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PubMed1982

Behavioral tolerance and cross-tolerance to dl-cathinone and d-amphetamine in rats.

The effects of dl-cathinone (0.25-48 mg/Kg, i.p. and d-amphetamine (0.25-8.0 mg/kg, i.p.) on milk intake in rats were determined before, during and after a period of repeated daily administration of dl-cathinone. Experimental sessions consisted of 15-min access to a sweetened milk solution each day. 7 days a week. After the determination of the acute effects of dl-cathinone and d-amphetamine on milk intake, rats were injected daily with either 4.0 mg/kg of dl-cathinone 15 min before each session and saline 15 min after each session; or saline 15 min before each session and 4.0 mg/kg of dl-cathinone 15 min after each session. Milk intake returned toward base-line levels for animals receiving daily dl-cathinone before the session over a period of 16 sessions, and remained slightly decreased compared to animals that received postsession injections. Dose-response functions for dl-cathinone and d-amphetamine were then redetermined by substituting a test dose for the usual presession injection once every 4 to 5 days. In animals that were receiving presession dl-cathinone, both drugs had less effect, indicating the development of tolerance to dl-cathinone and cross tolerance to d-amphetamine. The development of tolerance to the suppression of milk drinking was contingent upon the relationship of the time of the daily injection to milk availability. Animals that were receiving dl-cathinone after the session did not develop tolerance but were more sensitive to the effects of both drugs on milk intake. Dose-response functions for both drugs determined after 10 drug free days were similar to the initial dose-response functions, indicating the transient nature of the tolerance and supersensitivity.

Alkaloids↗

PubMed1996

Tolerance to rat liver allografts. III. Donor cell migration and tolerance-associated cytokine production in peripheral lymphoid tissues.

The aim of this work was to investigate the mechanism of spontaneous rat liver allograft tolerance. Liver allografts from a LEW donor into DA recipient (LEW-->DA) or of PVG-->DA were spontaneously tolerated (TOL) across a complete MHC mismatch. In contrast, DA-->LEW or PVG-->LEW liver allografts were rejected in 10 to 15 days (REJ). We examined whether donor cell migration to recipient lymphoid tissues might be associated with TOL. Many donor cells were observed in draining (celiac) lymph nodes (LN) and spleen, reaching a peak on day 1 and then decreasing rapidly thereafter. Irradiation of liver donors, which we have previously shown to delete tolerance, significantly reduced the number of donor leukocytes in recipient lymphoid tissues. While this suggested an association between donor cell migration and tolerance, the number, distribution, and type of donor cells in recipient lymphoid tissues of REJ was similar to those of TOL. Expression of cytokine mRNA in LN and spleen showed an early increase in the expression of IL-2 and IFN-gamma mRNA on day 1 and then a rapid decrease to constitutive levels. Spleen and LN levels of IL-6, IL-10, TNF-alpha, or TGF-beta mRNA showed much less up-regulation than IL-2 or IFN-gamma. Paradoxically, there was greater expression of IL-2 and IFN-gamma mRNA in TOL lymphoid tissues than in REJ, and this superinduction was partially prevented by donor irradiation. Superinduction of IL-2 and IFN-gamma was, therefore, more closely associated with TOL than was donor cell migration. This was confirmed by treatment of TOL recipients with a short course of methylprednisolone, which reduced survival of subsequent donor strain skin grafts. This finding has implications for treatment of human liver transplants and is evidence for a novel pathway of transplant tolerance.

Animals↗

PubMed1977

Studies on tolerance. II. The effect of timing on inhibition of tolerance to morphine by cycloheximide.

Cycloheximide (CX) given 1 hour before each weekly dose of morphine inhibits the development of tolerance. The temporal relationship of the doses of CX and morphine sulfate seems to be a most important factor. CX (1 mg/kg s.c.) given 24 hours before, 6 hours before or 6 hours after weekly morphine injections (10 mg/kg s.c.) does not affect the rate or the degree of tolerance development. The inhibition of tolerance seen after weekly administration of CX plus injections of morphine is not seen until several weeks after drug treatment has begun and the difference between the morphine only and the morphine plus CX groups persists for a number of weeks after drug treatment has been terminated. The inhibition of tolerance seen after CX does not appear to be due to any nonspecific debilitating effect of CX. However, it may be related to the ability of CX to suppress protein synthesis. The identity of the proteins involved or how they are involved in the tolerance phenomenon remains unclear.

Analgesia↗

PubMed1999

Peripheral tolerance to class I mismatched renal allografts in miniature swine: donor antigen-activated peripheral blood lymphocytes from tolerant swine inhibit antidonor CTL reactivity.

