The rapid onset of tolerance to ataxic effects of ethanol in mice

We have developed a precise quantal method for assessing the sensitivity to ethanol in the mouse. Mice placed on a clamped stationary horizontal dowel are scored ataxi or not ataxic depending on whether they are able to remian on the dowel during a 30-s observation period. A threshold blood ethanol concentration is determined by assaying tail blood drawn immediately upon recovery from ethanol-induced ataxia. This threshold is quite reproducible within a population of Swiss-Webster mice (coefficient of variation 9%). The precision of this method allowed us to follow the onset of rapid tolerance during a series of sequential IP ethanol doses. Tolerance persisted overnight in the absence of ethanol, and was found not to increase further with additional ethanol exposure on 2 subsequent days. The observed tolerance was shown not to be due to circadian changes in ethanol sensitivity or repeated practice on the task, indicating a true tissue tolerance.     

Lack of tolerance to the disinhibiting effects of alcohol in heavy drinkers

Rationale

Alcohol tolerance is observed as a diminished response to a given dose as a function of repeated administrations of the drug. Research has consistently shown that heavier drinkers display reduced reactions to alcohol (i.e., tolerance) compared with lighter drinkers. However, the majority of this work has focused primarily on measures of motor performance, whereas the development of tolerance to alcohol's impairing effects on cognitive processes, such as inhibitory mechanisms of behavioral control, remains relatively unexplored.

Objective

The purpose of the present study was to examine the relationship between drinking habits and the degree to which alcohol affects drinkers' inhibitory control and motor coordination.

Methods

Fifty-two non-dependent drinkers reported their recent drinking patterns. Their inhibitory control and motor coordination were measured in response to placebo and 0.65?g/kg alcohol.

Results

Alcohol significantly impaired inhibitory control and motor coordination compared with placebo. Moreover, greater quantity and frequency of recent consumption predicted less alcohol impairment of motor coordination. However, there was no relationship between recent drinking habits and the degree of impairment of inhibitory control.

Conclusions

These findings suggest that tolerance to the disinhibiting effects of alcohol might not readily develop as a result of recent, heavy drinking.     

Disruption of tolerance to the ataxic effect of ethanol by an extraneous stimulus

According to a conditioning analysis, pharmacological conditional responses (CRs) contribute to tolerance. We previously reported (24) that, as expected on the basis of this model, tolerance to the hypothermic effect of ethanol is attenuated by “external inhibition,” for instance, by presentation of a novel stimulus (a strobe). However, results of more recent research (2,12,13) indicate that novel stimuli augment the hypothermic effect of ethanol in rats receiving the drug for the first time. It is possible, therefore, that a novel stimulus apparently attenuates ethanol tolerance because it augments ethanol-hypothermia, rather than because it functions as an external inhibitor. Two experiments were designed to evaluate external inhibition of tolerance to another effect of ethanol—ataxia. Although the initial ataxic effect of the drug (unlike the hypothermic effect) is not enhanced by a novel stimulus, the stimulus reinstated ethanol-induced ataxia in tolerant rats. The results demonstrate external inhibition of ethanol tolerance in a preparation not confounded by the effects of the novel stimulus on initial responding to ethanol.     

