Associational and nonassociational mechanisms in locomotor sensitization to the dopamine agonist quinpirole

A pairing paradigm was employed to explore the contribution of associational mechanisms to the expression of sensitization to the dopamine agonist quinpirole. Rats received ten quinpirole injections in the test environment (Group Paired) or in the home cage (Group Unpaired), and saline in the alternate environment. A third group received saline injections in both environments (Group Acute). Subjects received quinpirole on the 11th injection as a test for locomotor sensitization, and saline on the next injection as a test for conditioned activity. The range of discriminative stimuli predicting a drug versus a non-drug injection was increased across three independent experiments in an effort to detect a possible associational effect. Regardless of the strength of discriminative stimuli, both Paired and Unpaired groups showed locomotor sensitization to 0.5 mg/kg quinpirole compared with the Acute group. However, the Paired group showed more locomotion than the Unpaired group in the last minutes of the sensitization test. With a lower sensitizing dose of quinpirole (0.1 mg/kg) used in one experiment, only the Paired group showed locomotor sensitization. For both doses, the Paired, but not the Unpaired groups showed conditioned locomotion. It is suggested that with moderate doses of quinpirole, expression of locomotor sensitization does not require drug-signalling cues though such signals may have a modulatory influence. With lower quinpirole doses, however, quinpirole sensitization is context-dependent.     

Rapid induction of Pavlovian approach to an ethanol-paired visual cue in mice

Rationale Although many studies have shown Pavlovian conditioned approach to cues paired with natural reinforcers, it has been quite difficult to induce such behavior with drug reinforcers. Objectives This experiment tested a novel Pavlovian procedure for inducing approach to a conditioned stimulus (CS) paired with ethanol. Methods Mice (NZB/B1NJ, DBA/2J) received intraperitoneal injections of ethanol (2 g/kg) immediately before 10-min exposure to a rectangular chamber that contained a distinctive visual cue (star) at one end (Paired group, CS+ trials). On alternate days, saline injection preceded apparatus exposure with no distinctive cues (CS− trials). Unpaired control mice received ethanol in the home cage 60–75 min after each CS+ trial. Results NZB/B1NJ Paired group mice spent increasing amounts of time (>85% of the session) in proximity to the star, whereas Unpaired group mice did not. DBA/2J Paired group mice spent slightly more time on the star side than Unpaired group mice but did not show an acquisition curve. Postconditioning tests showed a strong preference for the star side in Paired groups from both strains after saline injection. However, only NZB/B1NJ mice showed a preference after ethanol. Conclusions This study provides the first unambiguous demonstration of Pavlovian conditioned approach to an ethanol-paired visual stimulus in the absence of any contingency between the animal’s behavior and drug exposure. This effect, which is remarkable both in terms of its magnitude and the rapidity with which it was produced (within 2–3 trials), may be related to the cue-associated craving that accompanies alcohol and drug addiction.     

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.     

Protection from pentobarbital lethality mediated by Pavlovian conditioning

The lethal effects of pentobarbital overdose were dependent upon the context in which the drug was administered. Rats received repeated injections of pentobarbital (30 mg/kg), in a distinctive environment and saline in the home room. At test, rats received a large dose (95 mg/kg) of pentobarbital. Fewer deaths occurred in a contex previously associated with drug administration. The results are consistent with a Pavlovian model of drug tolerance.     

Haloperidol-induced catalepsy is modulated by the development of tolerance to amphetamine-induced anorexia

The effect of the development of tolerance to amphetamine-anorexia on both amphetamine-induced and haloperidol-induced motor effects was investigated. The animals in experiment 1 showed an acute anorexic reaction to 3 mg/kg amphetamine, whereas the rats in experiment 2 failed to meet the criterion level of acute anorexia. During initial training rats received 13 injections of saline or 3 mg/kg amphetamine intraperitoneally (i.p.) every other day. In both experiments, for one group each amphetamine injection was followed 20 min later by 30 min access to milk (CONT groups). In a second group, each amphetamine injection was followed 24 h later by 30 min access to milk (NONCON groups) and a third group received only saline injections and milk (controls). As expected, in experiment 1 originally anorexic animals in the CONT group developed tolerance, whereas the NONCON and control groups displayed no tolerance to amphetamine-anorexia. The NONCON group showed sig nificantly more stereotypy than either the CONT or control group. Furthermore, following 1.25 mg/kg haloperidol the CONT animals were less cataleptic than the NONCON and control groups which did not differ. In experiment 2, at the end of training the rats in all groups displayed no anorexia following amphetamine injection; they consumed an amount of milk equivalent to that normally consumed under no-drug conditions. Neither was there a difference in the amount of catalepsy between groups following injection of 1.25 mg/kg haloperidol.     

