromol/L). In group 4, the protocol was similar to group 3 except that infusion of DADLE was preceded by infusion of the KATP blocker glibenclamide (50 micromol/L). The salutary effects of both forms of preconditioning were primarily manifest as a better preservation of diastolic function, a reduced myocardial edema, and reduced creatine kinase leakage. This protection was abolished by administration of glibenclamide before DADLE. CONCLUSIONS: These data suggest that activation of delta-opioid receptors improves recovery of cold-stored hearts to a similar extent as ischemic preconditioning, most likely through an opening of KATP channels. This provides a rationale for improving the preservation of hearts for transplantation by pharmacologically duplicating the common pathway to natural hibernation and preconditioning.

Animals↗
PubMed2000

The cardiovascular responses of the red-eared slider (Trachemys scripta) acclimated to either 22 or 5 degrees C. I. Effects of anoxic exposure on in vivo cardiac performance.

The extreme anoxia-tolerance of freshwater turtles under cold conditions is well documented, but little is known about their cardiac performance in such situations. Using chronic catheterization techniques, we measured systemic cardiac power output (PO(sys)), systemic cardiac output (Q(.)(sys)), heart rate (fh), systemic stroke volume (V(s,sys)), systemic resistance (R(sys)) and mean arterial pressure (P(sys)) in red-eared sliders (Trachemys scripta). The effects of cold acclimation and anoxic exposure were studied. Turtles were acclimated to either 22 degrees C or 5 degrees C, and the anoxic exposure was either acute (6 h) at 22 degrees C or chronic (3 weeks) at 5 degrees C. Cold acclimation alone decreased PO(sys) by 15-fold, representing a Q(10) of 8.8. In addition, fh and V(s,sys) decreased significantly, while R(sys) increased and moderated the arterial hypotension. Acute and chronic anoxic exposures significantly decreased PO(sys), V(s,sys), fh and P(sys) and increased R(sys). But the changes were qualitatively much larger with chronic anoxia. For example, acute anoxia in 22 degrees C-acclimated turtles decreased PO(sys) by 6.6-fold, whereas chronic anoxia in 5 degrees C-acclimated turtles decreased PO(sys) by 20-fold. The remarkable cardiovascular down-regulation that accompanies long periods of cold anoxia in these turtles was characterized by comparing cardiovascular status during chronic anoxia at 5 degrees C with that during normoxia at 22 degrees C. Cardiac PO(sys) was reduced 330-fold, through decreases in Q(.)(sys) (120-fold), fh (24.2-fold), V(s,sys) (5.7-fold) and P(sys) (2. 2-fold), while R(sys) was increased 64.6-fold. We also compared cardiac glycolytic rates by assuming that PO(sys) was proportional to ATP supply and that glycolysis yielded 18 times less ATP per mole of glucose than oxidative metabolism. At 22 degrees C, the 6.6-fold decrease in PO(sys) with anoxia suggests that a Pasteur effect was needed in cardiac tissues during acute anoxia. However, this would not be so with chronic anoxia at 5 degrees C because of the 22-fold decrease in PO(sys). We propose that the suppression of the Pasteur effect and the large Q(10) values for cold acclimation would conserve glucose stores and enable turtles to withstand anoxia much longer under cold than under warm conditions.

Adaptation, Physiological↗
PubMedDate not supplied

Humidification for oxygen therapy in non-ventilated patients.

Oxygen therapy is a necessary treatment for some patients in hospital; however, as with any treatment there are side effects. These include drying and cooling of the respiratory tract. This can lead to unpleasant side effects discouraging patients from continuing with their treatment. To overcome this there are a variety of humidification devices, both heated and cold, which can help people tolerate their treatment. This article will discuss the AQUAPAK system which humidifies dry oxygen making it more comfortable for the patient to breathe and preventing dehydration of the respiratory system.

Equipment Design↗
PubMed2000

Advances in the prophylaxis and treatment of influenza illness. Based on a presentation by Frederick G. Hayden, MD.

