Rate Of Tolerance Development Research Articles

Pharmacological targeting of the GABAB receptor alters Drosophila's behavioural responses to alcohol.

When exposed to ethanol, Drosophila melanogaster display a variety of addiction‐like behaviours similar to those observed in mammals. Sensitivity to ethanol can be quantified by measuring the time at which 50% of the flies are sedated by ethanol exposure (ST50); an increase of ST50 following multiple ethanol exposures is widely interpreted as development of tolerance to ethanol. Sensitivity and tolerance to ethanol were measured after administration of the gamma‐aminobutyric acid receptor B (GABAB) agonist (SKF 97541) and antagonist (CGP 54626), when compared with flies treated with ethanol alone. Dose‐dependent increases and decreases in sensitivity to ethanol were observed for both the agonist and antagonist respectively. Tolerance was recorded in the presence of GABAB drugs, but the rate of tolerance development was increased by SKF 97451 and unaltered in presence of CGP 54626. This indicates that the GABAB receptor contributes to both the sensitivity to ethanol and mechanisms by which tolerance develops. The data also reinforce the usefulness of Drosophila as a model for identifying the molecular components of addictive behaviours and for testing drugs that could potentially be used for the treatment of alcohol use disorder (AUD).

ROLE OF PYRIDOXINE HYDROCHLORIDE IN THE DEVELOPMENT OF TOLERANCE TO THE TOXIC ACTION OF ISONIAZID IN ANIMALS

The objective of the study:to assess the impact of continuous and course (intermittent) use of pyridoxine hydrochloride in combination with isoniazid on the rate of tolerance development in rats under conditions of a toxicological experiment.Subjects and methods. Isoniazid (tablets, 0.3 g.) and the substance of pyridoxine hydrochloride (powder, 50.0 g.) were used for the experiment. Male white rats were used as experimental biological models.Main results. The article presents data on experimental study of toxicologic tolerance of rats to the anti-tuberculosis drug of isoniazid with its administration simultaneously with pyridoxine hydrochloride. The obtained data provided the evidence about the impact of pyridoxine hydrochloride on the rate of how fast the host developed the tolerance to the toxic action of isoniazid. It has been proved that intermittent (by short courses) use of pyridoxine hydrochloride with isoniazid versus its continuous use resulted in a slower development of toxicological tolerance to isoniazid in rats.

Quantitative analysis of rate and extent of tolerance of biomarkers: Application to nicotinic acid-induced changes in non-esterified fatty acids in rats

In this paper we quantitatively evaluate two feedback systems with a focus on rate and extent of tolerance and rebound development. In the two feedback systems, the regulation of turnover of response is governed by one or several moderators. In the basic system, one single moderator inhibits the formation of response. This system has been applied to cortisol secretion and serotonin reuptake inhibition. The basic system has been extended to adequately describe nicotinic acid (NiAc)-induced changes in non-esterified fatty acids (NEFA). In the extended system, the feedback is described by a cascade of moderators where the first inhibits formation of response and the last stimulates loss of response. The objectives of this paper were to analyze these systems from a mathematical/analytical and quantitative point of view and to present simulations with different parameter settings and dosing regimens in order to highlight the intrinsic behaviour of these systems and to present expressions and graphs that are applicable for quantification of rate and extent of tolerance and rebound. The dynamics of the moderators ( k tol ) compared to the dynamics of the response ( k out ), was shown to be important for the behaviour of both systems. For instance, slow dynamics of the moderator compared to the response ( k tol << k out ), resulted in overshoot and pronounced rebound. The extent of tolerance was studied over time at a single constant drug concentration and at steady state for different drug concentrations and was found to be largest at drug concentrations close to IC 50. An upper limit for the response could be identified and included in the quantification of extent of rebound. Especially, for the extended system, the duration of exposure was an important factor affecting size of rebound. The rate of tolerance development was addressed by quantitatively estimating the time to steady state for the two systems, in which the value of k tol and the length of the cascade were critical.

The natural history of egg allergy

Egg allergy is very common, affecting 1% to 2% of children. It is generally thought that the majority of children with egg allergy develop tolerance in early childhood; however, this has not been examined in a large cohort with egg allergy. The purpose of the study was to estimate the proportion of children with egg allergy who develop egg tolerance and to identify predictors of tolerance development. Retrospective chart review of patients with egg allergy seen in a tertiary referral clinic. Patients were considered to have developed egg tolerance if they tolerated concentrated egg. Kaplan-Meier analysis predicted resolution in 4% of patients with egg allergy by age 4 years, 12% by age 6 years, 37% by age 10 years, and 68% by age 16 years. Patients with persistent egg allergy had higher egg IgE levels at all ages to age 18 years. A patient's highest recorded egg IgE, presence of other atopic disease, and presence of other food allergy were significantly related to egg allergy persistence. A majority of patients with egg allergy will develop egg tolerance, although the rate of tolerance development is slower than described previously. Egg IgE is predictive of allergy outcome and should be used in counseling patients on prognosis. Most patients with egg allergy are likely to develop egg tolerance by late childhood, with the exception of patients with an egg IgE greater than 50 kU/L, who are unlikely to develop egg tolerance.

