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PubMed2006

Following the heart: temperature and salinity effects on heart rate in native and invasive species of blue mussels (genus Mytilus).

The three species of blue mussels, Mytilus trossulus Gould 1850, M. edulis Linnaeus 1758 and M. galloprovincialis Lamarck 1819, have distinct global distribution patterns that are hypothesized to reflect differences in their tolerances of temperature and salinity. We examined effects on heart rate (beats min(-1)) of acute exposure and acclimation to different combinations of temperature and salinity to test this hypothesis and, in the context of the invasive success of M. galloprovincialis, to gain insights into the factors that may explain the replacement of the temperate Pacific native, M. trossulus, by this Mediterranean Sea invader along much of the California coast. Heart rate of M. trossulus was significantly higher than that of M. galloprovincialis, consistent with evolutionary adaptation to a lower habitat temperature (temperature compensation) in the former species. Heart rates of M. trossulus/M. galloprovincialis hybrids were intermediate between those of the parental species. Following acclimation to 14 degrees C and 21 degrees C, heart rates of all species exhibited partial compensation to temperature. Heart rate increased with rising temperature until a high temperature was reached at which point activity fell sharply, the high critical temperature (H(crit)). H(crit) increased with increasing acclimation temperature and differed among species in a pattern that reflected their probable evolutionary adaptation temperatures: M. galloprovincialis is more heat tolerant than the other two congeners. Ability to sustain heart function in the cold also reflected evolutionary history: M. trossulus is more cold tolerant than M. galloprovincialis. Heart rates for all three congeners decreased gradually in response to acute reductions in salinity until a low salinity (S(crit)) was reached at which heart rate dropped precipitously. S(crit) decreased with decreasing salinity of acclimation and was generally lowest for M. galloprovincialis. Mortality during acclimation under common garden conditions was greatest in M. trossulus and was highest at high acclimation temperatures and salinities. These intrinsic differences in basal heart rate, thermal and salinity responses, acclimatory capacity, and survivorship are discussed in the contexts of the species' biogeographic patterning and, for the invasive species M. galloprovincialis, the potential for further range expansion along the Pacific coast of North America.

Acclimatization↗
PubMed2003

Combined solvent and water activity stresses on turgor regulation and membrane adaptation in Oceanimonas baumannii ATCC 700832.

Oceanimonas baumannii ATCC 700832 is a Gram negative marine bacterium capable of utilising phenol as asole carbon source. The ability of the bacterium to tolerate low water activity when utilising either succinate or phenol as a substrate in minimal medium was studied. The membrane lipid and protein composition showed two discreet adaptive phases as salinity increased. Firstly, when NaCl concentration was increased from 0.15% (w/v), the minimum at which growth was observed, to 1% NaCl (w/v), the ratio of zwitterionic to anionic phospholipids in the membrane increased significantly. At the same time the ratio of saturated to unsaturated fatty acids and the total membrane protein decreased significantly. The second phase was observed when salinity was increased from 1% to 7% NaCl (w/v) as the ratio of zwitterionic to anionic phospholipids decreased and membrane protein increased. However, the ratio of saturated to unsaturated fatty acids was unaffected. Salinity also affected the tolerance of cultures to elevated levels of phenol. Cultures grown in 0.15% NaCl (w/v) could tolerate 12 mM phenol, whereas in the presence of 1% NaCl (w/v) cultures continued to grow in up to 20 mM phenol and in 7% NaCl (w/v) cultures 8 mM phenol could be tolerated. Changes to the composition of the membrane phospholipids and fatty acids were also observed when phenol concentrations were at the maximum that could be tolerated. Under such conditions the ratio of zwitterionic to anionic phospholipids decreased twofold compared to cultures utilising 4 mM phenol as the substrate, in all salinities except in 7% NaCl (w/v) cultures, where there was no significant effect. The ratio of saturated to unsaturated fatty acids increased significantly in all salinities compared to cultures grown with 4 mM phenol.