Vaccine represents the primary means of preventing influenza. Although influenza vaccines provide a high rate of protection in young and ambulatory elderly, a lower rate of protection occurs in the frail elderly and immunocompromised hosts. Researchers have developed new vaccine strategies that use live attenuated, cold-adapted virus vaccines. In children, this cold-adapted influenza vaccine appears to offer broader protection than the classic inactivated vaccine given by injection. It was protective against an antigenic variant, and by protecting against influenza, it reduces influenza-related complications, such as otitis media and lower respiratory tract illness, as well as lessens antibiotic use associated with these complications. Cold-adapted vaccine is well tolerated and represents a very exciting advance in influenza vaccines. Two drugs, amantadine and rimantadine, have received Food and Drug Administration approval for the prophylaxis and treatment of influenza A virus infection. However, their use is limited by side effects, particularly with amantadine, in elderly people (an activity limited to influenza A) and the emergence of resistance. A new class of specific anti-influenza agents, the neuraminidase inhibitors, has demonstrated potent inhibition of both influenza A and B viruses. Two neuraminidase inhibitors, inhaled zanamivir and oral oseltamivir, have reached advanced clinical development and were approved for treatment of acute influenza in the United States in 1999. Both drugs have shown clinical efficacy both in treating and preventing influenza illness.

Antiviral Agents↗
PubMed1977

Structural changes in temporarily ischaemized and reperfused dog kidneys.

The functional and structural study of the ischaemic renal parenchyma has become a central problem from the aspects of kidney transplantation. Reliable data are needed to establish the tolerance of separate or simultaneous cold and warm ischaemia. The changes appearing after 1- and 2-hour ligation of the renal artery (warm ischaemia) followed by autogeneous reperfusion after 3 to 24 hours were analysed on dog kidneys by means of light and electron microscopy. After 1 hour ligation, the changes seem fully reversible as the structures (mitochondria, basal membranes, brush border) suffer no fundamental lesion in spite of a general oedema. In contrast, 2-hour ischaemia caused serious morphological lesions (breaking up of the mitochondrial cristae, decay of the brush border, cell desquamation, necrosis, extensive oedema) leading to no-reflow phenomenon and irreversibility.

Animals↗
PubMed1976

Responses of the autonomic nervous system during acclimatization tp high altitude in man.

A study has been conducted on 20 sojourners, between the ages of 20-30 years, to evaluate responses of the autonomic nervous system during acclimatization to high altitude. The responses measured consisted of heart rate (HR), blood pressure (BP), oral temperature (Tor), mean skin temperature (Tsk), cold pressor response (CPR), orthostatic tolerance to tilt, and urinary catecholamines. The subjects were tested initially at Delhi (altitude 260 m) and thereafter, on acute induction to an altitude of 3500 m periodically for 3 weeks. For comparison, the same responses were studied on 10 acclimatized lowlanders (AL) who had been staying at the same altitude for more than a year and on 10 high-altitude natives (HAN). The studies showed a rise in HR, BP, Tor, and urinary catecholamines, and a fall in Tsk, CPR, and orthostatic tolerance immediately on arrival at HA, indicating a relative hyperactivity of the sympathetic system. After a stay of 1 week, there was a gradual recovery in all the responses, though sympathetic hyperactivity was still maintained throughout the 3 weeks of stay. In AL also there was a preponderance of sympathetic activity, though of relatively lesser magnitude than that seen in sojourners. In HAN, on the other hand, there was a relative parasympathetic predomination. It has been concluded that in lowlanders it takes more than a year of stay at altitude for complete recovery of autonomic balance.

Acclimatization↗
PubMed2003

Novel plasmodesmata association of dehydrin-like proteins in cold- acclimated Red-osier dogwood (Cornus sericea).

Dehydrins are proteins associated with conditions affecting the water status of plant cells, such as drought, salinity, freezing and seed maturation. Although the function of dehydrins remains unknown, it is hypothesized that they stabilize membranes and macromolecules during cellular dehydration. Red-osier dogwood (Cornus sericea L.), an extremely freeze-tolerant woody plant, accumulates dehydrin-like proteins during cold acclimation and the presence of these proteins is correlated with increased freeze tolerance (Karlson 2001, Sarnighausen et al. 2002, Karlson et al. 2003). Our objective was to determine the location of dehydrins in cold-acclimated C. sericea stems in an effort to provide insight into their potential role in the freeze tolerance of this extremely cold hardy species. Abundant labeling was observed in the nucleus and cytoplasm of cold-acclimated C. sericea stem cells. In addition, labeling was observed in association with plasmodesmata of cold-acclimated vascular cambium cells. The unique association of dehydrin-like proteins with plasmodesmata has not been reported previously.