Drunk Worms Reveal Alcohol Tolerance Gene

Davies et al. took advantage of allelic variation in strains of the nematode Caenorhabditis elegans to identify a gene that contributes to tolerance to the effects of ethanol exposure. C. elegans exhibits a decline in locomotor activity as an acute response to ethanol. Over time, in the continued presence of ethanol, different strains of worms, N2 and CB4856, show slow and rapid development of tolerance, respectively. Through genetic analysis, the differences in the rate of tolerance development were mapped to the nrp-1 gene, which encodes the homolog to mammalian neuropeptide Y (NPY) receptors. The CB4856 allele of npr-1 is a lower function allele than that of the N2 worms, and these different alleles of npr-1 are known to account for the worm's differences in social behaviors (N2 are solitary, CB4856 are more social and exhibit clumping behaviors). The social behavior roles of NPR-1 and the ethanol tolerance effect were separable based on genetic interactions and targeted expression studies. Worms carrying mutations in genes involved in controlling social behaviors showed no difference in ethanol tolerance rates. However, ethanol may inhibit NPR-1 signaling, because withdrawal of ethanol causes N2 worms to exhibit clumping and other social behaviors. NPY signaling is implicated in alcohol responsiveness in mammals, and further investigation with the genetically tractable nematode may lead to additional insight into the molecular mechanisms that contribute to alcoholism. A. G. Davies, J. C. Bettinger, T. R. Thilel, M. E. Judy, S. L. McIntire, Natural variation in the nrp-1 gene modifies ethanol responses of wild strains of C. elegans . Neuron 42 , 731-743 (2004). [Online Journal]

Reduced tolerance to the anti-hyperalgesic effect of methadone in comparison to morphine in a rat model of mononeuropathy

The development of tolerance to chronically administered methadone and morphine was examined in a rat model of neuropathic pain after ischemic nerve injury. In drug naive neuropathic rats systemically administered morphine or methadone similarly and dose-dependently alleviated mechanical allodynia. Tolerance to the anti-hyperalgesic effect of equally effective doses of morphine (10 mg/kg) or methadone (5 mg/kg) developed upon administration twice daily. However, the rate of tolerance development was significantly slower for methadone in comparison to morphine. Chronic morphine treatment for 14 days induced almost complete loss of the anti-allodynic effect to morphine, whereas methadone still had partial effect after 21 days of chronic treatment. Partial cross-tolerance was observed between morphine and methadone. It is suggested that the delayed development of tolerance to methadone in neuropathic rats may be related to the higher intrinsic activity of methadone compared to morphine, as well as the N-methyl- d-aspartate receptor blocking property of methadone. The latter may also contribute to preservation of μ-opioid anti-nociception following chronic methadone treatment.

Genetic–environment analysis of sensitivity and acute tolerance to ethanol in mice

The purpose of this study was to characterize initial sensitivity (IS), acute functional tolerance (AFT), and rate of tolerance development to ethanol in lines of mice selected for aggression mice as well as to investigate the impact of isolate housing on these phenotypes. The results showed that for IS, there were no differences among treatment groups. For acute tolerance and rate of tolerance development, a Line×Sex×Housing interaction was present, with the response to housing being more pronounced in the low aggressive line than the high aggressive line, and the females being more affected than the males. Correlational analysis showed low to moderate associations between rate of tolerance development and IS, as well as between rate of tolerance and AFT. Housing condition significantly influenced female expression of ethanol phenotypes as compared to males. The line of the subject also influenced the magnitude of expression of these phenotypes. These findings suggest that environmental and genetic influences interact to influence acute tolerance and rate of tolerance development.

Genetic differences in morphine sensitivity, tolerance and withdrawal in rats

Significant genetic differences in the endogenous opioid system and in response to a variety of noxious stimuli are present in rodents. We now compared the response to noxious heat with the hot plate test, morphine sensitivity and the development of tolerance and dependence to morphine in spontaneously hypertensive (SHR), Wistar–Kyoto (WK) and Sprague–Dawley (SD) rats. Significant differences were observed in basal nociception among the three strains, where SHRs were hypoalgesic compared to WK and SD. The antinociceptive effect of morphine varied among strains (SD>SHR>WK) as did the rate of tolerance development (10 mg/kg morphine 2/day for 4 days) where WK>SD=SHR. SHR rats developed hyperalgesia following morphine administration during the course of tolerance development. Furthermore, although naloxone (2 mg/kg) precipitated withdrawal symptoms in all tolerant rats, the panorama of symptoms varied among the three strains. Thus, there are significant genetic differences in a variety of effect of opiates.

