Context-drug pairings enhance tolerance to ethanol-induced disruption of operant responding

Much of the research implicating learning in the development of tolerance to ethanol-induced impairment has used an experimental design in which different groups receive drug either before or after an opportunity to perform an instrumental or operant task. The stronger tolerance observed in subjects who perform while intoxicated is most often attributed to the reinforced practice of a learned compensatory response. Using an experimental procedure modeled after Chen (1979), the present study examined an alternative theoretical basis for tolerance in the before-versus-after design. Specifically, the effects of Pavlovian context-drug pairings were assessed under circumstances that precluded reinforced practice of the operant response. Three groups of food-deprived rats were initially trained to barpress for sucrose on an FR15 schedule. After 30 sessions, the bar was retracted and the dipper was covered for a 3-day tolerance acquisition phase. During this phase, each group received an IP injection 15 min before and 45 min after each session. The Paired group received ethanol (1.2 g/kg) before and saline after the session, thus pairing ethanol with cues of the test chamber. The Unpaired group received saline before and ethanol after the session, while the No-Drug group always received saline. During a final test phase, all groups received ethanol (1.5 g/kg) before access to sucrose on the FR schedule. The Paired group completed the first FR15 sequence more rapidly than either control group, indicating that context-ethanol pairings enhanced tolerance to the drug's disruptive effect on the initiation of operant responding. However, there was little evidence of conditioned stimulus control over tolerance to ethanol's thermal effect. Overall, these data suggest that stimulus-drug contingencies occurring in operant procedures may play an important role in development of tolerance to ethanol's behavioral effects.     

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.     

Evidence for dissociable mechanisms of amphetamine-and stress-induced behavioral sensitization: effects of MK-801 and haloperidol pretreatment

The present study examined the ability of pretreatment with MK-801 or haloperidol to block the induction of behavioral sensitization to amphetamine challenge by repeated immobilization stress in male Sprague-Dawley rats. Fifteen minutes before each of ten 30-min restraint sessions, rats were administered saline, MK-801 (0.01, 0.10 or 0.25 mg/kg IP) or haloperidol (0.10 or 0.25 mg/kg IP). Control rats received the same injection regimen without restraint. An additional experiment examined the ability of MK-801 to block the induction of sensitization by repeatedd-amphetamine. In this experiment, rats were administered saline or MK-801 (0.25 mg/kg IP) 15 min before each of ten amphetamine injections (1.0 mg/kg IP, administered under the same regimen as immobilization stress). Four days after the final immobilization or amphetamine injection, rats were tested for locomotor response to novelty, saline andd-amphetamine (1.5 mg/kg IP). Exposure to repeated immobilization stress significantly enhanced the locomotor response to amphetamine challenge but not to saline challenge whether rats were pretreated with saline, MK-801 or haloperidol. Secondary analysis of dose effects in each pretreatment group revealed that at 0.25 mg/kg, repeated MK-801 in itself induced sensitization to the response to amphetamine in control rats and potentiated stress-induced sensitization in restrained rats. In contrast, the sensitization induced by repeated amphetamine was attenuated by MK-801 pretreatment. Neither dose of haloperidol affected the locomotor response to saline or amphetamine in control or stressed rats. These results indicate that the effects of MK-801 on the induction of sensitization are complex and suggest that amphetamine-and stress-induced behavioral sensitization may arise through different mechanisms.     

Tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

We assessed the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), and sodium valproate (VPA) on convulsions elicited by amygdala stimulation in kindled rats in three similar experiments. In each experiment, amygdala-kindled rats were assigned to a drug group or to a corresponding vehicle control group. The rats in the three drug groups received a total of 10 bidaily (one every 48 h) IP injections of CBZ (70 mg/kg), DZP (2 mg/kg) or VPA (250 mg/kg) at a dose that initially blocked the forelimb clonus elicited by an amygdala stimulation (400 microA, 60 Hz, 1 s) administered 1 h after the injection. The rats in the three vehicle control groups were similarly treated except that they received injections of the saline vehicle. The drug tolerance test occurred 48 h after the final tolerance-development trial; the rats from each drug group and the corresponding vehicle control group received an injection of the appropriate drug followed 1 h later by the administration of a convulsive stimulation. The drug tolerance test revealed almost total tolerance in each of the three drug groups but no tolerance in any of the three vehicle control groups. Such large tolerance effects are inconsistent with the less dramatic effects reported in previous studies; possible reasons for this inconsistency were considered.     