Extinction and spontaneous recovery of ataxic tolerance to ethanol in rats

RATIONALE AND OBJECTIVES: Two experiments with rats using an ethanol ataxia method investigated extinction and spontaneous recovery of tolerance. Tolerance extinction has been shown with a variety of drugs and methods, but until now it has not been shown with ethanol ataxia. Extinction was investigated here because of its connection with cue exposure treatments, and also to allow an assessment of spontaneous recovery. Spontaneous recovery is the return of conditioned responses, such as those potentially contributing to tolerance, when time passes after extinction. In terms of response topography it resembles instances of relapse in humans. Its demonstration constitutes one technique for illustrating that the effects of extinction are often temporary. There are no published reports showing a recovery of tolerance to any drug due to the passage of time after extinction. A demonstration of spontaneous recovery contributes to an understanding of the effects and time course of tolerance extinction. It also raises the possibility that spontaneous recovery involving drug tolerance has mechanisms similar those involved in instances of spontaneous recovery studied more extensively with non-drug methods. METHODS: In one experiment, ataxic tolerance was conditioned to a strobelight conditioned stimulus (CS) by exposing rats to the strobelight while experiencing the effects of an ethanol injection. Tolerance was extinguished in 17 or 24 once-daily trials by presenting the strobelight without ethanol (with saline). The effect of those numbers of trials was assessed on the day after extinction in the presence of the strobelight when ethanol was again injected. The effect was compared to the effect of the strobelight and ethanol in naive rats and in rats that had received only tolerance conditioning. In a second experiment, ataxic tolerance was conditioned and then extinguished over 17 trials, just as in the other experiment. Different groups were then tested 1, 12, 18, and 24 days after extinction in the presence of the strobelight when ethanol was again injected. RESULTS: Ataxic tolerance was fully extinguished after either 17 or 24 trials, as shown by comparisons with the naive and conditioning-only controls. Tolerance was greater (it recovered) when the strobelight CS was reintroduced 24, 18, and even 12 days after extinction, compared with testing 1 day after extinction. CONCLUSIONS: Conditioned ataxic tolerance can be extinguished, just as other conditioned tolerances can. More important, the return of tolerance over time after extinction represents spontaneous recovery of ethanol tolerance, and indicates that as in other conditioning preparations, extinction does not result in unlearning of the original conditioning association. The identification of spontaneous recovery of tolerance isolates a robust source of the potential for drug use relapse: the mere passage of time after extinction.     

Acute tolerance to the ataxic effects of ethanol in short-sleep (SS) and long-sleep (LS) mice

 The objective of this series of studies was to examine the relationship between alcohol sensitivity and the development of very rapid acute tolerance to alcohol in mice. In order to measure acute tolerance to alcohol, a behavioral test was developed using a rotorod. In the first study, mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute hypnotic effects of ethanol were used, as well as mice from the base population (heterogenous stock, HS). Mice were trained to run on the rotorod at a speed of 14 rpm to a criterion of 200 s, in four daily training sessions. On the test day, baseline measurements of rotorod performance were taken and mice were injected IP with alcohol in doses from 0 to 2.5 g/kg. Animals were tested at 1-min intervals for the first 5 min following injection, then at 5-min intervals for a total of 30 min. The results demonstrated that SS and HS mice developed tolerance within 10 min following the alcohol injections. LS mice did develop some acute tolerance, but at a much slower rate than the SS or HS mice. In the second study, the effects of intoxicated practice on the rates of acute tolerance development were examined in the SS, HS and LS mice at a dose of 2.0 g/kg alcohol. A total of ten groups of each strain were given a different number of practice trials (ranging from one to ten) on the rotorod prior to a final test session at 30 min post-injection. The results provide evidence that SS and HS mice are capable of developing acute tolerance independent of practice. That is, the group of animals injected at 0 time and tested ten times up to 30 min were no better at the 30-min time point than the group injected at 0 time and tested only once at 30 min. On the other hand, the LS mice showed a modest practice effect, developing additional tolerance to the ataxic effects of alcohol with increasing intoxicated practice. Overall, these studies demonstrated that mice can develop acute tolerance within minutes following alcohol exposure, and that this ability is correlated with the initial sensitivity to alcohol. Received: 12 July 1997 / Final version: 26 August 1997     

A mathematical theory for temporal changes in tolerance to the behavioral effects of alcohol

