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.

Contingent tolerance to amphetamine hypophagia: new insights into the role of environmental context in the expression of stereotypy.

A growing literature attests to the fact that the environment in which a drug is given can have a profound effect on the development and expression of tolerance and sensitization. The dominant paradigm for studying such context-dependency is based on Pavlovian conditioning, in which a distinctive environment serves as a conditioned stimulus. Context dependency is demonstrated when tolerance or sensitization is expressed only in the environment in which the drug was given chronically. An alternative paradigm for studying context-dependency is to manipulate the contingencies of reinforcement operating in the environment in which the drug is administered. For example, tolerance to amphetamine-induced hypophagia is contingent on having access to food while intoxicated [Carlton PL, Wolgin DL. Contingent tolerance to the anorexigenic effects of amphetamine. Physiol Behav 1971;7:221-223]. Such context-dependency can be explained in terms of an instrumental (or operant) conditioning model, in which food serves as a reinforcer for the learned suppression of stereotyped movements that interfere with ingestion. Research based on this model suggests that the expression of sensitized stereotyped responses is subject to an operant level of control.

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.

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.

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.

Effect of sensitization of stereotypy on the acquisition and retention of tolerance to amphetamine hypophagia.

The purpose of this study was to determine whether prior sensitization of stereotypy interferes with the development and retention of tolerance to amphetamine-induced hypophagia. Rats were given intermittent injections of either amphetamine (2.5 mg/kg) to induce sensitization of stereotypy, or saline. Subgroups from each group then received daily injections of either amphetamine (2 mg/kg) or saline and access to milk for 30 min. Both sensitized and nonsensitized groups became tolerant to drug-induced hypophagia at about the same rate and to about the same extent. Such tolerance was accompanied by a decrease in the frequency of stereotyped movements while milk was available. The rats were then given daily milk tests for 4 weeks without injections. Subsequent tests with amphetamine revealed that both groups lost tolerance to drug-induced hypophagia and displayed more intense stereotypy than they had prior to drug withdrawal. We conclude that sensitization of stereotypy produced by intermittent injections of amphetamine (2.5 mg/kg) does not retard the development of tolerance to drug-induced hypophagia and does not alter the rat's ability to suppress stereotyped movements. However, the loss of tolerance following drug withdrawal may have been due to the development of more intense stereotypy and/or the "unlearning" of previously acquired strategies for suppressing stereotypy.

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.

Learned suppression of stereotypy in amphetamine-treated rats: implications for understanding tolerance to amphetamine 'anorexia'

The purpose of this study was to determine whether amphetamine-treated rats can learn to suppress stereotyped movements in order to feed. Rats implanted with cannulae were reinforced with intraoral infusions of milk for holding their heads stationary within a narrow area of space defined by intersecting photobeams. Four of six rats given chronic injections of amphetamine (2mg/kg) learned the response. The amount of milk ingested as a result of the infusions increased over trials at a rate that was comparable to that of rats given milk in bottles. Despite the development of such 'tolerance', analysis of the temporal distribution of photobeam interruptions revealed residual effects of the drug. Specifically, amphetamine-treated rats had longer latencies to initiate infusions and displayed a more fragmented pattern of responding than did saline controls. These results demonstrate that rats can learn to inhibit amphetamine-induced sterotypy and support the view that tolerance to amphetamine 'anorexia' involves learning to suppress stereotyped movements that interfere with feeding. Parallels to the suppression of involuntary movements in humans are noted.

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 amphetamine after milk showed a loss of sensitization (DR3 = DR1), whereas groups given the drug before 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.

Effect of prior sensitization of stereotypy on the development of tolerance to amphetamine-induced hypophagia.

The purpose of this experiment was to explore the relation between amphetamine-induced stereotyped movements and the development of tolerance to the initial hypophagic effect of the drug. If stereotyped movements contribute to hypophagia, then prior sensitization of stereotypy should exaggerate the initial hypophagic effect and retard the development of tolerance. To test this hypothesis, one group of rats was given intermittent injections of amphetamine (2.5 mg/kg) to induce sensitization, and another group was given saline as a control. Sensitization was characterized by increased head scanning movements and decreased stationary activity, locomotion and sniffing. However, dose-response tests revealed that sensitized rats did not show increased hypophagia in a milk drinking task. Subsequently, subgroups from each group received daily access to milk after injections of either amphetamine (2 mg/kg), to induce tolerance, or saline. Contrary to the hypothesis, rats that had previously been sensitized developed more tolerance than nonsensitized rats. It is suggested that tolerance may involve the channeling of one form of stereotyped movement (head scanning) into another form (licking of the drinking tube). Such channeling represents a constrained form of instrumental learning that is conceptually similar to the behavioral plasticity described in rats receiving electrical brain stimulation or tail pinch.

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.

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.

Role of associative and nonassociative mechanisms in tolerance to morphine "anorexia".