Studies utilizing partially inbred miniature swine have demonstrated that a short course of cyclosporin A leads to indefinite survival of two haplotype class I mismatched renal allografts. In the present study, we have examined peripheral regulatory mechanisms that may be involved in maintenance of tolerance by coculturing PBL from long-term tolerant animals with naive recipient-matched PBL in cell-mediated lympholysis assays. We show that PBL from tolerant animals, primed in vitro with donor Ag, suppress antidonor CTL reactivity by naive recipient-matched PBL. Suppression was not observed when PBL from naive animals, primed with donor-matched PBL, were cocultured with PBL from a second naive animal, nor did PBL from either tolerant or naive recipient-matched control animals, primed with third-party Ag, suppress the generation of anti-third-party CTL by a second naive animal. The suppression was cell dose-dependent, radiation-sensitive, required cell-to-cell contact not reversed by the provision of exogenous IL-2, and associated with lower levels of IL-2R expression on the suppressive effector group (particularly the CD8 single positive cells) when compared with the control effector group. These data indicate an association between the presence of peripheral regulatory cells demonstrable in vitro and the maintenance of tolerance to renal allografts.

Animals↗

PubMed2003

Effects of copper on wild and tolerant strains of the lichen photobiont Trebouxia erici (Chlorophyta) and possible tolerance mechanisms.

The influence of copper was assessed on wild and tolerant strains of the lichen photobiont Trebouxia erici and shown to have multiple toxic effects. Addition of 4 mM copper chloride into Trebouxia media reduced growth rates of the wild type to less than 1% of control levels. It also injured cell membranes, inhibited dehydrogenase activity, altered pigment composition, and reduced activity of photosystem II. Membrane damage was assessed through measuring electrical conductivity and potassium content, dehydrogenase activity by degree of conversion of 2,3,5-triphenyl tetrazolium chloride to red triphenylformazan, and functioning of PS II by chlorophyll a fluorescence. In respect to most parameters the tolerant strain was usually less affected by copper than the wild strain and, in some cases, not at all. We demonstrated by inductively coupled plasma atomic emission spectrometry and energy-dispersive X-ray microanalysis that enriched copper in the medium resulted in increased uptake by both wild and tolerant photobiont cells, but extracellular concentrations were significantly higher in the tolerant strain. This suggested that, at least in vitro, extracellular deposition was a mechanism of copper tolerance.

Adaptation, Physiological↗

PubMed1995

Consequences of the overexpression of ubiquitin in yeast: elevated tolerances of osmostress, ethanol and canavanine, yet reduced tolerances of cadmium, arsenite and paromomycin.

Ubiquitin is induced by diverse stresses in all eukaroytes probably in reflection of the need for more extensive protein turnover by the ubiquitination system in stressed cells. To determine if ubiquitin overexpression can confer general protection against different stresses, yeast cells were engineered to overexpress ubiquitin and the effects of this overexpression on different stress tolerances determined. Ethanol and osmostress tolerances were slightly increased by ubiquitin overexpression, tolerance to heat was unaffected, while still other tolerances were reduced as compared to cells with normal ubiquitin levels. It is noteworthy that tolerance of the amino acid analogue canavanine was markedly increased by ubiquitin overexpression, yet resistance to at least three other agents that contribute to accumulation of aberrant proteins (arsenite, cadmium, paromomycin) was decreased.

Arsenites↗

PubMed2004

Cadmium tolerance, cysteine and thiol peptide levels in wild type and chromium-tolerant strains of Scenedesmus acutus (Chlorophyceae).

Two strains of the unicellular green alga Scenedesmus acutus with different sensitivity to hexavalent chromium were compared for their tolerance of cadmium, by means of growth and recovery tests, and determination of cysteine, reduced glutathione and phytochelatin content, after short-term exposure to various cadmium concentrations (from 1.125 to 27 microM). Growth experiments showed that, after 7-day treatments with cadmium, the chromium-tolerant strain reached a significantly higher cell density and, after 24-h exposure to Cd, was able to resume growth significantly better than the wild type. Constitutive level of cysteine was higher in the chromium-tolerant strain, while glutathione levels were similar in the two strains. The higher content of cysteine and the maintenance of both reduced glutathione and phytochelatin high levels in the presence of cadmium, support the higher cadmium co-tolerance of the chromium-tolerant strain in comparison with the wild type one.

Analysis of Variance↗

PubMed2006

Daytime variations in glucose tolerance in people with impaired glucose tolerance.

