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Notice: This manuscript is a version of an article published in Neuroscience and Biobehavioral Reviews v. 24, no. 3 (May 2000)
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NEUROSCIENCE AND
BIOBEHAVIORAL
REVIEWS
PERGAMON
Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
www.elsevier.com/locate/neubiorev
Review
Contingent tolerance to amphetamine hypophagia: new insights into the
role of environmental context in the expression of stereotypy
D.L. Wolgin*
Department of Psychology, Florida Atlantic University, 777 Glades Road, P.O. Box 3091, Boca Raton, FL 33431 USA
Received 25 May 1999; received in revised form 1 October 1999; accepted 18 October 1999
Abstract
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. q 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Contingent tolerance; Sensitization; Instrumental learning; Amphetamine; Cocaine; Anorexia; Stereotypy; Context-dependency; Response–consequent relation
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Early theoretical framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. The mechanisms of amphetamine hypophagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. The mechanism of tolerance to amphetamine hypophagia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Learned suppression versus channeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. The temporal dynamics of learned suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Contingent loss of tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. The effect of sensitization on tolerance development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
A cardinal principle of behavioral pharmacology is that
drug effects are strongly influenced by the context in which
the drug is administered. In the drug tolerance/sensitization
literature, context usually refers to the physical environment
* Tel.: 1 1-561-297-3366; fax: 1 1-561-297-2160.
E-mail address: [email protected] (D.L. Wolgin).
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in which the drug is given. For example, it has been well
established that tolerance and sensitization to the behavioral
effects of a variety of drugs are context-dependent; i.e. they
are expressed in the environment in which the drug is
chronically administered but not in an environment not
previously associated with the drug (for reviews, see Refs.
[1–4]). These context-dependent effects are thought to be
mediated by associative learning, with the environmental
context serving as the CS and the drug serving as the US.
0149-7634/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0149-763 4(99)00070-6
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Repeated administration of the drug in the distinctive environment constitutes conditioning trials and results in the environmental context acquiring control over the expression of the drug
response.
It should be noted that the precise nature of the
associative control exerted by the environment is still
being debated (see, e.g. Refs. [1,5]). For example, with
respect to conditioned sensitization, it has been argued
that the environmental context in which the drug is given
acts more as an “occasion setter” than as a conventional CS
[1]. Similarly, associative accounts of tolerance differ as to
whether environmental stimuli elicit a drug-opposite CR
[3,6] or an isodirectional CR [7]. Despite these differences,
however, all of these views attribute context dependency to
an association between the environment in which the drug is
given and the drug’s effect.
For purposes of experimental control, environments used
in studies of context-dependency are designed to be distinctive, but devoid of biologically relevant stimuli, such as
food, water, or another animal, with which the subject can
interact. In the “real world”, however, drug use takes place
in much more complex and “interactive” environments.
Such environments contain a rich array of stimuli that
may modify the pharmacological and behavioral effects of
drugs. Indeed, an early textbook of behavioral pharmacology emphasized the relevance of operant conditioning principles in understanding how both antecedent and
consequent stimuli associated with drug administration
can alter a drug’s effects [8].
Viewed from the perspective of the operant paradigm, the
concept of context dependency takes on an entirely different
meaning. When a subject interacts with stimuli in its
environment while intoxicated, the consequences of its
behavior can alter the topography, temporal patterning, or
persistence of drug-induced responses [9]. In addition,
environmental stimuli that consistently precede such
responses, along with interoceptive stimuli arising from
the drug itself, can acquire discriminative stimulus control
over the occurrence of those responses. Clearly, the potential for drug–environment interactions is increased when
drugs are administered chronically. Such interactions can
shape the subject’s behavior, giving rise to patterns of
responding that would not have developed in an environment lacking these antecedent and consequent stimuli. In
other words, contingent relationships between behavior and
its consequences also constitute an environmental context
and, therefore, can be expected to contribute to contextdependent effects when drugs are administered chronically.
A classic example of this latter type of context dependency is the phenomenon of contingent tolerance to amphetamine-induced hypophagia. When rats are given repeated
injections of amphetamine in an environment containing
food, they develop tolerance to the initial suppression of
feeding. However, if they are given the same number of
drug injections in the absence of food, tolerance does not
develop [10]. Similar results have been found with cocaine
[11], cathinone [12], and methylphenidate [13]. Thus, the
opportunity to ingest food while intoxicated plays a critical
role in the development of tolerance to the hypophagic
effect of stimulant drugs.
Despite the apparent simplicity of this example, there is
substantial disagreement regarding which of amphetamine’s
behavioral effects are altered by the presence of food. Some
theorists have argued that contingent tolerance develops to
the anorexic effect of the drug [6,14]. According to this
view, food serves two functions: (1) It provides feedback
of a functional disturbance in nutritional homeostasis and
(2) it stimulates a physiological compensatory response to
counteract the anorexia.
An alternative view is that access to food influences the
expression of stereotyped behavior, which nonspecifically
interferes with feeding [15]. Normally, when rats are given
repeated injections of moderate to high doses of amphetamine ( . 1 mg/kg), the locomotor and stereotyped movements induced by the drug undergo sensitization.
Although access to food does not prevent the induction of
sensitization, it does influence the expression of stereotypy.
Indeed, as I will explain below, rats can learn to inhibit
stereotyped responses through instrumental or operant
conditioning. Such learning takes place because in an
environment containing food, suppressing stereotypy has
an important consequence: it allows the rat to eat.