Adaptation, Physiological↗
PubMed1991

Development of tolerance to the plasma amino acid-decreasing effect of ethanol in the rat.

Male Sprague-Dawley rats were treated for one month with daily intraperitoneal injections of ethanol (2 g kg-1), or saline. After this pretreatment, animals from each group were given acute doses of ethanol (2 g kg-1) or saline. Plasma amino acid concentrations and brain tyrosine, tryptophan, dopamine, 5-HT and 5-HIAA concentrations were measured in samples collected 1 h after the injections. Acute administration of ethanol induced a dramatic fall in the concentrations of 18 out of 20 plasma amino acids in animals pretreated with saline. In animals chronically pretreated with ethanol this decrease was much smaller. Furthermore, the decrease was significantly lower for 6 of the measured amino acids in the chronic ethanol group compared with the saline-treated control group. Tolerance to the plasma amino acid decreasing effect of ethanol had thus developed. This acquired tolerance might be explained by both pharmacokinetic and pharmacodynamic mechanisms. Chronic administration of ethanol induced increased concentrations of tyrosine and dopamine in the brain, probably due to increased transport of tyrosine into the brain caused by an increase in the ratio of tyrosine to large neutral amino acids in plasma.

Amino Acids↗
PubMed2003

Factors limiting the intertidal distribution of the mangrove species Xylocarpus granatum.

The tree species Xylocarpus granatum is commonly described as occurring in the upper intertidal zone of mangrove forests, but mature trees are occasionally found at lower elevations. In the Utwe River basin, on the Pacific island of Kosrae, we investigated the relative importance of several biotic and abiotic factors that may control the intertidal distribution of X. granatum. Factors we evaluated included differential seed predation across the lower, mid, and upper intertidal zones and seedling responses to salinity, tidal flooding, and shade. Seed predation was 22.4% over the first 34 days and varied little among zones or in gaps versus under the forest canopy. By day 161, there were still no differences in seed mortality, but a significant difference was found in seedling establishment, with much greater establishment in the upper intertidal plots. X. granatum seedlings in a greenhouse experiment exhibited greater growth in freshwater than seedlings in 23 ppt salinity, which is typical of salinity levels found in the mid intertidal zone in our field study sites in Micronesia, where mature X. granatum trees are generally absent. Seedlings grown in 23 ppt salinity, however, exhibited few visible signs of stress associated with patterns in growth. Seedlings grown in a simulated tidal flooding treatment (with 23 ppt salinity) also showed few signs of stress. Growth declined dramatically under 80% shade cloths, but there were few interactions of shading with either 23 ppt salinity or simulated tidal flooding. Differential seed predation is not likely to be the primary factor responsible for the intertidal distribution of X. granatum on Kosrae. However, seedling tolerance of flooding or salinity may be more important, especially relative to a potential contribution to secondary stress mortality. Other factors may ultimately prove to be more critical, such as physiological effects of salinity on seed germination, effects of tides on seed dispersal and rooting, or differential herbivory on seedlings.

Adaptation, Physiological↗
PubMed2006

Chromium(VI) bioaccumulation capacities of adapted mixed cultures isolated from industrial saline wastewaters.

Enrichment mixed cultures tolerating relatively high concentrations of chromium and salt ions were isolated and their bioaccumulation properties improved by adaptation. Mixed cultures were enriched in Nutrient Broth media containing 25-300 mg l(-1) Cr(VI) and 0%, 2%, 4%, 6% (w/v) NaCl. Bioaccumulation of Cr(VI) was studied in a batch system as a function of initial pH (7, 8 and 9), Cr(VI) and NaCl concentrations. Increasing NaCl and Cr(VI) concentrations led to significant decreases in percentage uptake and dried weight of mixed cultures but increased maximum specific chromium uptake. The maximum specific chromium uptake value at pH 8 was 58.9 mg g(-1) for 316.1 mg l(-1) Cr(VI) in the absence of NaCl, while at pH 9 it was 130.1 mg g(-1) in media including 194.5 mg l(-1) Cr(VI) and 2% NaCl concentrations. At 4% NaCl, the maximum Cr(VI) uptake of 127.0 mg g(-1) for 221.1 mg l(-1) Cr(VI) occurred at pH 9, while at 6% NaCl the maximum Cr(VI) uptake of 114.9 mg g(-1) for 278.1 mg l(-1) Cr(VI) was found at pH 7.