Temporal changes in the tolerance to alcohol are rarely discussed. In the behavioral theory proposed here, the rate of increase in tolerance during alcohol exposure is described by linear equations with zero intercept. These equations describe the rate of tolerance growth for acute tolerance, the rate of tolerance growth after alcohol dosing (chronic tolerance), and, for cases in which tolerance has been conditioned, the equations also describe changes in the rate of growth of tolerance when the stimulus set changes. This theory does not explain tolerance acquisition, but may be useful in investigating the physiological basis for tolerance acquisition because it provides numerical values for momentary tolerance that can be compared with concurrent physiological changes. The theory is testable and most of the published behavioral data on non-conditioned tolerance are consistent with the proposed theory. New empirical data on conditioned tolerance are needed to evaluate the proposed theory, and the design for an evaluation is suggested here. Despite its limitations, the theory serves as one example of what a mathematical theory for tolerance might be and may stimulate the development of competing theories with which it could be compared empirically.     

Acute tolerance to alcohol: changes in subjective effects among social drinkers

The development of acute of acute tolerance to the subjective effects of alcohol was examined in 32 social drinkers. Measures were made of self-reported level of intoxication and responses to questions from the alcohol scale of the Addiction Research Centre Inventory. The time to peak self-reported intoxication level was found to be 20 min earlier than the time to peak blood alcohol concentration. Changes from the ascending to the descending limb of the blood alcohol curve were found with five of the ARCI questions. In all cases the proportion of alcohol-typical responses was lower on the descending portion of the curve. even though blood alcohol levels were equivalent. Further analyses examined the effects of prior drinking history on the development of acute tolerance. Peak self-reported intoxication levels were significantly lower and occurred earlier for heavier drinkers. Furthermore, for four of the five ARCI questions heavier drinkers were less likely to give analcohol-typical response than lighter drinkers on the ascending portion of the curve.     

Acute tolerance to alcohol effects on inhibitory and activational mechanisms of behavioral control

OBJECTIVE: Acute alcohol tolerance refers to the observation of reduced impairment at a given blood alcohol concentration (BAC) on the descending versus ascending limb of the blood alcohol curve. Psychomotor performance measures used in human studies of alcohol tolerance provide reliable assessments of tolerance but do not identify specific mechanisms involved in the re-establishment of control, and little is known about how acute tolerance is expressed in terms of changes in fundamental mechanisms that regulate and control behavior. This study examined the expression of acute alcohol tolerance to impaired behavioral control in terms of changes in a drinker's ability to activate and inhibit behavioral responses as BAC ascended and declined following a dose. METHOD: Twenty social drinkers performed a cued go/no-go task that measured behavioral control after receiving a moderate dose (0.65 g/kg) of alcohol and a placebo. The development of acute tolerance was measured by testing behavioral control twice: once during the ascending phase and again at comparable BACs during the descending phase of the blood alcohol curve. RESULTS: Inhibitory and activational aspects of behavioral control both were impaired by alcohol. Acute tolerance developed to the impaired activation but not to the impaired inhibition of behavior. CONCLUSIONS: The results highlight the importance of considering behavioral requirements when testing for the development of acute tolerance under a dose of alcohol. By modeling behavioral control as the net effect of countervailing activational and inhibitory influences, the study suggests that fundamental mechanisms of control might not display uniform tolerance development.     

Contingent tolerance to the disruptive effects of alcohol on the copulatory behavior of male rats.

Sexually active male rats received five 30-min copulation tests with sexually receptive females, one every 4 days. One group of rats received alcohol (1 g/kg, IP) 45 min before, and an equivalent volume of saline 45 min after, each test; a second group received saline before and alcohol after each test; and a third, control group received saline both before and after. Four days after the last of the five tolerance-development trials, each rat received an injection of alcohol (1 g/kg, IP) 45 min before a copulation test so that the development of tolerance in the three groups could be compared. Tolerance to the disruptive effects of alcohol on mount, intromission, and ejaculation latencies, and on the duration of the postejaculatory interval was found to be significantly greater in the rats injected with alcohol before each copulation test than it was in the rats in the other two groups. These results constitute the first experimental evidence that tolerance develops to the disruptive effects of alcohol on male sexual behavior, and they support the theory that tolerance is an adaptive response to the disruptive effects of drugs on concurrent patterns of neural activity, rather than to drug exposure per se.     