2. Early theoretical framework
To develop the argument that contingent tolerance has
more to do with stereotypy than anorexia, I will begin
with a review of the original study by Carlton and Wolgin
[10]. Groups of rats maintained on a daily ration of 10–15 g
of food were given access to sweetened milk for 30 min on
alternate days. The Before group received an injection of
amphetamine (2 or 3 mg/kg) 20 min before the milk test and
an injection of saline afterwards; the After group received
the injections in the reverse order, and the Saline control
group received injections of saline at both time points. In the
Before group, amphetamine initially caused a marked
decrease in the mean amount of milk consumed, but by
the eighth trial intakes exceeded baseline levels; i.e. tolerance developed to the initial suppression of intake. At this
point, the order of injections for the After group was
reversed so that it now received amphetamine before the
milk tests. The After group showed no tolerance on the
first day of the reversal. However, with continued pretest
injections of the drug, tolerance developed at about the same
rate as it had in the Before Group. Thus, there was no
apparent benefit with respect to the rate of tolerance development as a result of the prior history of post-test amphetamine injections.
These findings were difficult to reconcile with the traditional view that drug tolerance resulted from biochemical
alterations triggered by mere exposure to the drug.
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281
Fig. 1. Effect of various doses of amphetamine (left panel) and cocaine (right panel) on the intakes of rats given milk either in bottles or via intraoral cannulas.
The rats were maintained on 15 g of food per day. The data are expressed as a percentage of intakes under the saline dose. Intakes were significantly higher in
the cannula condition at all common doses. (Cocaine graph adapted from Fig. 1 in Ref. [25]).
However, the results of an experiment by Schuster et al.
[16] provided a theoretical perspective that seemed to
account for the data quite well. In this study, rats treated chronically with amphetamine (1 mg/kg) were reinforced for pressing a lever on a multiple schedule of
reinforcement consisting of two components, each separately cued. In one component, the rats were differentially reinforced for responding at a low rate (DRL),
while in the other component they were reinforced for
responding after a fixed interval of time had elapsed
(FI). In two rats, amphetamine initially caused an
increase in the rate of responding in both components
of the schedule, which resulted in a loss of reinforcement in the DRL component but not in the FI component. With chronic treatment, tolerance developed only
to the rate-increasing effect of the drug in the DRL
component. In a third subject, however, amphetamine
initially caused a decrease in FI responding and a loss
of reinforcement. In this rat, tolerance developed in the
FI component.
On the basis of these findings, Schuster et al. [16]
proposed that tolerance develops when the acute effect of
a drug results in a loss of reinforcement, but not when the
drug increases, or has no effect on, reinforcement density.
Since tolerance could be differentially expressed on one
component of a multiple schedule but not on another in
the same rat, it was clear that more than pharmacological
exposure was responsible for such tolerance. And since
tolerance was correlated with reinforcement loss, these
results suggested that rats could compensate for such loss
by actively altering their behavior.
The implications of these findings for understanding
contingent tolerance seemed straightforward. Rats given
chronic injections of amphetamine prior to a feeding test
did not eat; consequently, they lost reinforcement. Rats
given the drug after the feeding test did not lose reinforcement. Hence, the Before group would be expected to learn
to compensate for the loss in some unspecified way,
resulting in the development of tolerance, while the After
group would not.
Although we did not recognize it at the time, the problem
with this interpretation is that it contradicts a basic assumption regarding the effect of amphetamine on food intake. To
say that amphetamine is anorexigenic is to say that it causes
a loss of appetite for food. But if this is true, then food
should no longer have reinforcing properties, and therefore,
should not serve as an incentive for a learned behavioral
compensation.
3. The mechanisms of amphetamine hypophagia
This conceptual paradox forced us to re-evaluate our
assumptions regarding the mechanism by which amphetamine suppresses food intake. Our thinking was greatly influenced by the results of an experiment in which various doses
of amphetamine (2–6 mg/kg) were given prior to daily milk
tests over an 8-month period [17]. Two findings from this
study stood out. First, although the rats developed tolerance
to the initial suppression of feeding at all of these doses,
many of them showed extremely variable intakes from day
to day. In some cases, their intakes alternated between 0 and
40 or even 50 cm 3. (Baseline intakes for these rats,
reassessed at the end of the experiment, ranged from 29–
38 cm 3.) Such variability seemed inconsistent with the view
that the drug simply decreased the activity of a homeostatic
system controlling food intake [14] or body weight [18].
Second, all of the rats exhibited stereotyped head movements that varied in intensity across subjects and drug
doses. Because such movements are incompatible with
drinking milk, these observations suggested that behavioral
interference may have contributed to the suppression of
feeding, a possibility raised earlier by several investigators
[19–21].
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To evaluate this possibility, we compared the effect of
amphetamine on the intakes of rats given milk either
through an intraoral cannula or in a bottle. We reasoned
that if amphetamine acts primarily by reducing the appetite
for food via anorexia, then intakes should be suppressed to
an equivalent degree with both methods of feeding.
However, if the drug disrupts feeding in part by inducing
incompatible patterns of behavior, then the suppression of
intakes should be greater with the bottle, the condition in
which the rats must maintain a stationary position in order to
feed.
Another way to characterize this distinction is in terms of
the effects of the drug on the appetitive and consummatory
phases of feeding [22,23]. The appetitive phase involves
locating, approaching, and maintaining contact with food.
This phase is important in the bottle condition, but not in the
cannula condition. The consummatory phase, on the other
hand, refers to the actual ingestion of food. This phase
occurs in both the bottle and the cannula conditions. Therefore, if amphetamine is equipotent in disrupting intake with
both methods of feeding, an effect of the drug on the
consummatory phase is implicated. However, if amphetamine is more potent in disrupting bottle feeding than
cannula feeding, an effect on appetitive behavior is indicated.