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.     

Magnitude of initial effect influences development of tolerance to morphine in rats responding under a fixed-ratio schedule of food presentation

This experiment examined whether development of tolerance to the rate-decreasing effects of morphine can be modulated by the magnitude of the initial effect of morphine. Lever pressing by rats was maintained under a fixed-ratio 30 schedule of food delivery in daily 30 min sessions. Subjects were assigned to two groups, which did not differ in initial sensitivity to morphine, and given daily injections of morphine under dosing schedules chosen to have different initial effects. Group 1 received daily pre-session injections of 10 mg/kg morphine, which initially suppressed lever pressing completely, and post-session injections of saline. Group 2 received morphine in two injections, one pre-session and one post-session. The initial daily doses 10 mg/kg pre- and 9 mg/kg post-session) decreased rates by 30% or less. The proportion of the 10 mg/kg dose administered pre-session was increased gradually over 10 weeks. Group 2 developed greater tolerance than did group 1, as assessed by changes in the dose of morphine required to suppress response rates by > 50%. After 3 months of repeated treatment, the ED(50) of morphine increased 2.5-fold in group 2, but only 1.4-fold in group 1. When the daily dose of morphine was raised to 20 mg/kg (10 mg/kg pre- and 10 mg/kg 14 h post-session) for all subjects, the ED(50) of morphine increased 6.7-fold in group 2, but only 2.6-fold in group 1. During repeated treatment, the groups did not differ in the dose of maloxene required to suppress response rates or elicit weight loss. Following termination of morphine treatment, the ED(50) of morphine returned to original values in group 2, but was 1.8-fold lower than initial values in group 1. Thus, a pronounced [??103] decreasing effect of morphine retarded development of tolerance, perhaps by a conditioning process.     

An analysis of the effects of contextual cues on the development of morphine tolerance in rats.

Tolerance to morphine analgesia was determined daily by exposing rats either to the same box or to different boxes by a repeated administration of morphine (5 mg/kg). In the Acquisition Phase, the rats received either morphine or saline in the same or different boxes for four consecutive days, and the process of tolerance development was assessed by a hot-plate test. Marked tolerance developed in the group exposed to the same contextual cue, whereas tolerance was attenuated in the group exposed to different cues. In the Extinction Phase, all rats received saline injections in the box exposed on Day 1 for four days. On the first day, hyperalgesia was observed only in the rats injected with morphine in the same contextual cue. In the Retest Phase, the rats underwent a second morphine injection and to some extent showed recovery from tolerance. In the Acquisition Phase, the number of animals showing abnormal activity with morphine injection increased monotonically in the group that was administered morphine in the same box (Group M-S) before injection, but in the group administered the drug in different boxes (Group M-D), no systematic development of the activity occurred. These results indicate that the hindering of a rat's ability to associate with environmental cues under the effect of morphine slows the development of tolerance, and the withdrawal and anticipatory symptoms, and the tolerance of morphine involves psychological and pharmacological factors.     

In a low-versus high-dose drug discrimination task, random reinforcement in one drug state alters discriminative control only in that state

This study investigated the effects of introducing random reinforcement training after a drug discrimination between 3.0 and 15.0mg/kg chlordiazepoxide had been acquired in rats; a two-lever food-rewarded operant procedure was used. Matched on the basis of dose-generalization test data, two dose-equisensitive groups were formed (A and B). Group A received 30 daily saline injections, which were followed by a random reinforcement session during which either left or right lever presses were reinforced on a probabilistic basis on each of the trials comprising a session. Group B received saline but no training or testing during this period. Subsequent testing revealed that responding conditioned to the low-dose training condition, but not to the high-dose training condition, was significantly changed in Group A. The randon reinforcement data further suggested that Group A did not discriminate saline from the low training dose. In Experiment 2, Group B of Experiment 1 was submitted to 30 random reinforcement training sessions, each preceded by a high training dose administration. Data showed that responding to the high dose, but not the low dose, was changed. For both experiments, chlordiazepoxide dose generalization following reacquisition was similar to that obtained before the random reinforcement phase. The findings indicate that the response pattern changed only for the stimulus condition present during random reinforcement. The random reinforcement manipulation did not disrupt the original discrimination between the high-and low-dose conditions.     

