Contingent suppression of tolerance to haloperidol: a dose-response analysis

Rats were given injections of haloperidol (HAL; 0.625 or 2.5 mg/kg) either before (Before groups) or after (After groups) access to sweetened milk on alternate days. Controls (Saline groups) were given injections of saline. At biweekly intervals ("test days"), all groups were given pretest injections of the drug in order to monitor the development of tolerance in the After and Saline groups. Rats in the Before groups showed no tolerance to the initial suppression of milk intake. In contrast, rats in the After groups had greater intakes, although the level of intake declined on subsequent test days in the group given the lower dose. Rats in the Saline groups drank less on the test days than any of the other groups, suggesting that sensitization occurred. These results are consistent with previous findings (29) that tolerance to HAL is suppressed following pretest injections of the drug. The degree of suppression appears to be inversely related to the frequency of such injections.     

Loss of tolerance to amphetamine-induced hypophagia in rats: homeostatic readjustment vs. instrumental learning.

According to the homeostatic model, the loss of tolerance to amphetamine-induced hypophagia requires a period of unrestricted feeding in the drug-free state, which transforms the compensatory response mediating tolerance ("hyperhunger") into a functional disturbance to homeostasis. In the absence of such a disturbance, tolerance should be retained. To test this prediction, rats tolerant to amphetamine's hypophagic effect were given a 4-week tolerance retention period during which milk intakes were restricted and deprivation levels held relatively constant. During this period the rats were assigned to one of the following drug treatment conditions: 1) saline injections both before and after daily milk tests (saline group); 2) saline injections before, and amphetamine injections after, daily milk tests (after group); 3) no injections and no milk tests (no-treatment group); or 4) amphetamine injections before, and saline injections after, milk tests (before group). Despite the restricted feeding regimen, both the saline and after groups lost tolerance. These results do not support the homeostatic model, but are consistent with the instrumental learning model, which views drinking milk in the undrugged state as analogous to receiving noncontingent reinforcement.     

Changes in behavioural contingencies produce a loss of tolerance to amphetamine hypophagia in rats despite continued feeding tests while drugged

Rats administered amphetamine prior to access to milk in bottles develop tolerance to the hypophagic effect of the drug by learning to suppress stereotyped behaviours that interfere with feeding. When tolerant rats are later allowed to drink milk from a bottle in an unintoxicated state, tolerance is lost, even when drug exposure is held constant by administration of the drug after the test. In the present experiment, we show that tolerance can also be lost in the face of continued administration of amphetamine prior to milk tests, as a result of changes in the contingencies of reinforcement that govern the suppression of stereotypy. Rats were injected with 2 mg/kg amphetamine and given access to milk in bottles for 16 trials. Tolerance to the hypophagic effect was confirmed by dose-response tests in which milk was available in bottles. The rats were then injected with 2 mg/kg amphetamine prior to intraoral milk infusions for 21 trials. This method of feeding did not require the suppression of stereotypy to obtain milk. Subsequent dose-response tests in which milk was again presented in bottles revealed that tolerance was lost, even though intoxicated feedings were never interrupted. These results demonstrate that the contingencies of reinforcement governing the suppression of stereotypy determine whether tolerance is retained or lost.     

Long-term retention of tolerance to amphetamine hypophagia following cessation of drug injections and feeding tests.

According to the instrumental learning model, tolerance to amphetamine hypophagia involves learning to suppress stereotyped movements that interfere with feeding. If both drug injections and feeding tests are then suspended, learning should be retained and no loss of tolerance should occur. However, previous studies have only assessed the retention of tolerance for 3-4 weeks. In the present study, retention intervals of 4-31 weeks were used. Rats were given daily injections of amphetamine (2 mg/kg) and access to milk for 30 min until tolerance developed to drug-induced hypophagia. Yoked controls were injected with saline. Both before and after this phase, dose-response (DR) tests were conducted. Drug injections and feeding tests were then suspended. At 4, 10, 18, and 31 weeks, both groups were injected with 2 mg/kg amphetamine and given access to milk for 30 min to assess the retention of tolerance. A final DR determination was then conducted. Most (88%) rats retained tolerance to 2 mg/kg amphetamine for 31 weeks. However, DR tests revealed that tolerance was not retained at 4 mg/kg. The results demonstrate that learned tolerance to amphetamine can be retained over long intervals when both drug injections and feeding tests are suspended.     