Contingent tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

The effect of convulsive stimulation during periods of drug exposure on the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), or sodium valproate (VPA) was studied in three similar experiments. In each experiment, amygdala-kindled rats were assigned to one of three groups: one group received a drug injection (CBZ, 70 mg/kg, IP; DZP, 2 mg/kg, IP; VPA, 250 mg/kg, gavage) 1 h before each of a series of 10 bidaily (one every 48 h) convulsive stimulations, a second group received the same dose of the drug 1 h after each of the 10 stimulations, and a third group served as a vehicle control. The drug tolerance test occurred in each experiment 48 h after the 10th tolerance-development trial; every rat received the appropriate dose of CBZ, DZP, or VPA 1 h before being stimulated. In each experiment, only the rats from the drug-before-stimulation group displayed a significant amount of tolerance to the drug's anticonvulsant effect. Thus the development of tolerance to the anticonvulsant effects of CBZ, DZP, and VPA was not an inevitable consequence of drug exposure; the development of tolerance was contingent upon the occurrence of convulsive stimulation during the periods of drug exposure. These results support the idea that functional drug tolerance is an adaptation to a drug's effects on ongoing patterns of neural activity, rather than to drug exposure per se.     

Loss of tolerance to morphine after a change in route of administration: control of within-session tolerance by interoceptive conditioned stimuli

Tolerance to morphine analgesia (tail-immersion test) was examined after manipulation of two aspects of a tolerance test: 1) the route of drug administration and 2) the time interval between the test dosing and the tolerance test. The intravenous (IV) and intraperitoneal (IP) routes were used, together with a novel test for tolerance in which the test morphine was infused IV just 2 min before measuring the opiate effect. The first experiment validated this test as an assay for tolerance by examining the log dose-response (LDR) curve changes produced by daily IP injection with 0, 20 or 200 mg/kg morphine; the IV test confirmed the expected parallel shift to the right and flattening of the LDR curve. In the second experiment, all rats of two groups were injected once daily for 3 weeks with 20 mg/kg morphine and with saline except that one group received the morphine IV (and saline IP), the other morphine IP (saline IV). The results indicated route-specific tolerance. On a test using 20 mg/kg given IV morphine, tolerance was significantly greater in rats treated with IV morphine than in those treated IP. However, a larger effect on tolerance was produced by a pretest application of 5 mg/kg morphine 30 min before the actual tolerance test. This manipulation was designed to prime short-term, adaptive processes hypothesized to occur within a normal tolerance test session as morphine is taking effect. The tolerance on the test increased (equivalent to 2 to 3 fold shift in the LDR curve) when the pretest morphine was given with the same route as the chronic morphine, regardless of treatment group. It was concluded that opiate tolerance may be modulated by conditioned stimuli produced by morphine acting through different routes. These interoceptive cues appear to modulate rapidly acquired and short-lived adaptive processes taking place within a given test session.     

Conditioned drug effects and absence of tolerance to d-amphetamine induced motor activity

Tolerance development to d-amphetamine induced motor motor activity was studied under various experimental conditions. Following seven daily habituation sessions, female, albino rats were subjected to 7 daily sessions in which NaCl was injected IP 30 min before placement into activity cages (NaCl controls). In the next 9 days, the rats underwent 3 drug sessions, each separated by 2 NaCl controls, in which d-amphetamine (0.5, 10. or 1.7 mg/kg) was likewise injected before placement. A course of repeated drug administration followed for the next 14 days. One group of rats was injected with the drug 30 min before placement into the activity cage, a second group received the drug 30 min after each session as a control for conditioned activity effects, while a third group received NaCl. On the fifteenth day, all rats recieved d-aphetamine 30 min before placement as a test for tolerance development. This session was followed the next day by a test for conditioned motor effects in which NaCl was injected IP 30 min before the session. Dose related increases in motor activity were observed during the drug control sessions. The magnitude of the drug effect did not decrease following any of the conditions during the course of repeated drug administration. Animals repeatedly injected with the drug 30 min after or with NaCl 30 min before each session were affected by d-amphetamine approximately the same as they were before repeated injections. Rats administered d-amphetamine 30 min before sessions during the course of repeated injections showed an enhanced response to d-amphetamine during the test for tolerance. The magnitude of the change was related to the magnitude of the conditioned motor activity response. These experiments emphasize the importance of learned or conditioned variables that may result from repeated drug administration in conjunction with behavioral tests.     