A potential role of saline trials in morphine-induced place-preference conditioning

The necessary conditions to alter rats' initial preferences for two sides of a shuttlebox were investigated, using procedures that are often used in the study of drug reinforcement. In Experiment 1, pairings of morphine sulfate (15 mg/kg, intraperitoneally) and either the nonpreferred side or a holding box was factorially combined with alternate-day pairings of saline and either the preferred side or a holding box. Pairings of saline and the preferred side were necessary and sufficient to increase preferences for the initially nonpreferred side. In Experiment 2, pairings of saline and the nonpreferred side, but not the holding box, strengthened the initial preference, regardless of whether morphine or saline injections preceded alternate-day holding-box placements. In Experiment 3, injection and placement in the preferred side in an unpaired manner, or placement only, decreased preferences for that side more than saline injections alone or no treatment. Paired saline injections and placement produced a greater change in preference than no treatment.     

Tolerance to morphine stimulus control: role of morphine maintenance dose

Experiments assessed the development of tolerance to morphine stimulus control during treatment with selected maintenance doses of morphine. Separate groups of rats were trained to discriminate saline and either 3.2 mg/kg or 5.6 mg/kg morphine under fixed-ratio schedules of food delivery. Dose-response functions for generalization of morphine stimulus control were determined before, during, and after repeated treatment with selected doses of morphine. Similar experiments were performed with repeated pentobarbital treatment in order to assess the pharmacological selectivity of tolerance. Repeated treatment with saline, 3.2 mg/kg morphine, or twice daily injections of 17.8 mg/kg pentobarbital produced no tolerance to morphine stimulus control. In contrast, treatment with daily injections of 10 mg/kg or twice daily injections of 10 or 17.8 mg/kg morphine produced a dose-dependent increase in the dose of morphine required for stimulus control. The magnitude of tolerance to morphine stimulus control varied directly with the maintenance dose of morphine and was slightly greater for a lower than a higher morphine training dose. Termination of repeated treatment was followed by a return to initial sensitivity, without additional training. Tolerance to morphine stimulus control was not necessarily accompanied by tolerance to its rate-suppressing effects.     

Sensitization of haloperidol-induced hypophagia is contingent on behavioral experience with food

Groups of rats were given injections of haloperiodol (0.31mg/kg) at weekly intervals either before or after access to sweetened milk. Control groups were given injections of saline. At the end of the chronic regimen, all groups received a single injection of haloperidol (0.15mg/kg) prior to milk access. Rats injected with the drug before milk during the chronic phase showed a progressive decrease in milk intake. When subsequently challenged with a lower dose, this group ingested less milk than any of the other groups, which did not differ from one other. These results demonstrate that sensitization of haloperidol-induced hypophagia is contingent on experience with milk while in the drugged state.     

Enhanced self-stimulation responding from the substantia nigra after chronic amphetamine treatment: A role for conditioning factors

Rats treated with 2 mg/kg of d-amphetamine and tested for self-stimulation responding supported from the substantia nigra (pre-trial group), showed a progressive augmentation in rates of self-stimulation responding relative to control animals following repeated drug/test pairings for 10 days. A similar behavioral profile was not observed among animals that received behavioral testing followed by drug administration (post-trial group) during the chronic phase. On test day (Day 11), rats that received repeated drug/test pairings during the chronic phase exhibited a facilitated self-stimulation response to a low test dosage of d-amphetamine (0.5 mg/kg) which otherwise had no behavioral effect, whereas rats exposed to chronic test/drug pairings during the chronic phase did not show enhaced self-stimulation rates to the test dosage of d-amphetamine. Animals chronically treated with pre-trial injections of amphetamine also showed facilitated self-stimulation responding when tested with saline, relative to animals that were chronically treated with post-trial injections of amphetamine and tested with saline. These findings were not parallelled by drug-induced changes in locomotor activity. Response sensitization after chronic amphetamine treatment does not appear to involve the accumulation of the drug in adipose tissue. A role for conditioning factors in the development of the response sensitization is discussed.     

Chronic inflammatory pain does not attenuate the development of tolerance to chronic morphine in adult male rats

The overall impact of chronic pain on the response to opioids is ambiguous in the literature, and comparisons between human and animal studies are complicated by vast differences between the manner and dosage of opioids given to humans treated for pain in comparison to rodents as well as a lack of healthy participant studies examining the impact of chronic opioids. The purpose of this study was to evaluate the impact of chronic pain on the development of tolerance to morphine and to assess how the concentration of drug affects this process. Twenty-four hours after the injection of CFA or normal saline in the left hind paw, the level of mechanical hypersensitivity was assessed and animals were randomly assigned to a morphine dose (1, 3 or 8 mg/kg or saline). Morphine was administered by subcutaneous injection twice a day for 5 days. On Day 6, animals were challenged with a single dose of 3 mg/kg morphine prior to formalin testing. Evidence of tolerance was mixed, and the results varied widely among the conditions. Analysis of mean paw withdrawal thresholds indicated that the analgesic efficacy of subcutaneous morphine diminished following repeated dosing. The presence of the chronic inflammatory pain condition during the morphine dosing period produced an increase in formalin pain behaviors compared to saline controls, such that animals given any dose of morphine during the 5-day dosing period showed higher responding to formalin following the 3 mg/kg dose than animals that had received saline injections. These results indicate that chronic pain does influence the development of opioid tolerance, but it does not prevent this phenomenon from occurring as suggested by some researchers.     