Role of initial sensitivity and genetic factors in the development of tolerance to ethanol in AT and ANT rats

The role of initial sensitivity and genetic factors in the development of tolerance to ethanol were examined in rats selected for low (AT) and high (ANT) sensitivity to the motor impairment effect of ethanol. Following chronic ethanol treatment (5 g/kg PO, daily for 20 days), the AT and ANT rats acquired tolerance to the motor impairment effect of ethanol at a similar rate. The AT rats, however, acquired tolerance to the hypothermic effect of ethanol at a higher rate than the ANT rats. Such ethanol treatment did not produce any metabolic tolerance to ethanol in these animals. Since there is no difference in the initial response to the hypothermic effect of ethanol between the AT and ANT rats, the observed differences in the rate of tolerance development might be related to a direct genetic factor. The similar rate of tolerance development to the motor impairment effect of ethanol between the two lines was attributed to an interaction between an indirect (initial sensitivity) and a genetic factor in tolerance development.

Nicotine interactions with ethanol tolerance

Nicotine (N) administration (0.05 mg/kg SC) was paired with ethanol (E, 2.5 g/kg, 15% v/v, IP) to determine if N alters either the acquisition of extinction of tolerance to the hypothermic and sedative effects of E. During tolerance acquisition the following groups were tested: E + N (N = 16), E + NaCl vehicle (V) (N = 16), V + N (N = 4) and V + V (N = 4). For 11 days a colonic temperature was taken, both drugs were injected and the rats were tested for locomotor activity for 45 min, after which a final colonic temperature was taken. N significantly enhanced the rate of tolerance development to the hypothermic effects of E and blocked a degree of the sedative effects. On Days 12 to 17 rats in all groups received V injections to extinguish tolerance. On Days 18 to 24 rats in the E + N group were tested with either E + N or E + V and rats in the E + V group were similarly divided. Previous treatment with N significantly attenuated the extinction process which in turn enhanced the reacquisition of tolerance.

Cross-tolerance between ethanol and chlordiazepoxide

Drug-induced hypothermia was used to investigate drug tolerance and cross-tolerance. C57BL/6J mice, which were injected with a single dose of chlordiazepoxide (CDP; 30 mg/kg) one day before and reinjected with an equivalent dose of CDP the next day, did not develop tolerance to the drug. However, ethanol-pretreated (3.5 g/kg, 24 hr earlier) mice, when injected with CDP (30 mg/kg), showed cross-tolerance to CDP. The cross-tolerance was short-lived (<48 hr). On the other hand, CDP-pretreated mice (30 mg/kg, 24 hr earlier) did not show cross-tolerance to ethanol. The lack of a reciprocating effect of CDP-pretreatment was not likely to be due to the difference in initial dosage between ethanol and CDP. It may be due to different rates of tolerance development or different mechanisms of actions between CDP and ethanol. Mice chronically treated with ethanol also showed a similar degree of cross-tolerance to CDP compared to those exposed to an acute dose of ethanol.

Role of serotonin (5-HT) in tolerance to ethanol and barbiturates.

Previously it has been shown that chronic administration of p-chlorophenylalanine (p-CPA), slowed the development of tolerance to ethanol, pentobarbital and cross-tolerance development to ethanol in rats chronically treated with pentobarbital. These findings have been extended by the following observations: (1) p-CPA slowed the development of tolerance to barbital as measured by motor impairment on the moving belt test, without altering the acute response. (2) p-CPA also reduced the tolerance to barbital as measured by sleeping time, in animals chronically treated with pentobarbital. (3) Administration of L-tryptophan increased the rate of tolerance development to ethanol as measured by motor impairment and hypothermia. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives.

Behavioral influences on tolerance to the effects of morphine on schedule-controlled behavior.

Responding of pigeons was maintained under a multiple fixed interval, fixed ratio schedule of food delivery, and 10 mg/kg morphine was administered daily. Responding during both schedule components was initially decreased and measurable tolerance developed to this effect after four daily injections. However, the rate of tolerance development differed depending on whether or not presence of the drug coincided with performance during experimental sessions. Tolerance developed more rapidly when morphine was given before daily experimental sessions than when morphine was given daily but animals did not perform daily in experimental sessions. Tolerance to the rate-decreasing effects of morphine depended on relations between presence of the drug and exposure to experimental sessions.