Cornus↗
PubMed1987

Characterization of cytotoxic cells in mice rendered neonatally tolerant of MHC alloantigens: evidence for repertoire modification.

A common prediction of clonal deletion/inactivation hypotheses is that cells with high avidity for tolerogen are preferentially eliminated, with low avidity cells being most likely to escape the tolerance induction mechanism. Thus it would be expected that the tolerogen-specific cells in tolerant mice would have a different repertoire than those in normal mice. To find evidence in favor of this prediction, neonatal B10.A mice were rendered tolerant to B10 by the injection of 15 X 10(6) (B10.A X B10)F1 spleen and bone marrow cells, and tolerance was assessed by the acceptance of B10 skin grafts for greater than 50 days. Mice rendered tolerant in this manner contain severely reduced (to less than 10% of normal) but detectable numbers of tolerogen-specific cytotoxic cell precursors that can be activated in the presence, but not absence, of exogenous interleukin 2. Spleen cells from the tolerant animals were compared with those of normal B10.A mice with respect to the expression of differentiation markers on the surface of B10-specific cytotoxic cells and their precursors, and the relative strength of the anti-B10 response toward Kb and Db as a measure of the repertoire of the cytotoxic cell populations. The T cell nature of the tolerogen-specific cytotoxic cells in both normal and tolerant mice was confirmed by their susceptibility to lysis by anti-Thy-1 or Lyt-2 antibody and complement. More importantly, cold target inhibition experiments showed that cytotoxic T cells from tolerant mice were inhibited to a greater degree by B10.A(2R) (KkDb) cold targets than B10.A(5R) (KbDd), suggesting that the response was preferentially directed at the D end of H-2, in direct contrast to normal B10.A spleen cells, which show a preferential response against Kb. Measurement of the frequency of anti-Kb and anti-Db cytotoxic T cell precursors in the spleens of normal and tolerant mice confirmed the differential specificities seen in the cold target experiments. The data suggest that neonatal tolerance induction results in repertoire modification of the anti-tolerogen response rather than a uniform decrease in anti-tolerogen reactivity. Possible mechanisms to explain the alteration in the repertoire of tolerant mice are discussed.

Animals↗
PubMed2005

Differential responses of silver birch (Betula pendula) ecotypes to short-day photoperiod and low temperature.

We investigated interrelations of dormancy and freezing tolerance and the role of endogenous abscisic acid (ABA) in the development of silver birch (Betula pendula Roth) ecotypes in controlled environments. Short-day treatment induced growth cessation, bud set and dormancy development, as well as initiation of cold acclimation and an increase in freezing tolerance. Subsequent low temperature and short days (12-h photoperiod) resulted in a significant increase in freezing tolerance, whereas bud dormancy was gradually released. The concentration of ABA increased in response to short days and then remained high, but ABA concentrations fluctuated irregularly when the dormant plants were subsequently exposed to low temperature during short days. Although there was a parallel development of freezing tolerance and bud dormancy in response to short days, subsequent exposure to low temperature had opposite effects on these processes, enhancing freezing tolerance and releasing dormancy. Compared with the southern ecotype, the northern ecotype was more responsive to short days and low temperature, exhibiting earlier initiation of cold acclimation, growth cessation and an increase in ABA concentrations in short days, and higher freezing tolerance, faster dormancy release and greater alteration in ABA concentrations when subsequently exposed to low temperature during short days. The rates and extent of the increases in ABA concentration may be related to increases in freezing tolerance and dormancy development during short days, whereas the extent of the fluctuations in ABA concentration may play an important role in enhancing freezing tolerance and releasing dormancy during a subsequent exposure to low temperature during short days.

Abscisic Acid↗
PubMed1996

Calcium antagonist treatment and cardiovascular responses to a cold pressor test at high altitude.