To determine whether tolerance to morphine-induced anorexia involves associative mechanisms, rats were given chronic injections of morphine (Group 1, 10 mg/kg; Group 2, 20 mg/kg) in the presence of one compound cue on alternate days and injections of saline in the presence of another compound cue on the intervening days. After tolerance developed to the initial suppression of intake, three tests of Pavlovian conditioning were conducted. On the compensatory response test, in which saline injections were given in the presence of the morphine cue, only Group 2 showed a significant increase in milk intake. On the explicit unpairing test and the environmental specificity test, in which morphine injections were given in the presence of the saline cue or in an entirely different room, respectively, neither group showed a significant loss of tolerance. The failure to demonstrate cue-dependent tolerance in this paradigm may have been due in part to inadvertent temporal conditioning and in part to the rapid development of nonassociative tolerance.

Tolerance to morphine "anorexia" is not contingent on experience with food while in the drugged state.

To determine whether tolerance to morphine-induced anorexia requires access to milk while intoxicated, rats were given chronic injections of morphine (10 or 20 mg/kg) either before (before subgroups) or after (after subgroups) access to milk on alternate days. There were marked individual differences in initial sensitivity to the drug. After chronic treatment, there was little difference in the level of tolerance in subjects given morphine either before or after access to milk. On the intervening nondrug days, rats in the before subgroups consistently drank less milk than the other subgroups. This effect was not the result of withdrawal distress. Substitution of saline for morphine (20 mg/kg) on a scheduled drug day resulted in enhanced milk intakes in both the before and after subgroups. The results suggest that tolerance to morphine anorexia does not involve instrumental learning.

Effect of lithium chloride-induced aversion on appetitive and consummatory behavior.

The effect of lithium chloride-induced conditioned taste aversions on appetitive and consummatory behavior was determined. Rats were given access to a 0.1% saccharin solution for 15 min either in bottles or by infusion through an intraoral cannula. Bottle-fed rats given postprandial injections of lithium chloride showed greater aversion to saccharin than cannula-fed rats. During extinction, cannula-fed rats gradually recovered to control levels of intake, whereas bottle-fed rats continued to avoid the saccharin. These results suggest that lithium chloride affects appetitive behavior to a greater extent than it affects consummatory behavior.

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.

Contingent suppression of tolerance to the "anorexigenic" effect of haloperidol.

Whether tolerance develops to the "anorexia" induced by haloperidol (HAL) was determined. Rats were given HAL (2.5 or 5 mg/kg) either before or after access to milk for 53 days. Controls were given injections of saline. On Day 54, when all groups received pretest injections of the drug, only rats previously given posttest injections of HAL were tolerant. The absence of tolerance in rats previously given pretest injections suggests that tolerance is suppressed when rats are given access to food in the drugged state. It is concluded that tolerance develops to HAL as a result of pharmacological exposure but is suppressed by the "anhedonic" effect of the drug. The relevance of these findings to the role of reinforcement in behavioral tolerance is briefly discussed.

Escalation of feline predation along a gradient from avoidance through "play" to killing.

In this article, we show that feline predation involves a continuous gradient of activation between defense and attack and that predatory "play" results from an interaction of the two. Benzodiazepines (oxazepam, diazepam) escalated attack toward killing, so that cats that had avoided mice prior to the drug now played with them, cats that had originally played now killed, and cats that killed mice now did so with less preliminary contact. In such shifts, no sharp demarcation between play and predation was evident. Lateral hypothalamic lesions disrupted the escalation of attack. During recovery, attack was escalated once again along the gradient toward killing, but in the absence of both defense and play. A similar result was obtained in intact killers and nonkillers by the application of mild tail pinch. These results suggest that play with prey is a misnomer for predatory behavior that fails to escalate along the gradient between defense and attack. Movement notation analysis revealed that playful movements are adaptive in that they protect the cat from injury.

Effects of "anorexia" on appetitive and consummatory behavior.

In order to assess the effects of anorexigenic agents on appetitive and consummatory behavior, rats were given sweetened milk either in a bottle or by infusion through an intraoral cannula. In the first experiment, amphetamine (AMP; 0, 0.25, 0.5, and 1 mg/kg) had no effect on the intake of cannula-fed rats but suppressed the intake of bottle-fed rats at the highest two doses. Although increased activity was observed at the highest dose, bottle-fed rats drank less than cannula-fed rats at each dose of the drug. Fenfluramine (FEN; 0, 2.5, 5, and 10 mg/kg) produced a dose-dependent decrease in intake with both methods of feeding, but the effect was greater in bottle-fed rats. Although FEN had marked sedative effects at the highest two doses, bottle-fed rats drank less than cannula-fed rats at each dose of the drug. In a second experiment, cannula- and bottle-fed rats were given milk adulterated with various concentrations of quinine hydrochloride (QHCl; 0, 0.0025, 0.005, 0.01, and 0.02%). QHCl had no effect on the intake of cannula-fed rats but decreased the intake of bottle-fed rats at the highest two concentrations. In a final experiment, the effect of AMP (1 mg/kg) was assessed in a conditioned aversion paradigm. Rats were given four conditioning trials in which access to a 0.1% sodium saccharin solution was followed by an injection of AMP. Again, bottle-fed rats showed greater suppression of intake than cannula-fed rats. Taken together, these results demonstrate that anorexigenic drugs affect appetitive behavior more than consummatory behavior. The implications of these findings for understanding the mechanism of behavioral tolerance are discussed.