Nicotine-induced attentional enhancement in rats: effects of chronic exposure to nicotine.

Consistent with human literature, previous studies identified attention-enhancing effects of nicotine in rats, using a 5-choice task. The present study addressed the influence of repeated exposure to nicotine on these effects. Over six weeks, the effects of nicotine (0.0, 0.05 and 0.2 mg/kg) given ten min before sessions were tested each week. In addition, rats were injected daily two hours after sessions. In the first week, when these post-session injections were of saline for all rats, pre-session nicotine had profound rate-disruptive effects at the larger dose. In weeks 2-6, when half the rats received post-session injections of saline and the other half of nicotine (0.4 mg/kg), the disruptive effects of pre-session nicotine had disappeared and it enhanced attentional performance on all response indices. These effects did not differ significantly between post-session treatment groups or weeks, although they appeared less pronounced in the last two weeks. When tested under modified task parameters in weeks 9 and 10, nicotine (0.1 mg/kg) robustly enhanced performance in both groups despite continuing daily post-session administration of nicotine or saline. These studies provide evidence that, following tolerance to initial disruptive effects, the nicotine-induced attentional enhancement is stable across lengthy periods of chronic exposure. This is important for potential therapeutic applications of the drug and indicates that these effects can be a continuous motive for smoking behavior.     

The effect of repeated desipramine administration on water intake in rats

Rats were maintained on a regimen of restricted access to water. Desipramine (DMI) IP 1 h prior to the access period dose-dependently reduced water intake. Following completion of the dose-response determination for the effect of desipramine or water intake, rats were divided into three groups for repeated administration. Rats in each group were injected both 1 h before and 15 min after the access period. The SAL-SAL group received saline both before and after the session, the DMI-SAL group received 10 mg/kg DMI before and saline after the session, and the SAL-DMI group received saline before and 10 mg/kg DMI after the session. Average water intake for rats in the DMI-SAL group decreased progressively during the first 5 days of repeated administration and then began to return toward baseline levels. Average water intake for rats in the SAL-DMI group decreased progressively from days 4–18 of repeated administration and then began to increase toward beseline levels. Rats repeatedly administered DMI (DMI-SAL and SAL-DMI groups) became tolerant to its effect on water intake, as indicated by a diminution of the DMI effect during repeated treatment and by a shift to the right in the DMI dose-response function after discontinuation of repeated DMI administration. Both groups of rats administered DMI repeatedly were less sensitive to amitriptyline-induced reduction of water intake than controls thereby indicating the development of cross-tolerance to amitriptyline. Cross-tolerance to scopolamine did not develop. These findings demonstrate a behavioral effect of DMI that results in the development of tolerance. The lack of cross-tolerance to scopolamine suggests that tolerance development is not due to altered central cholinergic function.     

Bidirectional contingent cross tolerance between the anticonvulsant effects of pentobarbital and ethanol.

In Experiment 1, two groups of kindled rats received a pentobarbital injection (15 mg/kg, IP) and a convulsive amygdala stimulation once every 48 h. In one group, pentobarbital was injected 1 h before each stimulation; in the other, it was injected 1 h after each stimulation. Only the rats that received pentobarbital before each stimulation became tolerant to pentobarbital's anticonvulsant effect. Cross tolerance to the anticonvulsant effect of ethanol (1.5 g/kg, IP) was also found to be greater in the pentobarbital-before-stimulation rats. Experiment 2 was designed to assess the transfer of tolerance in the opposite direction, that is, from ethanol to pentobarbital, and the results mirrored those of Experiment 1: convulsive stimulation during the periods of ethanol exposure facilitated the development of tolerance to the anticonvulsant effect of ethanol and its transfer to pentobarbital. These results support the theory that functional drug tolerance and cross tolerance are adaptations to the effects of drugs on concurrent patterns of neural activity rather than to drug exposure per se.     