Chromium↗
PubMed1995

Influence of salt concentration on the susceptibility of moderately halophilic bacteria to antimicrobials and its potential use for genetic transfer studies.

The influence of salinity on the susceptibility of 13 moderately halophilic collection strains belonging to the genera Chromohalobacter, Deleya, Halomonas, Vibrio, and Volcaniella to 10 common antimicrobials has been studied. Three different patterns of tolerance were found when salinity was varied from 10 to 1% (wt/vol) total salts in the testing media. The first one included the responses to ampicillin and rifampicin, where only minimal effects on the susceptibility were found. All moderate halophiles showed a high sensitivity to rifampicin regardless of the salt concentration. In the second group, including the responses to the aminoglycosides gentamycin, kanamycin, neomycin, and streptomycin, a remarkable and gradual increase of the toxicity was detected at lower salinities. Thirdly, the highest heterogeneity was found for the rest of antimicrobials assayed (trimethoprim, nalidixic acid, spectinomycin, and tetracycline), where the effect of salinity was moderate and dependent on both the individual strain and the antimicrobial tested. The data presented here should facilitate genetic studies on moderate halophiles. Thus, they simplify the design of selection media for genetic exchange experiments. Besides, by using low-salinity media, genes encoding resistance to a number of antimicrobials, especially to aminoglycosides, can be used as genetic markers for plasmids or transposons to be transferred to these extremophiles.

Anti-Bacterial Agents↗
PubMed2006

Opiate pharmacology of intrathecal granulomas.

BACKGROUND: Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. METHODS: Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. CONCLUSIONS: Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.

Analgesics, Opioid↗
PubMed1997

Role of behavioral and pharmacological variables in the loss of tolerance to amphetamine hypophagia.

Tolerance to amphetamine-induced hypophagia is lost when drug injections are withdrawn for 4 weeks while milk tests are continued (Wolgin and Hughes 1996). The purpose of this study was to determine whether the loss of tolerance is a function of drug withdrawal per se. Rats made tolerant to amphetamine (2 mg/kg, IP) were assigned to one of three groups. During the next 4 weeks (phase), one group continued to receive amphetamine injections prior to daily milk tests (Before group), one group received drug injections after the milk tests (After group), and one group received injections of saline prior to the milk tests (Saline group). Dose-response tests revealed that the Before group retained tolerance, whereas the After and Saline groups lost tolerance. When retested with chronic injections of amphetamine prior to milk, the After and Saline groups reacquired tolerance more rapidly, and to a greater extent, than non-tolerant controls. These results demonstrate that the loss of tolerance is not due to drug withdrawal per se, but may be due to the unlearning of behavioral strategies previously acquired under the drug.

Amphetamine↗
PubMed2000

Salinity induced behavioural changes in malate dehydrogenase and glutamate dehydrogenase activities in rice seedlings of differing salt tolerance.