To determine whether glucose tolerance varies throughout the day in people with impaired glucose tolerance (IGT). We studied 15 healthy IGT, and 18 matched normal glucose tolerant (NGT) individuals. Blood samples were taken every 30-120 min during a 24h period in which all individuals had three mixed meals and nocturnal sleep. We measured glucose, free fatty acids, specific insulin, intact proinsulin, cortisol and growth hormone. Variable responses were considered as concentrations and areas under the curves. Comparison between the groups was by Student's t-test, Mann-Whitney, and analysis of variance. Higher total glucose response, inappropriate normal total insulin response, and unproportionally increased proinsulin total response were observed in the IGT group. Lower glucose tolerance occurred in IGT after dinner, as in the NGT, and after breakfast associated with increased insulin response after breakfast, and similar proinsulin response after all three meals. IGT had higher glucose response than NGT after breakfast and lunch, similar insulin responses, and increased proinsulin-insulin ratio after all three meals. Data from this study demonstrate that IGT individuals present lower glucose tolerance in the evening, as those with NGT, and in the morning, as reported in patients with type 2 diabetes.

Adult↗

PubMed2006

Rapid ethanol tolerance mediated by adaptations in acute tolerance in inbred mouse strains.

It has been postulated that decreased acute sensitivity to ethanol is an important genetically-mediated risk factor for the development of alcoholism. Previous work in mice and rats has indicated that ethanol sensitivity can be reduced in a genotype-dependent manner by a single dose of ethanol 24 h prior to testing, so-called 'rapid' tolerance. The current studies were undertaken to determine if the observed rapid tolerance was mediated by alterations in initial sensitivity or acute functional tolerance (AFT), the two primary components of acute sensitivity. Separate groups of C57BL/6, DBA/2, ILS, and ISS inbred mouse strains were administered a single pretreatment dose of saline or ethanol (5 g/kg). The original and modified versions of the loss of righting reflex test, ethanol-induced hypothermia, and ataxia on a stationary dowel rod were tested 24 h later. Dependent on the test and strain, varying degrees of rapid tolerance were observed; a pronounced sensitization was detected in one case. There was a concomitant increase in the rate and/or magnitude of AFT with little change in initial sensitivity suggesting that rapid tolerance was mediated primarily by alterations in AFT. This conclusion may have implications for the contribution of acute sensitivity to human alcoholism.

Alcohol Drinking↗

PubMed2001

A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study.

BACKGROUND: The few published direct comparative studies of the tolerability and efficacy of atypical antipsychotic agents were performed in relatively homogeneous populations that may not be typical of patients seen in clinical practice. OBJECTIVE: The Quetiapine Experience with Safety and Tolerability (QUEST) study compared the relative safety, tolerability, and efficacy of quetiapine and risperidone in outpatients with a broad range of psychotic symptoms. METHODS: This was a multicenter, 4-month, open-label, randomized clinical trial. Patients were randomized in a 3:1 ratio to receive quetiapine or risperidone. Doses were adjusted to maximize efficacy and to minimize adverse events. Extrapyramidal symptoms (EPS) were assessed with an EPS checklist; adverse events were recorded. Efficacy was assessed using the Clinical Global Impression (CGI) scale, Positive and Negative Symptom Scale (PANSS), and Hamilton Rating Scale for Depression (HAM-D). RESULTS: A total of 728 patients were randomized, 553 to quetiapine and 175 to risperidone. Mean prescribed doses over the study period were 253.9 mg/d quetiapine and 4.4 mg/d risperidone. At the end of 4 months, EPS declined in both treatment groups, but quetiapine-treated patients were significantly less likely to require dose adjustment or concurrent anti-EPS medication (P < 0.001). The most common adverse events in the quetiapine and risperidone groups were somnolence (31.3% and 15.4%, respectively), dry mouth (14.5% and 6.9%), and dizziness (12.7% and 6.9%). Overall, tolerance to side effects with the 2 drugs, measured by dropout rates, was comparable. At each visit, a higher percentage of quetiapine-treated patients showed improvement on the CGI scale, but there were no significant between-group differences on the PANSS. At end point, quetiapine-treated patients had significantly lower HAM-D scores (P = 0.028). CONCLUSIONS: The results of this study suggest that quetiapine is as effective as risperidone for the treatment of psychotic symptoms, is more effective for depressive symptoms, may have a more favorable EPS profile, and has comparable overall tolerability.

Adolescent↗

PubMed2002

Effect of drought stress on the yield and composition of volatile oils of drought-tolerant and non-drought-tolerant clones of Tagetes minuta.