OBJECTIVE: We assessed the effects of the calcium antagonist felodipine on blood pressure, heart rate, oxygen saturation and cardiovascular responses to a cold pressor test at an altitude of 5200 m. Sixteen healthy climbers participated. A double-blind, placebo-controlled, randomized, crossover design was used. Placebo or felodipine were taken for 2 days and the treatment was changed after 3 days washout. RESULTS: During felodipine treatment there were no significant changes in blood pressure (125/89 vs 127/86 mmHg), heart rate (82 vs 81 beats.min-1) or oxygen saturation (86% vs 86%). Moreover, there were no changes in the cardiovascular responses to the cold pressor test. CONCLUSION: Felodipine is well tolerated at high altitude. It does not induce hypotension in normotensive men and does not affect cardiovascular reactivity to cold stress.

Adult↗
PubMed1999

The sfr6 mutation in Arabidopsis suppresses low-temperature induction of genes dependent on the CRT/DRE sequence motif.

The sfr mutations, which result in sensitivity to freezing after cold acclimation, define genes that are required for freezing tolerance. We tested plants homozygous for mutations sfr2 to sfr7 for cold-induced gene expression and found that sfr 6 plants were deficient in cold-inducible expression of the genes KIN1, COR15a, and LTI78, which all contain the C repeat/dehydration-responsive element (CRT/DRE) motif in their promoters. Similarly, sfr 6 plants failed to induce KIN1 normally in response to either osmotic stress or the application of abscisic acid. In contrast, cold-inducible expression of genes CBF1, CBF2, CBF3, and ATP5CS1, which lack the CRT/DRE motif, was not affected. The freezing-sensitive phenotype that defines sfr 6 also was found to be tightly linked to the gene expression phenotype. To determine whether the failure of cold induction of CRT/DRE-containing genes in sfr 6 was due to altered low-temperature calcium signaling, cold-induced cytosolic-free calcium ([Ca2+]cyt) elevations were investigated in the sfr 6 mutant, but these were found to be indistinguishable from those of the wild type. We discuss the possibilities that CRT/DRE binding proteins (such as CBF1) require activation to play a role in transcription and that the SFR6 protein is a vital component of their activation.

1-Pyrroline-5-Carboxylate Dehydrogenase↗
PubMedDate not supplied

[The effect of sanatorium-health resort treatment using foot baths on bronchial patency in children with chronic nonspecific diseases of the respiratory organs].

174 children aged 7-14 years in remission of recurrent asthmatic bronchitis and bronchial asthma took feet baths in addition to standard course of sanatorium treatment. Measurements of bronchial permeability and reactivity have demonstrated that foot baths have no negative effects on bronchial permeability in all the disease forms and maintain tolerance of the respiratory system to both cold and exercise.

Adolescent↗
PubMed1993

Molecular cloning of abscisic acid-responsive mRNAs expressed during the induction of freezing tolerance in bromegrass (Bromus inermis Leyss) suspension culture.

Abscisic acid (ABA) increases the freezing tolerance of bromegrass (Bromus inermis Leyss) cell-suspension cultures at 23 degrees C and elicits many metabolic changes similar to those observed during cold acclimation. Induction and maintenance of freezing tolerance by ABA is accompanied by the expression of novel polypeptides and translatable RNAs. The objective of this study was to isolate and characterize ABA-responsive cDNAs associated with ABA-induced freezing tolerance in bromegrass cell cultures. Among the 16 ABA-responsive cDNA clones isolated, 9 were expressed only with ABA treatment, 7 showed increased transcript level, and 1 was transiently expressed. Cold responsiveness was determined in three clones with increased transcript levels and in the transiently expressed clone. Deacclimation of ABA-hardened cells was a relatively slow process, because all of the novel transcripts persisted for at least 7 d after cells were cultured in ABA-free medium. Preliminary sequencing of cDNAs has identified several clones that share high sequence homology with genes associated with sugar metabolism, osmotic stress, and protease activity. Clone pBGA61 was fully sequenced and tentatively identified as an NADPH-dependent aldose reductase. The predicted amino acid sequence of the coding region shared 92% similarity with that predicted for barley aldose reductase cDNA. It is proposed that expression of genes related to sugar metabolism and osmotic stress may be required for ABA-induced hardening.

Abscisic Acid↗
PubMed1998

Mode of action of the COR15a gene on the freezing tolerance of Arabidopsis thaliana.