Context-specific morphine tolerance on the paw-pressure and tail-shock vocalization tests: evidence of associative tolerance without conditioned compensatory responding

Rationale: Demonstrations of associative tolerance to the analgesic effects of morphine, not confounded by practice or novelty effects, have been restricted to the tail-flick and flinch-jump tests. Objectives: Experiment 1 investigated whether associative tolerance would be found on two other nociceptive assessment methods: the paw-pressure withdrawal and tail-shock vocalization thresholds. Experiment 2 tested the hypothesis that conditioned compensatory behavioral responses are the substrate of associative morphine tolerance in the paw-pressure, tail-shock, and tail-flick tests. Methods: Rats were given eight morphine injections (20 mg/kg, i.p.) explicitly paired or unpaired with a distinctive context. Control animals were given saline injections over the course of conditioning. Animals were then tested after morphine (experiment 1) or placebo injections (experiment 2) in the context. Results: There was evidence of context-specific tolerance across both testing methods, with a rightward shift of dose–response curves of paired relative to unpaired animals. No evidence of conditioned compensatory responding was found on any of the three testing methods. Conclusions: The data indicated that, although Pavlovian processes can play a major role in tolerance acquisition, there was little support for the thesis that the conditioned tolerance response is a behavioral effect that is opposite in direction to the direct effects of the drug. Received: 22 December 1998 / Final version: 22 March 1999     

A quantitative theory of acute tolerance to alcohol

Rats exhibit profound individual differences in their propensity to ingest sugar and in their locomotor response to AMP. Intrinsic variation in the responsiveness of mesolimbic dopamine mechanisms has been suggested to account for these individual differences. In light of this overlap, it might be expected that individual differences in one behavior would predict individual differences in the other. The present study determined whether individual differences in sugar intake would predict individual differences in the locomotor response to AMP. Male Wistar rats were divided into low and high feeders based on a median split of their sugar intake in response to saline administration and were subsequently tested for their locomotor response to either 1.0 or 1.75 mg/kg AMP in experiment 1. High sugar feeders exhibited significantly more locomotion than low sugar feeders in response to 1.75 mg/kg AMP. This difference was observed immediately after injection and continued for approximately 90 min. There was no difference between the two groups in their locomotor response to 1.0 mg/kg AMP. In experiment 2, rats receiving 1.0 mg/kg AMP in experiment 1 were tested for the development of behavioral sensitization with repeated AMP administrations. Rats were administered 1.0 mg/kg AMP across 5 test days, interspersed with days in which they received AMP treatment in their home cages to minimize conditioning effects. High sugar feeders exhibited greater behavioral sensitization than low sugar feeders with repeated AMP administration. Starting on test day 3, high sugar feeders exhibited significantly greater AMP-induced locomotor activity than low sugar feeders. Taken together, these findings support the notion that there is overlap in the neurobiological substrates regulating sugar intake and responsivity to the locomotor activating effect of AMP. Furthermore, these results establish that the propensity to ingest sugar is a predictor of the susceptibility to the locomotor enhancing properties of AMP.     

An extinction cue reduces spontaneous recovery of ataxic ethanol tolerance in rats