The intraoral cannulas were constructed from polyethylene tubing and surgically implanted in the dorsorostral
region of the mouth to preclude forced swallowing of
milk. The tubing was routed subcutaneously along the
cheek to emerge at an incision on top of the head, where
it was slipped over an L-shaped piece of stainless steel
tubing and cemented in place. Milk was gravity-fed from
a 50 cm 3 syringe to the cannula through a fluid swivel at a
rate of about 1 cm 3/min. The swivel was held in a counterbalance arm, which allowed relatively unimpeded movement by the rat. Throughout the 30-min session, milk
flowed continuously through the tubing and the rat could
either move it to the back of its mouth and swallow it or let it
spill out. Spillage was recovered from trays placed beneath
the cage, measured, and subtracted from the volume missing
from the syringe at the end of the session. Saline-treated rats
typically ingested milk continuously for 30 min with this
method, allowing little milk to spill from their mouths.
Although they were free to move about as they drank,
they typically remained in one location and licked their
paws or the cage floor while ingesting the milk. Their
daily intakes closely paralleled those of bottle-fed rats [24].
The acute effects of various doses of amphetamine on the
intakes of bottle- and cannula-fed rats is shown in Fig. 1
(left). Amphetamine produced dose-dependent decreases in
intake with both methods, but the potency of the drug was
clearly greater in the bottle condition. For example, at low
doses (e.g. 1 mg/kg), amphetamine produced only a 5%
reduction in intake in the cannula condition, but a 40%
reduction in the bottle condition. At the 2 mg/kg dose,
intake was reduced by 20% with the cannula, but by 70%
with the bottle. Similar effects were obtained with cocaine
([25]; Fig. 1, right). These results demonstrate that amphetamine and cocaine affect both the appetitive and consummatory phases of feeding, but that the effect is greater on
appetitive behavior. Note, in addition, that at doses of
amphetamine typically used in feeding experiments (1–
2 mg/kg), there is little suppression of feeding in the cannula
condition, suggesting that at these doses anorexia is quite
mild.
The results of several other studies support this conclusion. For example, analyses of the microstructure of feeding
have found that under both amphetamine [26] and cocaine
[27], rats are hyperactive, have longer latencies to initiate
feeding, and frequently interrupt their meals with periods of
activity. Similarly, a number of studies have reported that
amphetamine produces reciprocal changes in feeding and
motor activity in both normal and brain-damaged rats
[28–33]. For example, following 6-hydroxydopamineinduced damage to the nigrostriatal system, amphetaminetreated rats showed reduced stereotypy and increased feeding compared to controls, despite the fact that hypothalamic
sites presumed to mediate the anorexic effect of amphetamine were spared [31]. Conversely, following kainic acidinduced damage to the striatum, amphetamine-treated rats
showed increased stereotypy [32] and decreased food intake
[33]. Finally, the suppression of feeding induced by amphetamine is blocked by “typical” neuroleptics, which also
block stereotyped movements, but not by “atypical”
neuroleptics, which do not [34,35]. Taken together
these findings reinforce the view that amphetamine
interferes with feeding primarily by inducing incompatible patterns of behavior.
4. The mechanism of tolerance to amphetamine
hypophagia
If amphetamine primarily affects the appetitive phase of
feeding, then the search for a mechanism of tolerance should
focus on changes in the motor effects of the drug that are
incompatible with ingestion. Fig. 2 (left panel) shows the
effects of daily administration of amphetamine (2 mg/kg) on
the activity and milk intakes of bottle-fed rats [15]. The
frequency of various categories of behavior (immobility,
stationary activity, locomotion, and three types of stereotyped behavior) was measured by rating the rats’ activity at
5 min intervals before, during, and after access to milk. As
shown in Fig. 2 (left panel), the recovery of milk intake in
bottle-fed rats was accompanied by a decrease in the
frequency of stereotyped movements and an increase in
the frequency of stationary activity (primarily drinking)
while milk was available. Both before and after the period
of milk availability, however, these rats engaged in continuous stereotyped movements (data not shown). In contrast,
cannula-fed rats showed no change in the frequency of
stereotyped behaviors (Fig. 2, right panel). This latter
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
Fig. 2. Left: Frequency of stereotyped head movements and stationary activity (top) and mean intakes ( ^ SE; bottom) of rats given daily injections of amphetamine (2 mg/kg) and access to milk in bottles for 24
trials. Activity was scored at 5-min intervals throughout the 30-min session. The development of tolerance to drug-induced hypophagia was accompanied by a significant decrease in stereotyped behavior and an
increase in stationary activity. PRE denotes mean intake on the last baseline trial. (From Fig. 4 in Ref. [15]). Copyright q 1987 by the American Psychological Association. Adapted with permission. Right:
Frequency of stereotyped head movements and stationary activity (top) and mean intakes (bottom) of rats given daily injections of amphetamine (2 mg/kg) and access to milk via intraoral cannulas for 24 trials.
There were no significant changes in either activity or intake over the course of the experiment. (From Fig. 3 in Ref. [15]). Copyright q 1987 by the American Psychological Association. Adapted with
permission.
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finding is important because it demonstrates that tolerance
did not develop to the motor effects of the drug.
Taken together, these results can be explained by means
of a simple instrumental learning model [36]. Because
amphetamine induces little anorexia at this dose, as
evidenced by the small decrease in intake in the cannula
condition, milk would retain its reinforcing properties and
could serve as an incentive to suppress stereotyped movements, which interfere with ingestion. If we assume that the
suppression of stereotypy requires practice, the gradual
increase in drinking over trials may be viewed as a learning
curve, illustrating how well, on average, the rats have
mastered the task of holding still. Since stereotypy does
not interfere with ingestion in cannula-fed rats, no learning
would occur in this group. Similarly, no suppression of
stereotypy would be expected in tolerant bottle-fed rats
during periods in which milk is not available, since at
those times there is no incentive to hold still.