Constitutive expression of the cold-regulated COR15a gene of Arabidopsis thaliana results in a significant increase in the survival of isolated protoplasts frozen over the range of -4.5 to -7 degreesC. The increased freezing tolerance is the result of a decreased incidence of freeze-induced lamellar-to-hexagonal II phase transitions that occur in regions where the plasma membrane is brought into close apposition with the chloroplast envelope as a result of freeze-induced dehydration. Moreover, the mature polypeptide encoded by this gene, COR15am, increases the lamellar-to-hexagonal II phase transition temperature of dioleoylphosphatidylethanolamine and promotes formation of the lamellar phase in a lipid mixture composed of the major lipid species that comprise the chloroplast envelope. We propose that COR15am, which is located in the chloroplast stroma, defers freeze-induced formation of the hexagonal II phase to lower temperatures (lower hydrations) by altering the intrinsic curvature of the inner membrane of the chloroplast envelope.

Acclimatization↗
PubMedDate not supplied

Rapid adaptation to neuronal membrane effects of ethanol and low temperature: some speculations on mechanism.

There is increasing evidence that ethanol exerts its primary effect at neuronal membranes by influencing specific lipid--protein or lipid--lipid interactions that control the state of organization of a specific membrane component; for example, a specific lipid--protein complex that controls a particular physiological property. This implies that tolerance to ethanol is the result of a change in the composition and/or state of organization of this critical membrane component. This altered state confers ethanol resistance. It may or may not have an effect on function in the absence of ethanol. One basis for these speculations comes from experiments using a sensitive and specific neurophysiological assay -- the rate of decay of posttetanic potentiation (PTP) at an identified synapse in an isolated, perfused Aplysia ganglion. We review evidence that PTP decay rate is strikingly accelerated by ethanol (a membrane-fluidizing agent) and strikingly decelerated below a transition temperature, presumably reflecting a transition in the structure of a membrane component. The ethanol and low-temperature effects are antagonistic. The system develops adaptation (tolerance) to either ethanol or low temperature within hours of its exposure. Tolerance persists for at least 12 hours, the longest interval tested thus far. In the absence of ethanol and at normal temperature the system behaves normally, that is it shows no "physical dependence". The system also has the remarkable property that when it becomes tolerant to either of these treatments, it shows tolerance to the other treatment that normally has the opposite effect. Therefore, the adaptation to either treatment cannot be a simple change in membrane composition governing overall membrane fluidity. A hypothesis which could explain the bidirectional cross-tolerance is considered in which adaptation to both treatments involves a shift from a homogeneous to a more heterogeneous composition of the critical membrane component, for example increasing heterogeneity in boundary lipid surrounding a critical membrane protein. It is becoming increasingly clear that ethanol exerts its primary effect by altering cell membrane structure -- by "fluidizing" or expanding neuronal and other membranes [1 - 6]. This effect results when ethanol, a somewhat hydrophobic molecule, intercalates between some fatty acid chains of membranes, reducing the degree of order of their alignment and increasing the lateral mobility of some membrane components. Decrease in the order of the fatty acid chains results in a measurable expansion of the membrane; and the change in fluidity is reflected in the change in mobility of appropriate probes that can be dissolved in the membrane [6, 7]. It is presumed that the physiological effects of ethanol are consequences of its fluidization of some critical membrane components; and that tolerance to ethanol is based on some form of resistance to this fluidization...

Animals↗
PubMed2005

Involvement of GIGANTEA gene in the regulation of the cold stress response in Arabidopsis.

The Arabidopsis GIGANTEA (GI) gene has been shown to regulate several developmental processes, including photoperiod-mediated flowering, phytochrome B signaling, circadian clock, and carbohydrate metabolism. However, little is known about the role of GI gene in mediating the cold stress response. Here, we show that GI gene is involved in mediating the cold stress response. GI gene was induced by cold stress, but not by salt, mannitol, and abscisic acid. Moreover, gi-3 plants showed an increased sensitivity to freezing stress. However, no significant differences were detected in the transcript levels of CBF genes CBF1, CBF2, and CBF3 as well as their targeted genes RD29A, COR15A, KIN1, and KIN2 between wild-type and gi-3 plants in response to cold stress. These results suggest that GI gene positively regulates freezing tolerance via a CBF-independent pathway. In addition, intermittent cold treatments had a greater effect on flowering time in gi-3 plants than that in wild-type plants, suggesting that there may be a link between flowering time and cold stress response through GI in Arabidopsis.