Procedures affecting maintenance and loss of tolerance to amphetamine-induced anorexia and cross-tolerance to haloperidol-induced catalepsy

Procedures affecting the maintenance and loss of tolerance to amphetamine anorexia were investigated. Following a period in which rats acquired tolerance to amphetamine-induced anorexia via the contingent- tolerance procedure, a variety of manipulations were investigated to determine which effected a loss of tolerance. The procedures included: continued milk availability or its absence, saline injections or no injections and a switch to non-contingent amphetamine injections. These procedures were each investigated while animals continued to be food-deprived or were maintained at their ad libitum weights. The animals maintained at 100% ad lib. lost tolerance whereas tolerance was maintained by the 85% groups, regardless of what other manipulations were given. Subsequently all animals were tested for catalepsy induced by 1.25 mg/kg haloperidol. Animals that had maintained tolerance to amphetamine anorexia (85% groups) were significantly less cataleptic than the animals that had lost tolerance to amphetamine anorexia (100% groups). The finding that tolerance to amphetamine anorexia is lost in animals that have ad lib. access to food indicates that a homeostatic imbalance caused by food-deprivation is perhaps the most important factor in the maintenance of tolerance to amphetamine anorexia.     

Development and reversal of sensitization to amphetamine-induced hypophagia: role of temporal,pharmacological, and behavioral variables

This study shows that sensitization can develop to amphetamine-induced hypophagia and examines the stability of this effect following subsequent pharmacological and behavioral experience. Rats given 36 injections of either amphetamine (2.5 mg/kg; Group A) or saline (Group S) at 3-day intervals developed sensitization of hypophagia, as assessed by a shift to the left in the dose-response (DR) function. Group A also displayed sensitization of stereotypy, whereas Group S showed little change except at the highest dose. Subgroups from each group were then given daily injections of amphetamine (2 mg/kg) either before or after access to milk for 4 weeks. Other subgroups were given injections of saline as a control. On a final DR determination, these control groups showed no further changes in milk intake. In contrast, groups given chronic injections of amphetamineafter milk showed a loss of sensitization (DR3=DR1), whereas groups given the drugbefore milk developed tolerance that was limited to the chronic dose. These results demonstrate that (1) sensitization of amphetamine-induced hypophagia and stereotypy can develop independently; (2) sensitization of hypophagia can be reversed, without inducing tolerance, by subsequent daily exposure to the drug; and (3) prior sensitization of hypophagia does not preclude the subsequent development of tolerance if the drug is later given in the context of feeding.     

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.     

Cellular and learned tolerances for pentobarbital hypothermia

The development of behavioral tolerance to pentobarbital-induced hypothermia, as separable from cellular and metabolic tolerance, was established. Pentobarbital (PB) was administered to 4 groups of rats, 2 groups of which received intermittent (INT) IP PB treatment. One of these groups, INT/EXP, experienced the hypothermic (measured as rectal body temperature) drug effect after PB injection. The other group, INT/NONEXP, was monitored for body temperature functions (room temperature) before receiving PB (vehicle administration) and then prevented from experiencing PB-induced hypothermia by maintenance of body temperature with a towel wrap restraint and a heating lamp. The INT/EXP group also received equivalent exposure to this towel wrap after vehicle administration. Two other groups received chronic PB treatment (IP and in ground chow), one with experience for hypothermia after injections (CHR/EXP) and one prevented from experiencing the hypothermia (CHR/NONEXP). These groups also received equivalent exposure to the body temperature (at room temperature) testing and towel wrap restraint, EXP rats after vehicle injections and NONEXP after drug injections. A postchronic test of all groups compared the extent of PB hypothermia to prechronic test effects to assess the degree of tolerance. The INT/EXP group demonstrated behavioral tolerance for PB-induced hypothermia, as contrasted with the INT/NONEXP group which demonstrated little or no tolerance. Prominent tolerance was noted in both chronic groups for PB hypothermia, without a significant difference between them. After the postchronic test, chronic treatment was discontinued for 9 days (withdrawal) followed by 9 days of extinction training (vehicle behavioral testing). The two intermittent groups demonstrated no change in the hypothermic drug response during the postwithdrawal and postextinction drug tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Performance influence on the development of tolerance to amphetamine

This experiment was performed to determine whether performance of a behavior in the drug state was necessary for behavioral tolerance to the effects of that drug to occur. Eight rats trained on a DRL 17.5-sec schedule received daily injections of 1.5 mg/kg d-amphetamine sulfate; four received amphetamine 30 min presession, and four received amphetamine 30 min postsession. Amphetamine given presession initially resulted in a disruption of timing behavior, an increase in response rate, an increase in short IRTs and a decrease in the number of reinforcements received. With continued administration of presession amphetamine the rats developed a partial tolerance to these disruptive effects. Postsession amphetamine had no effect on performance. When tolerance developed in rats receiving presession amphetamine, they were switched to postsession amphetamine; rats receiving postsession amphetamine were switched to presession amphetamine. Amphetamine produced the same disruption of performance in the rats switched to presession amphetamine as was observed in the initial pressession amphetamine group, indicating that tolerance did not develop to amphetamine given postsession. In addition changes in the pattern of responding were observed when amphetamine was initially administered presession.     