The instrumental learning model can also account for the
contingent nature of tolerance to amphetamine hypophagia
[10]. Rats given amphetamine before feeding experience the
drug in an environment that provides reinforcement (i.e.
milk) for suppressing stereotyped movements. Each trial
provides a new opportunity to master this task. In contrast,
rats given amphetamine after feeding experience the drug in
an environment in which no reinforcement is provided for
holding still, and therefore, do not learn to suppress stereotypy. When these rats are later given the drug before
feeding, they must begin the learning process de novo,
and therefore show no “savings” from their prior drug
experience.
This interpretation is supported by the results of an
experiment on tolerance to the rate-enhancing effects of
amphetamine on operant responding [37]. In this study,
rats were differentially reinforced for pressing a lever at a
low rate, i.e. on a DRL schedule of reinforcement. Amphetamine injections given prior to the task resulted initially in
an increased rate of responding, which resulted in a loss of
reinforcement. With repeated trials, the rats learned to inhibit their responses so that their inter-response times more
closely conformed to the requirements of the schedule. Rats
given injections of the drug after the task did not demonstrate such tolerance when they were subsequently tested
with pretest injections of the drug. These results confirm
that rats can learn to suppress maladaptive patterns of
behavior when appropriate reinforcement is available in
the environment.
There is ample evidence that amphetamine-treated rats
are sensitive to the density of reinforcement (e.g. [38]).
However, as a study by Smith [39] makes clear, the context
in which reinforcement loss occurs must also be considered.
In this study, rats were reinforced for pressing a lever on a
multiple random ratio (RR), DRL schedule. Amphetamine
initially disrupted responding, and caused a loss of reinforcement, in both components of the schedule. During
chronic administration of the drug, tolerance developed to
the rate-decreasing effect of the drug on RR responding, but
not to the rate-increasing effect on DRL responding.
However, when the rats were tested on the DRL component
alone, tolerance rapidly developed. When the RR component was reinstated, tolerance on the DRL component disappeared once again.
As Smith [39] noted, these results suggest that the development of tolerance is influenced by the global density of
reinforcement. That is, when the initial effect of the drug
results in a loss of reinforcement, the relative cost of that
loss influences the development and/or expression of tolerance. In the context of the multiple schedule, the proportion
of reinforcers lost in the DRL component was relatively
small compared to that in the RR component. Under these
conditions, tolerance was not expressed in the DRL
component. However, in the absence of the RR component, all of the reinforcers came from the DRL component, and under these conditions tolerance developed
rapidly. Thus, context determined whether tolerance
was expressed or not.
5. Learned suppression versus channeling
Although the instrumental learning model provides a
theoretical basis for understanding why tolerance to the
hypophagic effect of stimulants is contingent on having
access to food, the evidence presented so far is admittedly
circumstantial. First, the correlation between decreased
stereotypy and increased feeding does not prove that the
two events are causally related. Since rats cannot both
move their heads and lick a drinking tube simultaneously,
an increase in drinking would necessarily be associated with
a decrease in stereotyped movements whatever the
mechanism of tolerance. Second, the behavior that eventually replaces head movements, licking, is itself a highly
stereotyped response. Several studies have shown that the
topography of drug-induced stereotypy can be modified by
both environmental and experiential factors [40–44].
Consequently, it is possible that in the studies described
above, one form of stereotyped behavior (e.g. head scanning) was simply “channeled” into another (licking).
Although both the channeling and suppression interpretations are consistent with the instrumental learning model,
the ability of rats to actually inhibit stereotyped movements
implies a greater degree of “voluntary” control.
To address these issues, we designed an experiment to
dissociate the suppression of stereotypy from the act of
licking a drinking tube [45]. Groups of rats were implanted
with intraoral cannulas as previously described. In this case,
however, milk was not delivered noncontingently. Instead,
the rats were reinforced with intraoral infusions of milk for
holding their heads stationary within a narrow area of space
defined by intersecting photobeams. Access to this area was
provided through a circular opening in one wall of the cage.
The duration of each infusion was controlled by the rat; it
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285
Fig. 3. Left: Mean intakes of amphetamine-treated rats given intraoral infusions of milk while holding their heads stationary within intersecting photobeams
(Cannula) or given access to milk in bottles in the same location (Bottle). Amphetamine injections were given daily 20 min prior to each 30-min session. Right:
Dose–response functions determined before (DR 1) and after (DR 2) chronic administration of amphetamine (2 mg/kg). The data are expressed as a percentage
of intakes under the saline dose. (From Fig. 1 in Ref. [45]).
lasted as long as the rat’s head remained stationary within
the photobeams. The infusion rate was constant at 1 cm 3/
min. After the rats were reliably infusing milk, daily tests
with amphetamine (2 mg/kg) were begun. For one group, an
empty drinking tube was provided just beyond the photobeams, which could be licked during the infusion; for a
second group, no drinking tube was provided. We reasoned
that if tolerance involves channeling head movements into
licking, only the group having access to the drinking tube
should develop tolerance. On the other hand, if tolerance
involves learning to suppress stereotyped movements, both
groups should become tolerant. For purposes of comparison,
a third group was given injections of amphetamine and
access to milk in bottles.
Four of six rats given chronic injections of amphetamine
learned to self-administer infusions of milk by holding their
heads stationary within the photobeams. As shown in Fig. 3,
the amount of milk ingested as a result of the infusions
increased over trials at a rate that was comparable to that
of amphetamine-treated rats given milk in bottles. Tolerance was confirmed in both groups by a rightward shift in
the dose–response function. The opportunity to lick an
empty drinking tube did not affect the development of tolerance. Of the four tolerant rats, two had access to the empty
drinking tube while two others did not. Moreover, the two
rats that had access to the tube never licked it as they
received infusions of milk. These results clearly demonstrate that tolerance does not involve channeling and,
more importantly, that amphetamine-treated rats can learn
to suppress stereotyped movements in the absence of any
physical contact with a drinking tube.