Prior drug experience and effects of amphetamine on schedule controlled behavior

Food deprived rats were trained to lever press for food pellets on a fixed ratio 40 schedule of reinforcement. Following 18 days of training, rats received d-amphetamine IP (1.0 mg/kg) as a drug control. Three days later, half of the animals were given d-amphetamine and half were given NaCl for six days. Tolerance to the disruptive effects of d-amphetamine on FR responding was not noted in the drugged group. Both groups received 14 more daily sessions with NaCl followed by 12 additional days of drug. Rats with previous drug experience exhibited tolerance in 6 days, while the other group required 12 days. In a second study, rats were trained to respond on an unsignalled continuous avoidance schedule for 8–10 weeks. Two groups of rats were given 7 daily drug sessions in which d-amphetamine (1.0 mg/kg) was administered IP. Each drug session was followed by 2 daily NaCl control sessions. In the first 3 drug sessions of one group, d-amphetamine was injected IP 30 min after the end of the session. All other injections were given immediately before placement into the operant chamber. During the first session in which the drug was injected before placement into the chamber, response increases were significantly higher in rats with drug experience outside the behavioral situation than in drug naive subjects. These studies emphasize the importance of prior drug exposure when investigating behavioral effects of drugs.     

5-hydroxytryptamine depletion with para-chlorophenylalanine: effects on eating, drinking, irritability, muricide, and copulation.

Forty-four male rats were tested for eating, drinking, irritability, and copulation before and after intraperitonial para-chlorophenylalanine (PCPA) or control injections. Eleven of these rats were tested for muricide before and after PCPA injections (Group 1), while 18 others were tested only after PCPA injections (Groups 2). Group 1 rats received four 350 mg/kg PCPA injections spaced 6 days apart and showed hyperdipsia, weight loss, and a 24% increase in muricide. Group 2 rats received five daily 100 mg/kg PCPA injections repeated 11 days later and showed hyperdipsia and weight loss; in addition, 78% of them killed mice. Neither group showed significant changes in copulation. At the end of the experiment, t6 rats from Group 2 that were irritable and killed mice were injected intraperitonially with 5-hydroxytryptophan (80 mg/kg). Five of these rats lost their irritability and four stopped killing. The various behavioral changes were not corrleated significantly either with each other or with the degree of 5-hydroxytryptamine depletion. This tentatively suggests that PCPA may produce its effects on behavior by other means in addition to 5-hydroxytryptamine depletion.     

Copulatory behavior and sexual reflexes of male rats treated with naloxone

Two experiments explored a potential role for endogenous opiates in the regulation of sexual behavior of male rats. Specifically, we questioned whether such opiates regulated the refractory period following ejaculation during copulation, or the latency period for the evocation of penile reflexes (erections, cups, and flips) from supine males. Animals were injected IP with 15–45 mg/kg naloxone hydrochloride 30 min prior to the start of reflex testing, and with 7.5–45 mg/kg naloxone hydrochloride 30 min before testing for copulation. Naloxone resulted in a small but reliable decrease in the number of penile flips. Reflex latency and other measures of penile reflexes were unaffected. At all doses used, naloxone significantly prolonged the postejaculatory refractory period, and there were no other effects on copulation.     

Haloperidol increases the disruptive effect of alcohol on spatial working memory in rats: a dopaminergic modulation in the medial prefrontal cortex

Rationale The prefrontal cortex (PFC) has been considered the anatomic site for working memory. The medial portion of the PFC (mPFC) is also part of a "brain reward circuit" as constituted by the mesocorticolimbic dopaminergic system. Objective This study examined the effects of acute administration of alcohol (ETOH) in the mPFC or systemically on the performance of 5-s or 1-h delayed tasks in an eight-arm radial maze. Effects of haloperidol (HAL), a dopamine antagonist, combined with ETOH, were also examined in a 1-h delayed task. Methods Male Wistar rats trained in the radial maze and with bilateral cannulae implanted in the mPFC received intraperitoneal (IP) or intracortical (IC) drug administration. Results As compared to saline (SAL) IC, ETOH IC in doses of 100 μg and 180 μg (5 min before session) increased significantly the number of errors in the 1-h and 5-s post-delay performance, respectively. HAL in doses with little or no effect alone IC (10 or 32 μg, 10 min before session) or IP (3.2 mg/kg, 35 min before session) increased the disruptive effect of ETOH IC (100 μg) on 1-h delayed task. Conclusions These results showed that ETOH administered directly in the mPFC disrupts short- and long-term spatial working memory. The increase of the disruptive effect of ETOH produced by a dopaminergic blockage, particularly in the mPFC, suggests that the dopaminergic neurotransmission in this cortical area might modulate ETOH effects on spatial working memory.     