A drought-tolerant clone of Tagetes minuta L. (Asteraceae) was selected in vitro on a medium containing 60 mM mannitol. In the greenhouse, a decrease in soil field capacity (FC) from 100 to 40 % reduced oil yield by 49, 71 and 71 % for drought-tolerant, non-drought tolerant cloned and seed-grown plants, respectively. In soil at 40 % FC, the drought-tolerant clone had the highest leaf dry weight and oil yield. At 100 % FC, there was no significant difference in leaf dry weight, but the drought-tolerant clone had a significantly higher percentage oil content and yield than seed-grown plants. The main components of the oil were monoterpenes of which trans- and cis-tagetone together were 52.3 % - 64.2 %. Drought significantly altered the content of some oil components.

Acclimatization↗

PubMed1996

Acid tolerance in Listeria monocytogenes: the adaptive acid tolerance response (ATR) and growth-phase-dependent acid resistance.

Listeria monocytogenes acquired increased acid tolerance during exponential growth upon exposure to sublethal acid stress, a response designated the acid tolerance response (ATR). Maximal acid resistance was seen when the organism was exposed to pH 5.0 for 1 h prior to challenge at pH 3.0, although intermediate levels of protection were afforded by exposure to pH values ranging from 4.0 to 6.0. A 60 min adaptive period was required for the development of maximal acid tolerance; during this period the level of acid tolerance increased gradually. Full expression of the ATR required de novo protein synthesis; chloramphenicol, a protein synthesis inhibitor, prevented full induction of acid tolerance. Analysis of protein expression during the adaptive period by two-dimensional gel electrophoresis revealed a change in the expression of at least 23 proteins compared to the non-adapted culture. Eleven proteins showed induced expression while 12 were repressed, implying that the ATR is a complex response involving a modulation in the expression of a large number of genes. In addition to the exponential phase ATR, L.monocytogenes also developed increased acid resistance upon entry into the stationary phase; this response appeared to be independent of the pH-dependent ATR seen during exponential growth.

Adaptation, Physiological↗

PubMed2006

Carbohydrate preference, acid tolerance and bile tolerance in five strains of Bifidobacterium.

AIMS: To assess the suitability of bifidobacteria for inclusion in synbiotic products on the basis of carbohydrate preference, acid and bile tolerance. METHODS AND RESULTS: Five strains of Bifidobacterium were analysed for their carbohydrate preference from 12 substrates. Maximum growth rates were used to compare substrate preferences. Galacto-oligosaccharides and isomalto-oligosaccharides were well utilized by all the test species. Most bacteria tested could also utilize at least one type of fructan molecule. To determine transit tolerance of potentially probiotic bifidobacteria, acid and bile resistance was tested. A wide range acid resistance was found. Bile tolerance also varied. CONCLUSIONS: GOS and IMO were generally well utilized by the tested species. Other substrates were used to different degrees by the different species. Most bifidobacteria are poorly resistant to strongly acidic conditions with the exception of Bifidobacterium lactis Bb12. Bile tolerances were widely variable and it was shown that caution should be exercised when using colorimetric methods to assess bile tolerance. SIGNIFICANCE AND IMPACT OF STUDY: The study allows the comparison of the properties of bifidobacteria, allowing a cost effective screen for the best species for use in synbiotic products to allow better survival and efficacy.

Bifidobacterium↗

PubMed2004

Heterosis in the freezing tolerance of crosses between two Arabidopsis thaliana accessions (Columbia-0 and C24) that show differences in non-acclimated and acclimated freezing tolerance.

Heterosis is broadly defined as the increased vigour of hybrids in comparison to their parents. In the model plant Arabidopsis thaliana, a significant heterosis effect on leaf-freezing tolerance was observed in the F(1) generation of a cross between the accessions Columbia-0 (Col) and C24. Parental Col plants were significantly more freezing-tolerant than C24 plants in both the acclimated and non-acclimated (NA) states. Mid-parent heterosis was observed in the F(1) plants, both in the basic tolerance of non-adapted plants and in freezing tolerance after cold acclimation. Best-parent heterosis, on the other hand, was only found after cold acclimation. The heterosis effect was reduced in the F(2) populations such that only mid-parent heterosis was evident. The leaf content of soluble sugars (fructose (Fru), glucose (Glc), sucrose (Suc) and raffinose (Raf)) increased dramatically in the F(1) plants after cold acclimation as compared to the parental lines. The content of proline (Pro), however, was only moderately increased in the F(1) plants under the same conditions. Correlation analyses showed that only Raf content was consistently related to leaf-freezing tolerance in both the acclimated and NA states. A quantification of mRNA levels in leaves of parental and F(1) lines using quantitative real-time RT-PCR showed no clear indication for an involvement of the investigated genes (CBF (C-repeat binding factor)1, CBF2, (cold-regulated protein (COR) 6.6, COR15a, COR15b, COR47 and COR78) in the heterosis effect.