The two rats that did not learn to self-administer infusions
of milk never approached the circular opening during the
entire chronic phase of the experiment. Instead, they
engaged in continuous stereotyped sniffing and head scanning throughout each session. However, when subsequently
tested with saline injections on the dose–response determination, both rats self-administered about 40 cm 3 of milk.
Thus, their failure to learn to suppress stereotyped movements cannot be attributed to inadequate training or to
forgetting the appropriate response. Instead, it may have
been due to the absence of discriminative cues. Unlike a
standard feeding test, in which milk is provided in bottles
attached to the front of the home cage in full view of the rat,
here there were no cues (sight, smell) associated with the
availability of milk. If this analysis is correct, then providing
such environmental cues should facilitate learning to
suppress stereotypy.
6. The temporal dynamics of learned suppression
In order to analyze the development of learned suppression of stereotypy in more detail, we examined the temporal
distribution of photobeam interruptions over the course of
the experiment. For this purpose, we calculated the total
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Fig. 4. Daily milk intake and temporal distribution of photobeam interruptions on selected trials for rat CS1, which was injected with saline during the chronic
phase of the experiment. Bars represent the duration of photobeam interruptions in successive 60-s intervals (bins). Numbers adjacent to data points on the
intake graph correspond to the selected trials. Note that milk infusions were sustained over many consecutive bins and always began within the first minute.
(From data reported in Ref. [45]).
duration of interruptions in consecutive 60 s intervals
(“bins”) for each trial. These daily profiles of photobeam
interruptions provide a detailed picture of the rat’s ability to
control the disruptive effects of stereotypy on goal-directed
behavior both within and between trials.
Fig. 4 is typical of the results for rats tested with saline.
Daily milk intake is shown in the upper left panel; the
remaining panels show the temporal pattern of photobeam
interruptions on selected trials. These trials are indicated by
numbers adjacent to the corresponding milk intakes. These
rats almost always began to self-administer infusions of
milk during the first 60 s of the trial, and their intakes
were sustained over many consecutive 60-s intervals. This
initial period of drinking was punctuated by brief
intermittent pauses, as indicated by bin durations of less
than 60 s. Such sustained periods of drinking, which were
separated from other periods of drinking by at least 60 s,
were defined as a “bout.” Within a trial, subsequent
bouts of drinking, if any, were of shorter duration
than the initial bout, and were generally separated from
the initial bout by several “empty” bins (e.g. trials 10 and
14). Only rarely was a fragmented pattern of photobeam
interruptions observed.
In contrast, amphetamine-treated rats had longer latencies
to initiate milk infusions and showed a more fragmented
pattern of photobeam interruptions. This pattern is illustrated in Fig. 5. Note that when milk infusions began for
the first time (trial 10), the photobeam interruptions
occurred late in the session. On subsequent trials, relatively
normal bouts of drinking were found only rarely (e.g. trial
26). On most trials, infusions were either very fragmented or
they occurred late in the session. The profiles for the other
tolerant rats were qualitatively similar.
Quantitatively, amphetamine-treated rats differed from
saline controls in two respects. First, the mean number of
bouts within a trial was greater in the amphetamine group
(3.97 vs. 1.69; tÖ7Ü à 4:56; P , 0:003). Second, the mean
number of consecutive 60-s bins in the first bout of drinking
(whenever it occurred) was greater in the saline group than
in the amphetamine group (15.99 vs. 4.91;
tÖ7Ü à 5:41; P , 0:001). These differences reflect the
greater degree of behavioral fragmentation in amphetamine-tolerant rats, which resulted from the intrusion of
stereotyped movements into the “behavioral stream.”
Thus, even though amphetamine-treated rats showed
substantial recovery of milk intake, it is clear that the drug
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
287
Fig. 5. Daily milk intake and temporal distribution of photobeam interruptions on selected trials for rat CA3, which was injected with amphetamine (2 mg/kg)
during the chronic phase of the experiment. Bars represent the duration of photobeam interruptions in successive 60-s intervals (bins). Numbers adjacent to data
points on the intake graph correspond to the selected trials. In general, the pattern of photobeam interruptions is fragmented and the latency to initiate milk
infusions is delayed on some of the trials. (From data reported in Ref. [45]).
continued to exert profound effects on the temporal patterning of their behavior.
These results provide important insights into the
behavioral nature of tolerance to amphetamine-induced
hypophagia. Clearly, tolerant rats do not become refractory
to amphetamine’s motor effects; nor are they able to
completely suppress the expression of stereotyped movements. Rather, there is an interplay between the contingencies of reinforcement, which encourage a stationary head
posture, and the unconditioned motor effects of the drug.
As we shall see below, the motor effects undergo sensitization during the course of chronic amphetamine treatment,
which may contribute to the disintegration of sustained
drinking behavior described above.
7. Contingent loss of tolerance
So far, the discussion has focused on the role of
instrumental learning on the acquisition of contingent tolerance. But as Poulos et al. [14] first demonstrated, the loss of
tolerance to amphetamine hypophagia is also contingent on
having access to food in the test environment. That is, if
drug injections are suspended, rats lose tolerance if they are
given milk tests during the drug-free interval, but they do
not lose tolerance if milk tests are also suspended during this
period [14]. How does the instrumental learning model
account for this example of context dependency?
Before addressing this question, some clarification is
needed regarding the conditions necessary for the loss of
tolerance to amphetamine hypophagia. One might assume
that the loss of tolerance results from both the suspension of
drug treatment and the continuation of milk tests. But
studies involving other drugs suggest that this may not
necessarily be the case. For example, contingent tolerance
to the anticonvulsant effects of ethanol [46], carbamazepine
[47], and diazepam [48] is lost even if rats are given drug
injections after convulsant stimulation. These results
demonstrate that cessation of drug treatment per se is not
necessary for the loss of tolerance. Instead, experiencing the
criterion response (in this case, seizure activity) while in the
undrugged state appears to be critical.