Effect of l-tryptophan on the acquisition of tolerance to ethanol-induced motor impairment and hypothermia

Rats were rendered tolerant to ethanol by daily gavage of 4--5 g/kg. The degree of motor impairment on the moving belt test and of hypothermia after i.p. test doses of ethanol was measured prior to and at various times during the chronic treatment, to assess the rates of tolerance development. L-Tryptophan (75 mg/kg twice daily) was administered chronically to elevate brain serotonin level. This treatment did not alter the motor impairment or hypothermia produced by the initial test doses of ethanol (2.0 and 2.5 g/kg respectively). However, the development of tolerance to both the motor impairment and hypothermia effects of ethanol was accelerated in the tryptophan-treated rats. This finding complements our earlier observations that depletion of 5-HT with p-CPA slows down tolerance. Blood ethanol measurements at 20 min (motor impairment) or 90 min (hypothermia) after the administration of the test dose reveal no significant difference between the control and tryptophan-treated rats, suggesting that tryptophan did not influence the metabolism of ethanol. This finding supports the hypothesis that brain serotonin modulates the development of tolerance to ethanol.

Behavioral and electroencephalographic correlates of the chronic use of marijuana—A review

Research and discussion related to the behavioral and electroencephalographic effects of long-term use of marijuana or its constituents are reviewed. It is concluded that tolerance develops to the behavioral and electroencephalographic depressant aspects of the cannabis drugs but little attentuation develops to the stimulant effects. The rate of tolerance development is considerably influenced by learning factors such as the opportunity or necessity to make behavioral responses that counteract the decrements in performance resulting from the drug's influence. Evidence is presented indicating that the animal and human literature are in considerable agreement if socially acquired cues and expectancies and dosage/frequency parameters are taken into consideration.

Facilitation by dexamethasone of tolerance to ethanol in the rat

The purpose of this study was to examine the relationship between the development of tolerance to ethanol and the hypothalamic-pituitary-adrenal cortex (H-P-AC) system by modifying the H-P-AC system through the use of a synthetic glucocorticoid, dexamethasone. Also this study determined whether repeated drug administration and environmental adaptation would facilitate development of tolerance. Rats injected daily with dexamethasone and ethanol showed an antagonism to the acute effects of ethanol and a higher rate of tolerance development to the depressant effect of ethanol than animals administered ethanol only. These results were discussed in relation to a possible stimulant effect of dexamethasone on behavior, an increase in the metabolism of ethanol, and a possible accumulation of dexamethasone in the brain, affecting an organism's response to ethanol. It also was shown that daily ethanol administration and adaptation to the testing environment facilitated the development of tolerance, compared to ethanol administration only.

Effect of p-chlorophenylalanine on the acquisition of tolerance to ethanol and pentobarbital.

Rats were rendered tolerant to ethanol or pentobarbital by daily oral administration. Motor impairments after test doses of ethanol or pentobarbital were measured prior to and at various times during chronic treatment in order to assess the degree of tolerance development. Chronic administration of p-chlorophenylalanine (p-CPA) in a dosage regimen which produced and maintained approximately 95% depletion of brain serotonin (5-HT) did not alter motor impairment after initial acute administration of ethanol or pentobarbital. However, the rate of tolerance development to the motor-impairing effects of both drugs was slowed down in p-CPA-treated rats, p-CPA did not appear to exert this effect by altering the disposition of ethanol or pentobarbital, since blood levels determined 20 min after administration of the test doses were similar in animals treated with p-CPA and in controls. These findings suggest that brain 5-HT may have a role in tolerance development to ethanol and pentobarbital.

Tolerance to the hypothermic effects of 9-tetrahydrocannabinol as a function of age in the chicken.

1. (-)-Delta(9)-Tetrahydrocannabinol was administered to chicks (Gallus domesticus) of various ages and body temperature and tolerance to the hypothermic effects of the drug were examined as a function of age.2. The hypothermic effects were found to be greater in neonatal than older animals and likewise tolerance took longer to develop in younger chicks.3. The rate of tolerance development, however, could be increased in the neonate by preadministration of a high dose of the drug.

A quantal method for the study of tolerance to analgetics

A quantal modification of a thermal analgesimetric procedure was applied to the study of tolerance in albino rats. Four potent narcotic analgetics, morphine sulfate, methadone hydrochloride, metopon hydrochloride, and levorphan tartrate, were administered daily for seven weeks and the amount of each drug required to produce a chosen degree of analgesia, the AD50, determined at weekly intervals. Analysis of the data so obtained indicated that the rate of tolerance development is different for each of these four drugs. The rate was most rapid with levorphan, while metopon, methadone, and morphine showed lesser rates. The results seem to agree reasonably well with clinical impressions and the procedure is suggested as a simple and reliable method for the measurement of tolerance development to analgetics in animals.