David L. Wolgin

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.

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.

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.

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 (4–40 mg/kg). Following chronic injections of the drug (16 mg/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 32 mg/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.

Effects of "anorexia" in 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.

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.

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.

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 (2 mg/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 stereotypy 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.

Role of behavioral and pharmacological variables in the loss of tolerance to amphetamine hypophagia

Abstract 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 druginduced 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 druginduced hypophagia and does not alter the rats 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.