Mechanisms of the initial treatment phenomenon to diazepam in the rat

The initial treatment phenomenon (ITP) to diazepam was investigated using a conditioned suppression of drinking (CSD) paradigm. Female Sprague-Dawley rats were trained to a stable baseline of punished and unpunished responses in the CSD paradigm. In Experiment 1, a control group (1) received vehicle after the CSD session on each of seven drug test days, while group 2 was treated with 3.0 mg/kg diazepam IP after each of these sessions. On drug test days 8–12, diazepam was administered to both groups before the CSD session. Drug test days were separated by 2–3 days when the animals were untreated but performed in the CSD. Prior exposure to diazepam in group 2 after sessions 1–7 conditioned the animals so that a greater release in punished behavior was seen during sessions 8–12 than in the control group (1). In Experiment 2, one group (3) of rats was administered diazepam vehicle after the CSD session for 4 drug test days and another group (4) was injected with 5.6 mg/kg diazepam after the CSD session on these same days. On the next 4 drug test days both groups received diazepam before they performed in the CSD. An ITP was observed in both the control (3) and the drug-conditioned (4) group, although the ITP was less obvious in the conditioned group. After a 28-day period of CSD exposure without vehicle or drug treatments, 5.6 mg/kg diazepam was administered to both groups before the CSD session for an additional 8 drug test days. During this last period both groups exhibited an ITP with no essential differences. These experiments demonstrate that the initial treatment phenomenon is complex, involving several components that include a behavioral tolerance to the disruptive effect of diazepam.     

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.     

Conditioned saccharin aversions in rats as a result of cutaneous nicotine or intraperitoneal nicotine administered in divided doses

Nicotine base was used in a conditioned taste aversion (CTA) paradigm to avert male Sprague-Dawley rats to saccharin solution (0.1%, w/v). Experiments investigated different dose routes of nicotine administration and duration of action as determinants in nicotine-induced CTA. In Experiment 1 nicotine was injected intraperitoneally (IP) at doses of 0.5, 1.0, or 3.0 mg/kg 30 min after drinking saccharin solution. Using a two-bottle choice test, no CTA was observed, although all nicotine animals showed obvious symptoms of malaise including seizures in the highest dose group. Experiment 2 showed dose-related CTA when nicotine (10.0, 30.0, or 50.0 mg/kg) was cutaneously applied 30 min following saccharin drinking. Experiment 2B showed that the aversions were due to associative rather than nonassociative factors such as sensitization or enhanced neophobia. In Experiment 3, the following group treatments were begun 30 min after saccharin drinking to distribute identical total nicotine doses over an extended period of time: One IP injection of 2.0 mg/kg nicotine (in a saline vehicle) and four injections of saline solution, three injections of 0.67 mg/kg nicotine and two injections of saline, five injections of 0.40 mg/kg nicotine, or five injections of saline. All injections were spaced 30 min apart. Compared with saline-injected controls, CTA occurred in the rats receiving either three or five injections of nicotine but the group receiving one injection did not differ from the control group. There was no difference in CTA between the groups receiving three or five injections.     