Rationale and objectives Ethanol ataxia experiments with rats investigated cue effects on conditioned tolerance. Spontaneous recovery (SR) was assessed 1 day and 18 days after extinction with conditioned stimuli (CSs) paired or unpaired with an ethanol unconditioned stimulus (US). Behavioral tolerance was assessed by not tilting the apparatus during conditioning. Non-associative processes were assessed post-conditioning with or without a buzzer cue. Boutons (1993, Psychol Bull 114:80–99) memory theory was tested using an extinction cue and an associatively neutral cue presented during SR testing.Methods Tolerance was conditioned to a room + strobelight CS by ethanol injections experienced on a tilting floor (standard conditioning). Controls received no ethanol or ethanol, either during the CS without the floor tilting or 11 h post-CS. SR testing occurred 1 day or 18 days after extinction (experiment 1). Conditioning was followed by tolerance and CR tests either with or without a 15-s buzzer cue (experiment 2). In extinction, the CS and cue occurred without ethanol; the cue occurred before 7% or none of the extinction trials. Testing occurred 18 days after extinction with or without that cue (experiment 3), or with an equally familiar (neutral) cue presented before conditioning (experiment 4). Results Tolerance developed without floor tilting. CS–US unpairings prevented tolerance. Tolerance SR occurred 18 days but not 1 day after extinction only after CS–US pairings (experiment 1). Post-conditioning tests showed no unconditioned effects of the cue (experiment 2). Testing with no cue 1 day after extinction with the cue resulted in no tolerance increase. The extinction cue reduced SR (experiments 3 and 4); the neutral cue did not (experiment 4).Conclusions Cues correlated with extinction reduce SR. Non-associative and practice processes, Boutons (1993, Psychol Bull 114:80–99) memory theory, alternative interpretations, and clinical implications are discussed.This research was supported by funding from Denison University.     

A blood marker for pharmacodynamic tolerance to alcohol

The treatment of alcoholism may be delayed because of the difficulty in confirming a diagnosis. There are currently no direct blood tests to objectively determine the presence of pharmacodynamic tolerance to alcohol. The state of the membrane fluidity of the peripheral blood erythrocyte may provide a biophysical measurement of the pharmacodynamic tolerance to alcohol. This discussion proposes methods that potentially may be applied to the clinical purpose of diagnosing alcoholism in humans. The methods have been used to successfully measure pharmacodynamic tolerance in animals and humans. The development of the physiologic state of acquired tolerance and dependence is related to alcohol intake. Chronic alcohol consumption that leads to pharmacodynamic tolerance may be assessed by measuring the membrane fluidity of the peripheral blood erythrocyte. Physiologic recovery from tolerance and dependence to alcohol may also be assessed during withdrawal in which the reversal of changes in membrane fluidity is measured in the abstinent state. Relapse to drinking may be detected in the state of the membrane fluidity of the peripheral blood erythrocytes that reflect the return of tolerance and dependence. Tolerance to alcohol may be a manifestation of the inheritability to alcoholism. Alcoholics and high risk individuals appear to have an increased, innate (genetic) tolerance to alcohol. High risk individuals are nonalcoholic, blood relatives of alcoholics. Animal studies suggest that innate (genetic) tolerance and dependence to alcohol may be related to the biophysical state of erythrocyte membrane fluidity. The assessment of these changes in membrane fluidity of the erythrocyte may be performed in the peripheral blood in humans. A trait marker (in the genetically predisposed) for high risk individuals and a state (in the actively drinking) marker for pharmacodynamic tolerance in the erythrocyte might be developed. In this way, a blood test may be used to detect the inheritability for alcoholism and the development of pharmacodynamic tolerance to alcohol. No blood test for pharmacodynamic tolerance is currently available. This article represents an extrapolation from animal and human research data. The proposals contained therein may not be considered readily, clinically applicable.     