Abscisic Acid↗
PubMed2002

Modality-specific facilitation and adaptation to painful tonic stimulation in humans.

The study assessed the influence of stimulus modality on adaptation or facilitation of pain during tonic cold and tourniquet pressure stimulation. Experimental set-up for the cold stimulation consisted of a thermo-tank with water, cooled to 3 degrees C, circulation pump, electronic thermometer and an electronic 10 cm visual analogue scale (VAS). Experimental set-up for the tonic pressure stimulation consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor, and an electronic VAS. The first experiment assessed temporal profiles of pain intensity and skin temperature during immersion of the non-dominant hand and lower arm into cold water for 3 min or until the pain tolerance limit was reached. The second experiment assessed temporal profile of cuff pain intensity during constant compressions for 10 min beginning at pain intensities of 2, 4, and 6 cm on the VAS ("VAS 2", "VAS 4" and "VAS 6" sessions). Subjects enduring cold stimulation for less than 3 min were defined as non-adapting to cold and vice versa. The intensity of cold pain in non-adapting subjects increased significantly faster than in adapting subjects and reached significantly higher magnitude. The course of pain intensity during constant compression, estimated by a linear regression line, was increasing or decreasing, representing facilitation or adaptation of pain, respectively. The typical profile of adaptation consisted of an "overshoot" in pain intensity, followed by a decrease in pain intensity. There was significant correlation in VAS slopes between sessions separated by 2-5 days, suggesting consistent pattern in pain responses to tonic pressure stimulation. Adaptation or facilitation rates and the overshoot magnitude were dependent on the initial pain intensity (2, 4, or 6 cm on the VAS). The facilitation rate was highest and the adaptation rate was lowest during the "VAS 2" session, while the facilitation rate was lowest and the adaptation rate was highest during the "VAS 6" session. The overshoot magnitude was lowest during "VAS 6" session. Adapting and non-adapting/facilitating responses to cold and to pressure during "VAS 6" session were not correlated, suggesting that pain course and therefore stimulus tolerance during tonic stimulation are modality-specific. The results of the study suggest that tolerance of tonic painful pressure and cold stimulations is specific to stimulus modality and may represent separate nociceptive mechanisms.

Adaptation, Physiological↗
PubMed2002

Initial sensitivity, tolerance and cross-tolerance to allopregnanolone- and ethanol-induced hypothermia in selected mouse lines.

RATIONALE: Acute ethanol administration induces hypothermia in genetically susceptible animals. Tolerance to this effect may develop with repeated administration. Allopregnanolone is an endogenously produced neuroactive steroid that acts at the GABA-A receptor. We postulated that allopregnanolone would induce hypothermia, and that lines of mice selectively bred for high (COLD-1 and COLD-2) or low (HOT-1 and HOT-2) sensitivity to ethanol's hypothermic effects would also be differentially sensitive to allopregnanolone-induced hypothermia. We also postulated that tolerance would develop to these two drugs by similar mechanisms, such that tolerance to one would impart cross-tolerance to the other. OBJECTIVES: To assess sensitivity, tolerance and cross-tolerance to allopregnanolone's and ethanol's hypothermic effects in HOT-1 and 2, and COLD-1 and 2 mice. METHODS: Mice were administered one of several doses of allopregnanolone each day, for 4 days, and initial sensitivity and tolerance to allopregnanolone-induced hypothermia were assessed. On day 5, ethanol was administered to assess cross-tolerance. In a separate experiment, COLD-1 and 2 mice were made tolerant to ethanol's hypothermic effects, and challenged with allopregnanolone to assess cross-tolerance. RESULTS: COLD mice exhibited greater initial sensitivity to the hypothermic effect of allopregnanolone, as compared to HOT mice. Tolerance to allopregnanolone-induced hypothermia was greater in COLD mice than in HOT mice, but only COLD-1 mice showed cross-tolerance to ethanol. Both replicate lines of COLD mice developed tolerance following repeated administration of ethanol, but only COLD-2 mice showed cross-tolerance to allopregnanolone. CONCLUSIONS: These results demonstrate shared genetic influence over allopregnanolone and ethanol's initial hypothermic effects. They also suggest genotype-dependent differences in the mechanisms for tolerance to these two compounds.

Animals↗