Acclimatization↗

PubMed2006

Constraints of tolerance: why are desiccation-tolerant organisms so small or rare?

Drying to equilibrium with the air kills nearly all animals and flowering plants, including livestock and crops. This makes drought a key ecological problem for terrestrial life and a major cause of human famine. However, the ability to tolerate complete desiccation is widespread in organisms that are either <5 mm long or found mainly where desiccation-sensitive organisms are scarce. This suggests that there is a trade-off between desiccation tolerance and growth. Recent molecular and biochemical research shows that organisms tolerate desiccation through a set of mechanisms, including sugars that replace water and form glasses, proteins that stabilize macromolecules and membranes, and anti-oxidants that counter damage by reactive oxygen species. These protections are often induced by drying, and some of the genes involved may be homologous in microbes, plants and animals. Understanding how mechanisms of desiccation tolerance may constrain growth might show how to undo the constraint in some economically important macroorganisms and elucidate the much-studied but elusive relationship between tolerance of stress and productivity.

Animals↗

PubMed1996

Behavioral tolerance and cross-tolerance to the response rate-decreasing effects of mu opioids in rats.

The present study was designed to characterize the degree of cross-tolerance between the response rate-decreasing effects of morphine and three mu opioids with varying relative intrinsic efficacies at the mu receptor, buprenorphine, butorphanol and fentanyl, and a non-opioid (+) amphetamine, in a behavioral-tolerance paradigm. Lever pressing of rats was maintained by a fixed-ratio 20-schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine in separate groups of rats administered morphine either before (pre-session) or after (post-session) experimental sessions. Each of the mu opioids and the non-opioid (+)-amphetamine dose-dependently decreased response rates. In the pre-session group, daily administration of morphine shifted the morphine dose-effect curve 0.33 log unit rightward, indicating that tolerance had developed, and shifted the butorphanol dose-effect curve 0.96 log unit rightward. Daily pre-session administrations of morphine did not shift the dose-effect curves for buprenorphine, fentanyl, or (+)-amphetamine. In the post-session group, daily administration of morphine did not shift the morphine, butorphanol, buprenorphine, fentanyl, or (+)-amphetamine dose-effect curves. These data suggest that pharmacological variables, such as the drug's relative intrinsic efficacy at the mu receptor, can play a role in behavioral tolerance and cross-tolerance.

Journal Article↗

PubMed1973

Immunological tolerance to a hapten. I. Induction and maintenance of tolerance to trinitrophenyl with trinitrobenzene sulfonic acid.

Treatment of mice with a nonimmunogenic preparation of free reactive hapten, trinitrobenzene sulfonic acid (TNBS), leads to the induction of a state of tolerance to the hapten, 2,4,6-trinitrophenyl (TNP). This is determined by the lack of response to the haptenic moiety in an immunogenic hapten-carrier conjugate (TNP-SRBC) as assayed both by serum antibody titrations and the hemolytic plaque assay. The tolerance produced is specific for the hapten, since the anticarrier responses are essentially unaltered compared with the control values. The unresponsiveness induced by TNBS treatment is a dose-dependent phenomenon, becoming less complete at lower doses of TNBS. The tolerance is of a definite length, both in its induction phase and in the duration of the established unresponsive state. Tolerance can be maintained and extended, and may also be reentered once escape has been initiated.

Animals↗

PubMed1965

IMMUNOLOGIC TOLERANCE IN THYMECTOMIZED, IRRADIATED RATS GRAFTED WITH THYMUS FROM TOLERANT DONORS.

Lewis rats, thymectomized at 5 weeks of age and irradiated at 8 weeks, received grafts of adult thymus and marrow, one or both grafts being derived from donors tolerant to bovine gamma-globulin. Challenge 3 or 6 weeks after grafting showed that delayed sensitization could not be induced in animals which received a tolerant thymus or tolerant thymus and marrow, though sensitization to a heterologous antigen (chicken ovalbumin) occurred normally. Arthus reactivity was regained slowly in animals receiving normal thymus and marrow and, to an equal extent, in those receiving grafts from tolerant donors.

Anaphylaxis↗