If this principle applies to the loss of tolerance to amphetamine hypophagia as well, then rats should lose tolerance if
they are given the opportunity to drink milk in the
undrugged state, even if they continue to receive drug injections at some other time. A study by Wolgin and Hughes
[49] showed that this is indeed the case. As shown in Fig. 6
(top), tolerant rats given injections of amphetamine after
daily milk tests (After group), showed a loss of tolerance,
as evidenced by a shift in their dose–response function.
Note that the loss was limited to the dose previously given
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
Fig. 6. Top: Development and loss of tolerance to amphetamine-induced hypophagia. Dose–response functions were determined before (DR 1) and after (DR
2) daily treatment with amphetamine (2 mg/kg) for 55 trials. The development of tolerance is indicated by the rightward shift in DR 2. Rats in the After group
were then given injections of saline before, and injections of amphetamine (2 mg/kg) after, daily milk tests for 4 weeks. Rats in the Saline group were given
injections of saline both before and after the milk tests for the same period. On a subsequent dose–response determination (DR 3), both groups showed a loss of
tolerance, as evidenced by a leftward shift in DR 3. The loss was more general in the Saline group, however. (Adapted from Fig. 2 in Ref. [49]). Bottom: Motor
activity (frequency of locomotion 1 stereotyped movements expressed as a percentage of the frequencies of all categories of behavior) accompanying the
development and loss of tolerance to amphetamine-induced hypophagia. Prior to the development of tolerance (DR 1), rats in both groups engaged in motor
activity on at least 80% of the rating periods when tested with doses of 1–4 mg/kg. Following chronic administration of amphetamine (2 mg/kg), activity
dropped significantly at the 1 and 2 mg/kg doses in both groups (DR 2). With the loss of tolerance (DR 3), activity returned to pretolerance levels. (Adapted
from Fig. 4 in Ref. [49]).
chronically during tolerance acquisition (2 mg/kg). Tolerant
rats given saline injections during this period (Saline group)
showed a somewhat more general loss of tolerance, at both
the 1 and 2 mg/kg doses. Despite these quantitative differences, these results clearly show that the critical factor in the
loss of tolerance to amphetamine hypophagia is drinking
milk in the undrugged state, not the cessation of drug treatment per se.
We can now return to the question of how the
instrumental learning model accounts for the contingent
loss of tolerance. When tolerant rats drink milk in the
undrugged state, they are, in effect, receiving noncontingent
reinforcement; i.e. they no longer need to suppress stereotypy in order to get milk. With continued experience drinking milk under these conditions, they gradually learn that
behavioral strategies for suppressing stereotypy are no
longer required to ingest milk. Consequently, when the
rats are later given access to milk in the drugged state,
they no longer suppress stereotyped movements (see Fig.
6, bottom) and are therefore unable to drink. However, when
these rats were again given daily injections of amphetamine
prior to milk tests, they reacquired tolerance at a faster rate
than nontolerant controls. Thus, having once learned how to
inhibit stereotypy, they were able to reacquire this skill
more quickly.
The key point is that, like the acquisition of tolerance, the
loss of tolerance is a function of the instrumental relationship between the rat’s behavior and its consequences. When
feeding is contingent on suppressing stereotyped movements, rats learn to do so. When the context changes, so
that this contingency is no longer operative, these behavioral strategies are no longer exhibited.
A recent study by Hughes and Wolgin [50] provides
strong support for this interpretation. Rats were given
daily injections of amphetamine (2 mg/kg) and access to
milk in bottles for 30 min. After they developed tolerance
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
289
Fig. 7. Frequency of various components of motor activity during the development of sensitization. The rats were given injections of amphetamine (2.5 mg/kg)
at 3-day intervals for 36 trials. The data for each category of behavior are expressed as percentages of the frequencies of all categories. Non-stereotyped
responses are displayed as bars, stereotyped responses as line graphs. The maximum raw score for each category on each trial was 96 (16 rats £ 6 rating
periods). Sensitization consists of a change in the pattern of movement from primarily locomotion and stereotyped sniffing to one dominated by focused head
scanning movements. (From Fig. 1 in Ref. [52]).
to the hypophagic effect of the drug, as indicated by a shift
in the dose–response function, they were given additional
drug trials, but with milk delivered intraorally via an
implanted cannula. Thus, ingestion was no longer contingent on suppressing stereotyped movements. Not surprisingly, four of five rats showed a resurgence of stereotyped
behavior while drinking from the cannula. When tolerance
was subsequently reassessed by again presenting milk in
bottles, these rats exhibited a loss of tolerance. In contrast,
one rat continued to suppress stereotyped head movements
while ingesting milk from the cannula. Consequently, this
rat never learned that the contingencies of reinforcement
had changed. When tolerance was later reassessed in the
bottle condition, this rat did not show a loss of tolerance.
These results provide two new insights regarding the loss
of tolerance. First, because rats that lost tolerance were
injected with amphetamine prior to cannula feeding, it is
clear that drug exposure per se (or lack thereof) has
nothing to do with whether or not tolerance is retained.
Tolerance can be lost when drug treatment is suspended
entirely [49], when it is given after milk tests [49] and,
as in the present case, when it is given prior to testing.
What is critical is the context in which milk is
presented, i.e. whether feeding is still contingent on
suppressing stereotypy. If it is, then tolerance will be
retained. If it is not; then tolerance may be lost. Second,
ultimately it is the rat’s behavior that determines whether
tolerance is lost or not. Even if the environmental context
has changed, tolerance will not be affected unless the rat’s
behavior produces appropriate feedback. Thus, a rat that
remains stationary while drinking from a cannula will not
learn that feeding is no longer contingent on suppressing
stereotypy, and, therefore, will retain tolerance when later
given milk in a bottle.