Tolerance to the discriminative stimulus properties of d-amphetamine

Male rats (F-344) responding for milk on a VI 20 sec schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with d-amphetamine (0.50, 1.00 or 1.50 mg/kg) or saline 15 min prior to daily training sessions. Dose-response functions determined for each of the three (n = 6) training-dose groups indicated that ED₅₀ values were directly correlated with training dose. Two days following chronic amphetamine injections (a total of 78 mg/kg over 4 days) rats were tested for tolerance at a dose which normally produced about 80% drug-lever responding. Rats in all three groups showed tolerance to the cue properties of amphetamine. In the 0.50 and 1.00 mg/kg groups, complete tolerance was shown as evidenced by the fact that the drug lever responding did not differ from that which was appropriate following saline injections.     

Behavioral tolerance to flurazepam

Rats were trained to earn 180 food pellets in daily, fixed-interval 1-min sessions. When performance had stabilized, a Before group was given a weekly 16 mg/kg flurazepam injection IP for 3 weeks immediately before the sessions, while an After group received their weekly injections immediately after the sessions. Then, the After group received 3 such weekly injections before the sessions. Behavioral tolerance developed by the 2nd flurazepam injection for the Before group, but for the After group, the 3 postsession flurazepam injections resulted in subsequent tolerance to presession flurazepam injection for session lever presses, but not for the time taken to earn 180 pellets. Dispositional tolerance to the serum elimination rate of flurazepam did not develop over the course of 3 injections. Behavioral suppression still evident in the initial portion of sessions with the 2nd and 3rd presession injection coincided with the duration of rising and high levels of serum flurazepam.     

Extinction procedures abolish conditioned stimulus control but spare sensitized responding to amphetamine

The effect of extinction on previously established environment-specific sensitization of the locomotor activating effects of 1.0mg/kg d-amphetamine sulfate was studied in an attempt to investigate the relation between sensitization and conditioning of the drug effect. During the conditioning phase, groups of eight rats each were administered drug, i.p., prior to being placed in activity boxes and saline in their home cages (paired group), drug in the home cages and saline in the activity boxes (unpaired group), or saline in both environments. Evidence for conditioning and environment-specific sensitization was found following the conditioning phase in tests during which animals were administered saline or amphetamine, respectively. On a final test for environment-specific sensitization that followed the extinction phase (during which all animals received saline injections in both the activity boxes and the home cages), sensitized responding to amphetamine was found in both the paired and unpaired groups, suggesting that prior to extinction the expression of sensitization in the unpaired group had been under inhibitory control.     

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.     

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     

Tolerance to the disruptive effects of arecoline on schedule-controlled behavior

The roles of dispositional, physiological, and behavioral factors in the development of tolerance to the effects of arecoline on operant behavior were assessed. In Experiment I, rats were trained to press a lever on a variable-interval 15-s schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days of arecoline administration prior to each session, the dose-effect relationship for total number of responses did not shift. However, the dose-effect relationship for total number of reinforcers shifted to the right. In Experiment II, rats were trained to respond on a fixed-ratio 20 schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the session and a second group received arecoline injections 30 min after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship for the presession group than it did for the postsession group. These data demonstrate the importance of behavioral factors in the development of tolerance to arecoline.     

Tolerance to ethanol's effects on operant performance in rats: role of number and pattern of intoxicated practice opportunities

Acquisition and retention of tolerance to ethanol's rate-decreasing effects on operant performance were examined in rats which received a 52-day regimen of ethanol or saline injections prior to and/or after each daily session. Eight groups of rats differed on: (a) number of days with intoxicated practice (pre-session ethanol); (b) intermittent (spaced) or daily (massed) intoxicated practice; and (c) post-session ethanol or saline on nonintoxicated practice days. Massed practice groups were given their presession saline days prior to their pre-session ethanol days. Ethanol dose-effect tests were given prior to, during, and after the chronic injection regimen. Under both spaced and massed practice conditions, the magnitude of tolerance developed increased directly with the number of pre-session ethanol days, even when absolute ethanol exposure was constant. No group showed complete tolerance loss. The post-session ethanol supplements (a) facilitated tolerance development in spaced practice groups and tolerance loss in massed practice groups, (b) blocked ethanol's low dose rate-increasing effects, and (c) produced an acute withdrawal-like performance disruption the next day. The results suggest that both intoxicated practice and practice during acute ethanol withdrawal influence the acquisition and retention of compensatory behaviors during ethanol tolerance development.     