Acamprosate reduces context-dependent ethanol effects

Abstract Rationale. Previous studies have indicated that the conditioned effects of environmental stimuli contribute to ethanol tolerance and abuse. Acamprosate was recently suggested to reduce the effects of environmental stimuli previously associated with ethanol administrations. This action is believed to contribute to the clinical benefits of acamprosate treatment in alcoholics. Objectives. In the present experiment, a classical drug-conditioning paradigm was used to test whether acamprosate modulates the effects of ethanol-paired environmental stimuli on spontaneous motor activity. Methods. Wistar rats were divided into three groups: cued, uncued and control. The cued group daily received ethanol injections (2.0 g/kg, IP) in a specific testing environment. The uncued group daily received ethanol injections (2.0 g/kg, IP) in their home cage but never experienced ethanol in the testing environment. The control group was injected with saline and never experienced ethanol. After 8 conditioning days, the rats were IP injected with various ethanol doses (saline, 1.0, 1.5 or 2.0 g/kg) and their spontaneous motor activity in the testing environment was recorded to investigate their respective tolerance to ethanol inhibitory effects. In the second part of the study, the same procedure was repeated with chronically acamprosate-treated rats. The chronic acamprosate treatment (400 mg/kg per day) started 2 weeks before the conditioning procedure by diluting acamprosate in the drinking bottles and was maintained throughout the whole experiment. Results. The cued rats showed a significant environment-dependent tolerance to ethanol inhibitory effects relative to the uncued and control rats. This higher ethanol tolerance of the cued rats was mainly due to a faster recovery from ethanol's inhibitory effects on spontaneous activity. Furthermore, the cued rats showed a higher level of activity in the testing environment after the saline injection. However, it is not clear whether this hyperactivity is a conditioned compensatory response or an increased exploratory behavior. Acamprosate totally abolished the environment-dependent tolerance to ethanol, whereas it did not alter the hyperactivity of the cued rats in the testing environment. Conclusions. The results of the present study suggest that acamprosate reduces ethanol-conditioned effects. Such an action may be of importance to explain the anti-relapse effects of acamprosate. Electronic Publication     

Context-specific tolerance to the ataxic effects of alcohol

Tolerance to alcohol and many other drugs can become conditioned to specific contextual cues present at the time of drug administration. Context-specific tolerance occurs to a variety of alcohol's effects, including changes in hormone levels, body temperature and locomotor activity. The present study investigated whether context-specific tolerance can occur to the ataxic effects of alcohol. Baseline levels of motor coordination were assessed using a tilting plane apparatus. During a 7-day tolerance acquisition phase, subjects received an injection of either alcohol (1.5 g/kg i.p.) or saline (15 ml/kg i.p.) in a novel testing room and were then placed in the tilting plane apparatus for a period of 20 min. Approximately 5 h after the first injection, subjects received a second injection in the colony room and were then placed in their home cages. One group of subjects, the paired group, received alcohol in the testing room and saline in the colony room. An unpaired group received saline in the testing room and alcohol in the colony room. A no alcohol control group received saline in both environments. Following the tolerance acquisition phase, all subjects were injected with alcohol (1.5 g/kg i.p.) and tested for ataxia in the tilting plane apparatus. Subjects in the paired group were less ataxic than subjects in the control group during all four testing blocks following alcohol administration. In contrast, subjects in the unpaired group were less ataxic than the control subjects only during the 15-min testing block. Relative to baseline scores, the paired group exhibited deficits only during the 5- and 10-min testing blocks, while subjects in the unpaired and control groups exhibited deficits during all four testing blocks. These data strongly suggest that tolerance to the ataxic effects of alcohol can become conditioned to contextual cues present at the time of alcohol administration.     

The contribution of environmental cues to cross-tolerance between ethanol and pentobarbital

The contribution of Pavlovian conditioning of environmental cues has been studied in relation to tolerance to ethanol-induced hypothermia and cross-tolerance to pentobarbital. Two groups of 12 male Sprague-Dawley rats were exposed every other day to a distinctive set of environmental cues paired with an IP injection of either ethanol 2.5 g/kg or an equivalent volume of isotonic saline. On alternating non-drug days, both groups received saline in the animal room. When they were tested for tolerance to the hypothermic effect of ethanol 2.5 g/kg and cross-tolerance to pentobarbital 25 mg/kg in each environment, tolerance and cross-tolerance in the ethanol-treated group were significantly more pronounced in the ethanol-paired environment than in the saline-paired environment. This indicates the importance of a conditional factor in tolerance and cross-tolerance in this paradigm. Determination of blood levels of ethanol and pentobarbital at various times after injection indicated that conditioned tolerance and cross-tolerance can be explained in part by dispositional factors.