Subjective alcohol effects and drinking behavior: the relative influence of early response and acquired tolerance

OBJECTIVES: (1) To establish the reliability and validity of a modified version of the Self-Rating of Alcohol (SRE) form. (2) To differentiate early subjective alcohol response (SR) from acquired tolerance in the prediction of drinking outcomes. METHOD: 353 undergraduates completed an online survey. SR was assessed using the SRE form and a modified SRE including items assessing global stimulant and sedative effects. The Daily Drinking Questionnaire-Revised (DDQ-R), and the Rutgers Alcohol Problems Index (RAPI) assessed alcohol use and problems, respectively. RESULTS: The revised version of the SRE showed good internal consistency and incremental validity. Early SR assessed by the modified SRE was consistently associated with use and problems. Acquired tolerance was significantly related to use and problems above and beyond early SR. CONCLUSIONS: The modified SRE incorporating stimulant and sedative responses demonstrated good psychometric properties and the potential to capture unique variability in drinking outcomes. Differentiating early SR from tolerance showed that each contributes uniquely to drinking behavior and problems. Thus, future studies would benefit from examining the unique contribution of each aspect of SR.     

Assessment of tolerance to the hallucinogenic effects of DOM

DOM was administered to five subjects, each of whom received 6 mg of the drug daily for 3 consecutive days. Tolerance was observed. This finding is correlated with prior studies of behavioral biochemical and electrophysiologic aspects of DOM tolerance in cats.     

Development of tolerance to the side effects of primidone

Side effects and antiepileptic drug levels were measured during initiation of and chronic treatment with primidone (PRM). A significant change in the toxicity/serum level ratio was observed 6 h after the initial PRM dose. The amount of toxicity manifested by patients receiving PRM as their initial antiepileptic drug was not different from that of those patients previously treated with phenytoin (PHT) or carbamazepine (CBZ). These findings indicate rapid development of functional tolerance to side effects of PRM, which is not altered by previous exposure to PHT or CBZ. Phenobarbital pretreatment appears to produce cross-tolerance to the effects of PRM.     

Development of tolerance to the antiaggressive effects of morphine

Many reports have demonstrated that there is a development of tolerance to many effects produced by morphine. This study was conducted with the aim of determining whether the antiaggressive actions of morphine develop tolerance after chronic administration. Acute morphine administration produced antiaggressive effects which disappeared after chronic (7 days) treatment in isolated mice. An increase in non-social exploration was observed, representing morphine-induced hyperactivity, after acute treatment, which was not present after chronic administration. In conclusion, there is a development of tolerance to the antiaggressive and motor effects of morphine.     

Alcohol is an effective cue in the conditional control of tolerance to alcohol

To assess the effectiveness of a pharmacological cue as a conditional stimulus in the Pavlovian model of drug tolerance, two groups of Wistar rats received equal numbers of IP injections of a low and a high dose of alcohol. One group (Paired) received a low dose (0.8 g/kg) of alcohol followed 60 min later by the high dose (2.5 g/kg). Another group (Unpaired) received the low and high doses on an unpaired basis. When tested for tolerance to the hypothermic effect of the high dose of alcohol, only the Paired group showed tolerance, and only if the low dose preceded the high. When a saline injection preceded the high dose injection, the Paired group showed a loss of tolerance. The Paired group also showed a compensatory hyperthermia following the low dose injection. Animals from the Paired group that received repeated administrations of the low dose followed by saline, showed a significant extinction effect as compared with animals that received repeated saline injections only. These findings support the Pavlovian model of conditional tolerance, extending the realm of effective conditional stimuli to include a low dose of a drug.     

Conditioned tolerance to the heart rate effects of smoking

This study extended our findings that behavioral tolerance to nicotine in animals can be influenced by conditioning to cardiovascular tolerance in humans. Subjects smoked one-half a cigarette during each of five trials. In the ten-minute intersmoking interval the contexts that preceded smoking were varied. Smokers in the Changing group attended to a different five-minute segment of a Sherlock Holmes radio mystery before each trial, while those in the Repeated group listened to the same segment of the tape. Presmoking heart rates were stable across the groups from trials 1 to 5. As predicted, heart rate for subjects who smoked in the same context showed tolerance to smoking from trials 1 to 5 (84.5 to 78 bpm), while subjects who smoked in in the same context showed tolerance to 83.9 bpm). COa levels increased equally for both groups over the five trials. The results of this study suggest tolerance to smoking can be influenced by learning.