The activities of malate dehydrogenase in whole tissue extract (NAD(+)-MDH) as well as in mitochondrial (NAD(+)-MDH) and chloroplastic (NADP(+)-MDH) preparations of aminating (NADH-GDH) and deaminating(NAD(+)-GDH) glutamate dehydrogenases were studied in two sets of rice cultivars differing in salt tolerance grown under moderate (7 dS m(-1)) and high (14 dS m(-1)) NaCl salinity levels. A contrasting response to salinity on enzyme activities was found between the sensitive and tolerant cultivars during a 5-20-day growth period of study. NaCl salinity in situ caused increase in all three MDH activities in salt tolerant cvs. CSR-1 and CSR-3 whereas in salt sensitive cvs. Ratna and Jaya 16-100% inhibition in activities was noted. Chloroplastic MDH was extremely sensitive to NaCl. In seedlings of salt tolerant cultivars concomitant increase in both aminating and deaminating GDH activities was observed with increase in salinity level, whereas in sensitive cultivars under higher salinity level decrease in GDH activity was noted. Under in vitro conditions NaCl concentration in the range 1-1000 mM caused gradual inhibition in MDH activity. With 400 mM NaCl in vitro, complete loss of mitochondrial and chloroplastic MDH activities was observed. GDH activity increased with increasing concentration of NaCl up to 200 mM NaCl and other salts in vitro and was inhibited thereafter. However 800 mM NaCl caused complete loss of deaminating GDH activity from sensitive cultivar but not from tolerant cultivar. Results suggest varying behaviour of MDH and GDH in two sets of rice cultivars differing in salt tolerance and that inhibition in the activities of dehydrogenases in salt sensitive rice cultivars due to salinity may be one of the possible reasons for decreased growth of rice plants under saline conditions.

Journal Article↗
PubMed2006

Threshhold for recovery in the marsh halophyte Spartina alterniflora grown under the combined effects of salinity and soil drying.

A study quantifying the physiological threshhold at which Spartina alterniflora plants are able to tolerate the interactive effects of salinity and soil drying was conducted in a climate controlled greenhouse. The experiment consisted of two levels of salinity (3-5 ppt, L and 35-38 ppt, H) as well as four dynamic water levels: flooding (water level maintained 3-5 cm above the soil surface at high tide and 10 cm below the soil surface at low tide for entire study duration, F), 8-day drought (water level maintained at least 20 cm below the soil surface at high tide for 8 days then flooded, 8 days), 16-day drought (water level maintained at least 20 cm below the soil surface at high tide for 16 days then flooded, 16 days), and 24-day drought (water level maintained at least 20 cm below the soil surface at high tide for 24 days then flooded, 24 days). Plant gas exchange and growth responses were measured along with soil conditions of redox potential and water potential. Significant decreases were seen in plant gas exchange and growth in response to increases in salinity and soil drying. Survival was 100% for all flooded treatments while increased salinity combined with soil drying decreased survival to 86% in both low salt/24-day drought plants (LD24) and high salt/16-day drought plants (HD16). The lowest survival rate was seen in the high salt/24-day drought treatment (HD24) at 29%. Therefore, it appears that the critical time for recovery from the combined effects of increased salinity and soil drying may greatly diminish after two weeks from the onset of stress conditions. Consequently, if salinity continues to increase along the MRDP, marshes dominated by S. alterniflora may be more susceptible to short-term drought and likewise large-scale marsh browning.

Adaptation, Physiological↗
PubMed1985

Tolerance, cross-tolerance, and receptors after chronic nicotine or oxotremorine.

Saline, 8.0 mg/kg/hr nicotine, or 1.0 mg/kg/hr oxotremorine was continuously infused into the jugular veins of DBA female mice. After 10 days of treatment, respiratory rate, Rotarod performance, Y-maze crossings, Y-maze rears, heart rate, and body temperature were measured after challenge with 2.0 mg/kg nicotine or saline or 0.2 mg/kg oxotremorine. Nicotine-infused mice were tolerant to the effects of nicotine for all six tests and oxtremorine-infused mice were tolerant to the effects of oxotremorine for all six tests and to the effects of nicotine on heart rate and body temperature. Oxotremorine infusion reduced the Bmax for [3H]-L-QNB binding, but had no effect on Bmax for either [3H]-DL-nicotine or [125I]-alpha-BTX binding. Conversely nicotine infusion did not alter the Bmax for [3H]-L-QNB binding, but increased the Bmax for both [3H]-DL-nicotine and [125I]-alpha-BTX binding. These results indicate that tolerance developed to the effects of two cholinergic agents, nicotine and oxotremorine, and that some cross-tolerance to the effects of nicotine occurred in oxotremorine-treated mice. Treatment with oxotremorine caused down-regulation of muscarinic receptors, while treatment with nicotine caused up-regulation of nicotinic receptors. Although some cross-tolerance to the effects of nicotine occurred in oxotremorine-treated mice, this did not appear to result from changes in nicotinic receptors.