Effects of naltrexone on amphetamine-induced locomotion and rearing: acute and repeated injections

 The present experiment investigated the ability of the opiate receptor antagonist naltrexone to block the increased locomotion and rearing produced acutely by amphetamine as well as the sensitization of these responses produced when this drug is administered repeatedly. Rats in different groups received an injection of amphetamine (1.5 mg/kg, IP) or saline preceded 30 min earlier by an injection of naltrexone (0, 0.5, 1.0, 5.0 or 10.0 mg/kg, IP). Naltrexone dose-dependently reduced the rearing but had no effect on the locomotion produced by this dose of amphetamine. The locomotion and rearing observed following saline were not affected. This pattern of results was observed following each of six additional pairs of injections, one pair of injections given every third day. Once, soon (2–4 days) and once, long (9–12 days) after the last injection, all animals were injected with amphetamine (0.75 mg/kg, IP) in the absence of naltrexone (tests for sensitization). Animals having been pre-exposed to amphetamine preceded by naltrexone showed no evidence of sensitized rearing on either test, indicating that naltrexone blocked sensitization of this response to amphetamine. These animals, however, exhibited sensitized locomotion on both tests. These results suggest an important but complex role for dopamine-opioid interactions not only in the production of acute locomotor responding to amphetamine but also in the sensitization of locomotor responding when this drug is administered repeatedly. The present findings also suggest that amphetamine-induced rearing is more dependent than locomotion on neuronal mechanisms involving dopamine-opioid interactions. Received: 12 March 1996 / Final version: 2 January 1997     

Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats

Despite the high prevalence of tobacco abuse among adolescents, the neurobiology of nicotine addiction has been studied mainly in adult animals. Repeated administration of this drug to adult rats induces behavioral sensitization. Nicotine activates the HPA axis in adult rats as measured by drug-induced increases in ACTH and corticosterone. Both behavioral sensitization and corticosterone are implicated in drug addiction. We examined the expression of behavioral sensitization induced by nicotine as well as the changes in corticosterone levels after repeated injections of nicotine in adolescent and adult animals. Adolescent and adult rats received subcutaneous (s.c.) injections of saline or 0.4 mg/kg of nicotine once daily for 7 days. Three days after the last injection animals were challenged with saline or nicotine (0.4 mg/kg; s.c.). Nicotine-induced locomotion was recorded in an activity cage. Trunk blood samples were collected in a subset of adolescent and adult rats and plasma corticosterone levels were determined by radioimmunoassay. Adult, but not adolescent, rats expressed behavioral sensitization. Pretreatment with nicotine abolished corticosterone-activating effect of this drug only in adult animals, indicating the development of tolerance at this age. Our results provide evidence that adolescent rats exposed to repeated nicotine display behavioral and neuroendocrine adaptations distinct from that observed in adult animals.     

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.     

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. Received: 17 September 1996 / Final version: 10 March 1997     

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.     

Role of drug-administration cues in the associative control of morphine tolerance in the rat

This research investigated the role of injection procedures as a potential confound in the study of associative and nonassociative morphine tolerance development. Rats administered a series of morphine injections paired with a distinctive context environment can develop tolerance controlled associatively by the context. However, rats given morphine unpaired with the context may also develop some degree of tolerance. This study examined whether this tolerance represents an associative effect with animals using the injection ritual as a cue predictive of morphine delivery. Following 14 days of habituation to handling and injection stimuli, rats were given eight morphine injections (20 mg/kg, IP) explicitly paired or unpaired with a distinctive context. Animals were then tested for morphine analgesia in the context after either a 30-day rest condition or a 30-day period of daily saline injections. Analgesia was assessed by the tail-flick method, and tolerance was defined as the shift to the right of the dose-response curve of morphine-experienced relative to saline control animals. Paired animals across both retention conditions displayed tolerance, whereas tolerance retention in unpaired animals was observed only in those animals not given saline injections over the 30-day interval. Results support an associative interpretation of tolerance observed in unpaired conditions and suggest that the injection ritual may provide highly salient cues for the support of associative tolerance effects.