8. The effect of sensitization on tolerance development
If contingent tolerance involves learning to suppress
stereotyped movements in order to feed, then prior sensitization of stereotypy might be expected to retard the subsequent development of tolerance to the hypophagic effect
of the drug. Implicit in this prediction is the assumption that
sensitized stereotyped movements are less subject to voluntary control. Therefore, as sensitization develops, there
should be a progressive disintegration of adaptive, goal
directed behaviors like feeding due to an inability to
suppress the more intense stereotyped responses (cf. Refs.
[21,51]).
To test this prediction, rats were given injections of
amphetamine (2.5 mg/kg) to induce sensitization of stereotypy [52]. At this dose of amphetamine, sensitization
consists of a change in the pattern of movement from
primarily locomotion and sniffing to one dominated by
focused head scanning. As shown in Fig. 7, on the first
few trials, rats given amphetamine displayed stereotyped
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
Fig. 8. Top: Effect of saline and various doses of amphetamine on milk intakes in sensitized and nonsensitized rats before (DR 1) and after (DR 2) a 48-day
period in which the rats received daily injections of amphetamine (2 mg/kg) and access to milk for 30 min. Both the sensitized and nonsensitized rats showed
tolerance at the 0.5, 1 and 2 mg/kg doses. (From Fig. 4 in Ref. [52]). Bottom: Motor activity (frequency of locomotion 1 stereotyped movements expressed as a
percentage of all categories of behavior) before and after the development of tolerance to amphetamine-induced hypophagia in sensitized and nonsensitized
rats. Prior to the development of tolerance (DR 1), the rats in both groups engaged in motor activity on more than 70% of the rating periods when tested at doses
of 1–4 mg/kg. (Note, however, that the type of activity differed between the groups.) On DR 2, conducted following the development of tolerance, the
frequency of activity decreased significantly at the 1 and 2 mg/kg doses in both groups. (From Fig. 4 in Ref. [52]).
sniffing on 60–80% of the rating periods, and either stationary activity (primarily grooming) or locomotion during the
remaining periods. On subsequent trials, the frequency of
stereotyped sniffing gradually declined to , 20%, while the
frequency of focused stereotyped head scanning increased
to about 80%. In addition, there was a shift in the onset of
head scanning (not shown), so that it appeared progressively
earlier in the session. In contrast, controls given saline
injections exhibited immobility, stationary activity, or locomotion, but no stereotypy.
Following the sensitization phase, both groups were
given daily injections of amphetamine (2 mg/kg) and access
to milk. Despite clear differences between the groups in the
psychomotor effects of the drug at the end of the
Fig. 9. Effect of various doses of amphetamine on milk intakes of sensitized and nonsensitized rats before (DR 1) and after (DR 2, DR 3) a 38-day period in
which the rats received daily injections of amphetamine (2 mg/kg) and access to milk for 30 min. (DR 3 was a replication of DR 2 to confirm the reliability of
the results.) The data are expressed as a percentage of intakes under the saline doses for each DR determination. Although both the sensitized and nonsensitized
rats showed tolerance, direct comparisons between the groups revealed that the nonsensitized group drank significantly more at the 4 mg/kg dose than the
sensitized group. pDiffers from DR 1; [ p] Main effect of DR (From Fig. 1 in Ref. [54]).
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
291
Fig. 10. Effect of saline and various doses of amphetamine on motor activity (locomotion 1 3 categories of stereotyped movements) in sensitized and
nonsensitized rats. Each bar indicates the relative amounts of each movement category, expressed as a percentage of the total number of responses from
all of the behavioral categories. At each dose, the left bar represents data collected before the tolerance phase (DR 1) and the middle and right bars, data
collected after the tolerance phase (DR 2, 3). The maximum score was 40 for the sensitized group and 35 for the nonsensitized group (8 or 7 rats £ 5 rating
periods). Sensitized rats showed more oral stereotypy at the 4 mg/kg dose than nonsensitized rats. pDiffers from DR 1. (From Fig. 2 in Ref. [54]).
sensitization phase, both groups developed tolerance to
amphetamine-induced hypophagia. Dose–response tests
conducted before and after the tolerance phase revealed a
somewhat greater rightward shift in the nonsensitized
control group, but substantial tolerance (Fig. 8, top) and
suppression of stereotypy (Fig. 8, bottom) were still found
in the sensitized group. Thus, contrary to our expectations,
prior sensitization of stereotypy did not retard the development of tolerance to drug-induced hypophagia (see also Ref.
[53]).
Even more surprising was the finding that during the
tolerance phase, sensitization of stereotypy developed in
the previously nonsensitized group. This was apparent
from an analysis of ratings taken during the 5-min intervals before and after milk was available each day. In
the absence of milk, head scanning increased from 25%
of all observations prior to the tolerance phase to 63%
at the end of that phase. In contrast, when milk was
available, head scanning occurred only 20% of the time
in the post-tolerance period. Thus, these rats developed
sensitization of stereotypy at the same time that they
were learning to suppress stereotyped movements in
order to feed. Similar results have been found with
cocaine [25].
Clearly, having access to milk does not prevent the induction of sensitization of stereotypy. Equally important,
however, is that sensitization does not seem to interfere
with the rat’s ability to suppress stereotypy when milk is
available. Before we accept this conclusion, however, a
potential criticism should be addressed. In the studies
reported so far, the dose of amphetamine used to induce
sensitization of stereotypy (2.5 mg/kg) was very similar to
the dose used in the tolerance phase (2 mg/kg). Even after
sensitization developed, the type of movements induced by
this dose were similar to, albeit more intense than, the movements normally experienced by rats during the tolerance
phase of the experiment. It is possible that if a higher sensitizing dose were used, one which produced both quantitative
and qualitative changes in the pattern of stereotyped movements, sensitization would interfere with the development
of tolerance to amphetamine hypophagia.
