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.

Forelimb placing and hopping reflexes in haloperidol- and morphine-treated cataleptic rats.

Although both haloperidol and morphine produce catalepsy, there are fundamental differences in their neurological effects (De Ryck, Schallert, & Teitelbaum, 1980). Haloperidol-treated rats show brisk righting, bracing, and clinging reflexes, effects suggesting that motor subsystems subserving static postural support are dominant over those involved in more phasic locomotor and orienting movements. In contrast, morphine-treated rats show impaired righting, bracing, and clinging, effects suggesting that postural support mechanisms are suppressed. In order to determine whether phasic postural reactions other than righting are also differentially affected by these drugs, forelimb placing and hopping reflexes were evaluated in rats given either haloperidol (0, 0.25, 0.5, 1, and 5 mg/kg) or morphine sulfate (0, 10, 20, and 40 mg/kg). Morphine produced a dose-dependent impairment in all tests. In contrast, haloperidol did not impair contact placing to dorsal stimulation of the limb or chin placing. Hopping and contact placing to lateral stimulation of the limb were impaired by haloperidol, perhaps because stimulation induced a competing tendency to brace. These results provide additional evidence that morphine and haloperidol produce functionally different neurological states.

Tolerance to amphetamine anorexia: role of learning versus body weight settling point.

Three experiments were conducted to clarify the role of learning and body weight settling point in the development of tolerance to amphetamine anorexia. In the first experiment, rats that had become tolerant to the suppressant effect of amphetamine on milk intake were anorexic when subsequently offered other foods or water during a transfer test. These results appear to support a conditioning interpretation, which predicts a loss of tolerance when cues associated with drug administration are altered. Subsequent experiments examined the long-term effect of changing diets. In Experiments 2 and 3, rats made tolerant with milk as the diet showed prolonged anorexia when switched to Purina pellets or slightly bitter milk. However, when switched from pellets or adulterated milk to milk, tolerant rats were anorexic only 1 day and then ingested significantly more of the new diet. These results are inconsistent with a conditioning interpretation. Further analysis revealed that tolerant rats maintained their weight below the level of saline controls despite the recovery of food intake. Moreover, the level at which they maintained their weight varied with the palatability of the diet. These results suggest that amphetamine lowers the settling point for body weight and that tolerance does not develop to this effect (cf. Stunkard, 1981). From this perspective, the reinstatement of prolonged anorexia when apparently tolerant rats were switched to a less palatable diet can be understood as an attempt to attain a lower weight level.

Role of anorexia and behavioral activation in amphetamine-induced suppression of feeding: implications for understanding tolerance.

In order to gain further insight into the mechanism of contingent tolerance to amphetamine anorexia (Carlton & Wolgin, 1971), an attempt was made to determine the role of anorexia and behavioral activation (increased locomotion and/or stereotypy) in the initial suppression of feeding produced by the drug. Rats administered chronic injections of either saline or amphetamine (2 or 4 mg/kg) were given milk either directly into the mouth through an intraoral cannula or in a standard drinking tube. It was reasoned that although drug-induced anorexia would affect intake with both methods of feeding to the same degree, the disruptive effect of behavioral activation would be greater in bottle-fed rats. The results revealed that bottle-fed rats given amphetamine showed substantially greater suppression of intake than cannula-fed rats. Saline-treated rats showed almost identical milk intake with the two methods. Recovery of intake occurred in all drugged rats except those given 4 mg/kg and fed by bottle. In the tolerant groups, rats fed by bottle and given 2 mg/kg recovered at a faster rate than cannula-fed rats at either dose. These results demonstrate that in the normal drinking condition, the initial suppression of intake is caused by a combination of anorexia and behavioral interference and that tolerance occurs to both of these effects.

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.

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.

Amphetamine tolerance and body weight set point: a dose-response analysis.

The theory that amphetamine anorexia and tolerance reflect the lowering of a set point for body weight regulation was evaluated. In the first experiment, rats given either 2 or 4 mg/kg d-amphetamine and access to milk ultimately achieved comparable levels of tolerance and maintained their weight at 94%-96% of control levels. Thus, the level of maintained body weight was not dose-dependent. In the second experiment, increasing the doses resulted in renewed anorexia and weight loss, and the appearance of behavioral stereotypies. Whereas mean intake then recovered, body weight remained at 79%-82% of control levels. However, milk intake for individual rats was extremely variable. Such variability is inconsistent with the notion that body weight was actively regulated by caloric intake. Drug withdrawal had little further effect on intake, and it led to weight "rebound" in only one group. When subsequently retested with the original doses, both groups were again anorexic and showed more intense stereotypy. This finding suggests that drug withdrawal caused a general increase in sensitivity to amphetamine, rather than a set-point-related change in feeding. Taken together, the data do not support the set point theory of amphetamine tolerance.

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.

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.

Tolerance to amphetamine: contingent suppression of stereotypy mediates recovery of feeding.

In this article, the effect of chronic injections of amphetamine on feeding and behavioral activation was analyzed. Rats were given milk either through an intraoral cannula or in a standard drinking tube, and the level of their behavioral activation was monitored before, during, and after access to the milk. Cannula- and bottle-fed rats given saline showed similar patterns of intake and activity. Bottle-fed rats given amphetamine (2 mg/kg) showed substantially greater suppression of intake than did cannula-fed rats, but recovered more rapidly, confirming earlier findings (Salisbury & Wolgin, 1985). Such recovery was accompanied by a suppression of stereotyped head scanning movements during access to milk, but not before and after milk access. In contrast, cannula-fed rats given amphetamine showed stereotyped head scans throughout the session for the duration of the experiment. These results suggest that tolerance to the suppression of intake by amphetamine involves learning to suppress stereotyped head movements. The constraints on such learning are 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.

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.

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 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.

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.

A proposed natural geometry of recovery from akinesia in the lateral hypothalamic rat.

The Eshkol-Wachmann movement notation is used to analyze and describe neurological recovery from the akinesia caused by severe bilateral lateral hypothalamic (LH) damage in rats. Exploratory movement recovers along several relatively independent dimensions which appear successively. First, lateral head scanning movements recover. At about the same time or later, longitudinal (backward-forward) head scans appear. After movements along these two dimensions increase in amplitude and involve the whole body, vertical (dorsal-ventral) head scans with snout contact (along vertical surfaces) typically appear, and increase gradually in amplitude. Later, vertical rearing without snout contact emerges. Recovery proceeds cephalocaudally, as more caudal limb and body segments are recruited along each of the above dimensions separately. LH rats show delayed recruitment of caudal limb and body segments ('strait-jacket phenomenon'). Support of the body and management of limb and body segments' contact with the ground also recover relatively independently, in a proximodistal fashion. In recovery, arrests between bouts of activity become shorter. Movement first becomes organized in relation to the animals' own body, and only much later, in relation to the environment. In each sequence of movement after pronounced immobility, the rat recapitulates the process of recovery; and, any time it starts to move, it repeats the movements at a particular amplitude several times until there is an increase to the next larger size movement ('warm-up' phenomenon). These regularities explain the apparently bizarre stereotyped behavior in partial enclosures ('behavioral traps') seen in LH rats recovering from akinesia. They also explain some aspects of exploration in rats and normal social behavior of wild animals, particularly in situations involving fear and conflict.

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.

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.

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.