Animals↗
PubMed1990

Cloning of salinity stress-induced genes from the salt-tolerant nitrogen-fixing cyanobacterium Anabaena torulosa.

A subtractive hybridization procedure was used to clone genes of the cyanobacterium Anabaena torulosa expressed in response to salt stress. The method uses total RNA from salt-treated cells, labeled in vitro, as the probe. Hybridization to restriction digests of total DNA was used for interspecies comparison; the procedure was also successful for isolation of cosmids by colony hybridization, semiquantitative dot blots, and cosmid characterization by Southern blotting. Analysis of eleven independent cosmids containing genes whose transcription is abundantly induced by salt suggests that a substantial portion of the A. torulosa genome, probably in excess of 100 kilobases, responds to salt.

Cloning, Molecular↗
PubMed2001

The tolerability, safety, and success of sputum induction and combined hypertonic saline challenge in children.

Induced sputum using hypertonic saline (HS) is a useful research tool to study airway inflammation (AI). HS provocation testing can also be used to measure airway hyperresponsiveness (AHR). A combined HS challenge and sputum induction procedure has been developed to permit assessment of AI and AHR in a single test. The aim of this study is to report the success and tolerability of sputum induction alone, and in combination with a HS bronchial provocation challenge. Sputum induction alone was performed with beta2-agonist pretreatment. In the combined challenge, no beta2-agonist pretreatment was used. A high-output ultrasonic nebulizer with valve box and tubing were used to deliver 4.5% saline in doubling time periods from 0.5 s to 4 min. Outcomes assessed were completion of the test protocol, adequacy of sputum samples, decrease in FEV1, and adverse effects during the procedure. Fifty-three children who underwent a sputum induction alone, and 182 children who underwent a combined sputum induction and bronchial provocation using HS. Sputum induction alone was well tolerated, with 98% of children completing the procedure and only 4% experiencing a significant (> 15%) fall in FEV1. An adequate sample of sputum was obtained in 92% of children. The combined challenge was completed by 90% of children. A distressing cough occurred in 13% of children and irritation of the mucosa in 1% of children. In the combined challenge an adequate sample of sputum was obtained in significantly fewer children than with sputum induction alone (70% versus 92%, p < 0.05). Sputum cellular changes reflected the shorter nebulization time with sputum induction alone. We conclude that induction of sputum using HS after pretreatment with bronchodilator is well tolerated with a high success rate in children. Combining the HS challenge with sputum induction provides additional information and is a useful means of comparing AHR and AI simultaneously, but at the expense of having a reduced success rate in obtaining an adequate sample of sputum, as well as increased side effects.

Adolescent↗
PubMed1995

Lack of cross-tolerance for hypophagia induced by DOI versus m-CPP suggests separate mediation by 5-HT2A and 5-HT2C receptors, respectively.

Intraperitoneal administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced significant decreases in the first-hour food intake on day 1 and on day 2 relative to saline-treated animals. Complete tolerance developed to DOI-induced hypophagia by day 3. However, there was no cross-tolerance to m-chlorophenyl-piperazine (m-CPP)-induced hypophagia. Similarly, complete tolerance developed to m-CPP-induced hypophagia by day 3, but again there was no cross-tolerance to DOI-induced hypophagia. These findings suggest that DOI and m-CPP-induced hypophagia are mediated by different mechanisms, most likely by selective stimulation of 5-HT2A receptors by DOI and 5-HT2C receptors by m-CPP. The functional sensitivity changes did not parallel changes in hypothalamic [3H]-mesulergine-labeled 5-HT2C receptors or [3H]-ketanserin-labeled 5-HT2A receptors following chronic m-CPP or DOI treatment, although both treatments significantly reduced 5-HT2A and 5-HT2C receptors in cortex. Thus, future studies investigating the effects of daily m-CPP and DOI administration on phosphoinositide hydrolysis or mRNA for 5-HT2C and 5-HT2A receptors in the hypothalamus might help explain the functional sensitivity changes observed in the present study.