The development of pharmacological tolerance to the effect of nicotine on schedule-controlled responding in mice

The effects of nicotine in mice responding on a fixed-ratio schedule for a sweetened milk reinforcer were determined before, during, and after daily administration of the drug. Druing chronic treatment, responding was initially depressed in a group of mice given presession injections of nicotine and gradually returned to prechronic baseline levels. Responding to single doses of nicotine shifted to the right following chronic treatment for animals receiving either presession or postsession chronic injections of 1.2 mg/kg nicotine. Following termination of chronic treatment, both groups lost tolerance to the chronic dose at similar rates. These data indicate that animals given chronic pre- and postsession injections of nicotine develop tolerance to the pharmacological effects of the drug and that behavioral variables do not influence the development of tolerance to nicotine.     

Experiential constraints on the development of tolerance to amphetamine hypophagia following sensitization of stereotypy: instrumental contingencies regulate the expression of sensitization

 In previous research, sensitization of stereotypy induced by injections of 2.5 mg/kg amphetamine did not interfere with subsequent tolerance development to the hypophagic effect of 2 mg/kg. This study examined the effect of a higher sensitizing dose. Rats given intermittent injections of 5 mg/kg amphetamine and then challenged with various doses of amphetamine showed focused head scanning at 2 mg/kg and oral stereotypy at 4 mg/kg. In contrast, saline controls showed diffuse sniffing and head scanning at 2 and 4 mg/kg. Subgroups from each condition were then given daily injections of either amphetamine (2 mg/kg) or saline and access to milk for 30 min. Dose-response tests revealed that both drugged groups learned to suppress stereotypy in order to feed at 2 mg/kg, but only the non-sensitized group could do so at 4 mg/kg. These results demonstrate that (1) rats learn to suppress only those stereotyped movements that they experience in the context of feeding and (2) instrumental contingencies can influence the expression of behavioral sensitization. Received: 18 December 1997 / Final version: 3 June 1998     

Sensitization to haloperidol-induced suppression of milk intake: effect of interdose interval

The purpose of this study was to determine the effect of manipulating the interdose interval (IDI) on the suppression of milk intake induced by haloperidol (HAL). Groups of rats were given chronic injections of either HAL (0.625 mg/kg) or saline at IDIs of 1, 2, 7, or 14 days. Dose-response curves were determined at the conclusion of the chronic phase. The results indicated that injections of HAL given at IDIs of 1 or 2 days produced neither tolerance nor sensitization, whereas injections given at intervals of 7 or 14 days produced sensitization. Sensitization was also observed in the control groups, perhaps as a result of the intermittent schedule of HAL injections given during the dose-response tests. Sensitization to HAL was not accompanied by changes in sensitivity to amphetamine. The results of this experiment are consistent with those of other studies in showing that the behavioral effects of neuroleptics are strongly influenced by the schedule of injections. In addition, evidence is presented that sensitization to HAL-induced hypophagia is contingent on behavioral experience under the drug.     

Effects of acute and chronic cocaine on milk intake, body weight, and activity in bottle- and cannula-fed rats

The effects of cocaine on the milk intake, body weight and activity of bottle- and cannula-fed rats was compared under both acute and chronic dosing conditions. Bottle-fed rats were initially more hypophagic than cannula-fed rats when given acute injections of cocaine (4-40mg/kg). Following chronic injections of the drug (16mg/kg), bottle-fed rats developed tolerance, as shown by a rightward shift in the dose-response function for milk intake. Such tolerance was accompanied by a decrease in drug-induced motor activity. In contrast, cannula-fed rats showed marked sensitization of stereotyped movements. Bottle -fed rats showed marked sensitization of stereotyped movements. However, weight loss per se was not a determining factor in tolerance development, because cannula-fed rats given chronic injections of 32mg/kg cocaine lost even more weight, but did not become tolerant. These results suggest that, at moderate doses, cocaine suppresses feeding primarily by inducing behaviors that are incompatible with the appetitive phase of feeding, and that tolerance involves learning to inhibit such responses in order to feed.