To address this issue, Hughes et al. [54] gave rats injections of 5 mg/kg amphetamine at three-day intervals for 30
trials to induce sensitization of stereotypy, and then tested
the development of tolerance to drug-induced hypophagia,
using the standard dose (2 mg/kg) of the drug. At the end of
the sensitization phase, amphetamine-treated rats exhibited
stereotyped head scanning (74%) and oral stereotypy (24%).
When these rats were later given the standard dose of
amphetamine during the tolerance phase, they still learned
to suppress stereotyped movements in order to drink milk.
As shown in Fig. 9 (left panel), tolerance to amphetamine
hypophagia was confirmed by a rightward shift of the posttolerance dose–response function, and was associated with
a corresponding decrease in stereotyped activity (see Fig.
10, left panel). Thus, once again, prior sensitization of
stereotypy did not prevent the development of tolerance to
the hypophagic effect of the drug.
But is this conclusion valid? Fig. 9 (right panel) shows
that the nonsensitized group also showed a shift in its posttolerance dose–response functions, but in this case tolerance
generalized to a higher dose (4 mg/kg) as well. Thus, tolerance was more general in the nonsensitized control group
than in the sensitized group, suggesting that sensitization of
stereotypy may, in fact, have limited the development of
tolerance to drug-induced hypophagia. Hughes proposed
an interesting explanation for this finding, based on the
instrumental learning model. She noted that in the nonsensitized group, the pattern of stereotyped responses elicited
by the 4 mg/kg dose (sniffing, head scanning) was qualitatively similar to that elicited by the lower, chronic dose (see
Fig. 10, right panel). Consequently, behavioral strategies for
suppressing stereotypy that were acquired at the 2 mg/kg
dose could generalize to the 4 mg/kg dose. In the sensitized
group, however, the pattern of stereotypy elicited by the
4 mg/kg dose contained a relatively high percentage of
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D.L. Wolgin / Neuroscience and Biobehavioral Reviews 24 (2000) 279–294
oral stereotypy (Fig. 10, left panel). Because little oral
stereotypy was experienced by this group at the lower,
chronic dose, it did not learn to suppress those
responses during the tolerance phase. As a result, tolerance could not generalize to the higher dose during the
dose–response tests.
In summary, rats exposed to a relatively high sensitizing
dose of amphetamine were still capable of learning to
suppress stereotyped movements provided that they experienced those movements in an environment in which they
could drink milk. Thus, there is no evidence that prior sensitization of stereotypy per se interferes with the subsequent
development of tolerance to amphetamine-induced hypophagia. It is still possible, however, that sensitization exerts
a more subtle effect on the ability to suppress stereotyped
movements. As noted earlier, the temporal pattern of drinking, as measured by photobeam interruptions, is more fragmented in tolerant rats than in saline controls [45]. Thus,
while sensitization of stereotypy may not interfere with the
development of tolerance as measured by the recovery of
milk intake, it may exert an effect on the temporal patterning
of drinking behavior.
Current research on the role of environmental context in
the development of tolerance and sensitization has focused
almost exclusively on associative mechanisms. Although
this work has provided important insights into the mechanisms controlling these phenomena, we should not lose sight
of the fact that context can mean more than just the physical
environment in which the drug is given. As research on
contingent tolerance demonstrates, instrumental contingencies operating in a particular environment also constitute a
context, and can exert a profound effect on the development
and/or expression of tolerance and sensitization. When a rat
is given chronic injections of amphetamine in an environment in which it can ingest milk, the expression of stereotypy is very different than when the rat is given the drug in
an environment without milk. To fully understand the role
of environmental context in tolerance and sensitization,
therefore, we must broaden the scope of our analyses and
consider both associative and operant mechanisms. Note
that the experimental paradigms for investigating these
mechanisms are very different. For the former, exposure
to a distinctive physical environment while intoxicated
is sufficient. For the latter, a more interactive environment is required, one in which the rat’s behavior has
consequences.
9. Conclusions
The ability to suppress stereotyped movements, even
after sensitization of stereotypy has developed, challenges
several commonly held assumptions regarding stimulantinduced stereotypy in general and sensitization in particular.
In contrast to the flexibility, adaptiveness, and goal directedness of normal “voluntary” behavior, stereotyped movements are, by definition, repetitive, aimless and involuntary.
Because such movements are typically studied in environments such as open fields or activity boxes, which are
devoid of biologically meaningful stimuli, it is easy to
think of these movements as being irrepressible. But if
rats can learn to suppress even sensitized stereotyped movements, then our assumptions about the uncontrollability of
these movements are not justified.
In humans, stereotypy of movement or thought is considered a sign of pathology, e.g. in schizophrenia, autism,
obsessive-compulsive disorder, addiction, and Tourette’s
syndrome [55], precisely because it disrupts adaptive,
goal-directed behavior. However, like rats given amphetamine, human patients with tardive dyskinesia, Tourette’s
syndrome, l-DOPA-induced chorea and autism can
suppress their seemingly involuntary tics, dyskinesias and
stereotypies when reinforced for doing so [56–61]. Understanding the neurological mechanisms by which “involuntary” movements can be suppressed through instrumental
learning would provide potentially important insights for
the clinical management of these disorders. Although little
is known about these mechanisms at the present time, there
is some evidence that proprioceptive feedback plays a role
in the inhibition of dyskinetic movements [58].
Acknowledgements
Supported by USPHS grant DA04592 from the National
Institute on Drug Abuse. I thank Katherine Hughes for many
stimulating discussions and for helpful comments on an
earlier draft of the manuscript. I also thank my students
and staff for their able assistance in conducting the studies
cited in this review and two anonymous reviewers for incisive criticism that substantially improved the manuscript.
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