Amphetamines↗
PubMed1992

Mechanisms of induction of tolerance to syngeneic IgE.

We have previously shown that T cell tolerance to syngeneic IgE in mice is delayed after birth for 2-3 weeks and is induced concurrently with the appearance of IgE in serum. Although inoculation of IgE in saline on the day of birth caused T cell tolerance, an apparent inconsistency was our inability to tolerize mice after day 2, despite evidence indicating that endogenously-produced IgE is effective at the age of 2-3 weeks. Data presented here indicate that repeated i.p. inoculations, during this period, of smaller doses of IgE in saline induce tolerance in many individual mice, thus mimicking to a degree the naturally occurring events. Another earlier finding was that normal adult B cells, but not T cells, can tolerize T cells to IgE when administered on the day of birth. We have now observed that B cells bearing surface IgE are much more tolerogenic than the remaining B cells.

Animals↗
PubMed2000

Humanized severe combined immunodeficient mice as a potential model for the study of tolerance to factor VIII.

A Severe Combined Immunodeficient (SCID) mouse model has been established to evaluate experimental conditions leading to the production of factor VIII (FVIII) autoantibodies. To this end, we humanized 10 groups of 7 mice with peripheral blood mononuclear cells of 10 unrelated healthy blood donors (15 x 10(6) cells/mouse). Mice were injected with saline or immunized i.p. with 50 IU of a plasma derived human FVIII 24 h after reconstitution. Further immunization was made with 25 IU of FVIII every fortnight during 6 weeks and animals were sacrificed after 8 weeks. All reconstituted mice showed a spontaneous production of anti-FVIII antibodies in the absence of immunization with the corresponding antigen. However, no differences were observed regarding the quantity or the quality of these antibodies produced in the immunized or the saline group, indicating that tolerance to FVIII had been transferred with cell reconstitution. Affinity purified FVIII specific antibodies were capable of inhibiting FVIII activity and preventing the binding of FVIII to phospholipids in a dose-dependent manner. Immunoprecipitation experiments showed that the antibodies recognized only the C1 and C2 light chain domains. Since antibodies of interest can be found in the SCID mouse model and, moreover, since they are qualitatively comparable with the source donor's antibodies, this model provides a tool to study the regulation of tolerance against self antigens in normal subjects and in acquired haemophilia patients.

Animals↗
PubMed1987

Role of Pavlovian conditioning in the development of tolerance and cross-tolerance to the hypothermic effect of ethanol and hydralazine.

The role of Pavlovian conditioning in the development of tolerance to the hypothermic effect of ethanol and of cross-tolerance to hydralazine was investigated. In the first study, two groups of rats were treated on alternate days with ethanol (2 or 4 g/kg, respectively, IP) in a novel and distinctive environment (DR). On the non-alcohol days, they received saline in the home room (HR). A control group received saline in both environments. Tolerance to the hypothermic effect of ethanol in the DR was demonstrable in both the 2 and 4 g/kg treatment groups. Tolerance in the HR, however, was observed only in the 4 g/kg treated group. Cross-tolerance to the hypothermic effect of hydralazine was observed for both ethanol-treated groups in the DR but not in the HR. In the second study, ethanol treatment was carried out by daily intubation with 6 g/kg ethanol in the home cage. Tolerance to ethanol-induced hypothermia was demonstrated either in the home cage or in a novel environment. This treatment, however, failed to confer cross-tolerance to the hypothermic effect of hydralazine. These findings suggest that conditioning plays a predominant role in the tolerance produced by low but not by high treatment dosage. The data also suggest that conditioning might be a separate component in tolerance development, which is of special importance in tolerance to behavioral effects in the whole animal rather than to cellular or molecular effects.

Animals↗