T
Tolerance
Consuelo San Martín, Aracelli Cañete,
Vanetza Quezada and Gonzalo Miguez
Universidad de Chile, Santiago, Chile
Definition
Tolerance is the decrease in the response to a
determined amount of a drug. This effect may
also be expressed as a necessity for increasing
the dose of a drug to obtain the initial effect.
Tolerance can be classified in two categories:
acute tolerance and chronic tolerance. One key
difference between them is that acute tolerance
results from drug-compensatory processes elicited
by the drug itself. In contrast, chronic tolerance is,
at least in part, a result of learning mechanisms
(i.e., Solomon and Corbit 1974; Siegel 2001).
Acute tolerance is the decrease in the response
to a drug during a single administration. Drugs
disrupt homeostasis of the organism, and to
restore homeostasis the organism responds in an
unconditioned or reflexive way to compensate for
the drug-induced disruption. This unconditioned
response constitutes acute tolerance. Conse-
quently, the net result in behavior observed after
drug administration is the summation of the pri-
mary change produced by the drug, and of the
secondary compensatory responses (i.e., acute
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J. Vonk, T.K. Shackelford (eds.), Encyclopedia of Animal Cognition and Behavior,
https://doi.org/10.1007/978-3-319-47829-6_1101-1
tolerance). This latter effect can be seen in isola-
tion when the primary reaction produced by the
drug is no longer present, for example, within a
single administration of morphine the subject can
develop acute tolerance, producing hyperalgesia.
Then when morphine is metabolized and elimi-
nated (and its analgesic effect ends) an increased
sensitivity to painful stimuli is often observed,
because the compensatory responses continue
and therefore the sensitivity increase.
Chronic tolerance, on the other hand, is
a decrease in the effect of the drug over the course
of a series of administrations. Like acute toler-
ance, chronic tolerance is generally thought
to be mediated by compensatory responses;
however, while acute tolerance is solidly under-
stood as a consequence of drug-compensatory
process provoked by the drug administration
itself, diverse accounts have been provided to
explain the psychological mechanisms underlying
chronic tolerance.
Mechanisms of Chronic Tolerance
Multiple models have been proposed to explain
chronic tolerance. Considering that tolerance
involves changes in behavior with repeated or
chronic experience with a drug, these theories
are in most cases based on theories of learning.
One account is the opponent-process theory
2 Tolerance
(Solomon and Corbit 1974). This theory assumes
that when organisms react to stimuli, this reaction
generates two processes that sum to influence
behavior. The first, involves a direct response
known as the a-process which is counteracted
by a second, process, that acts in the opposite
direction of the a-process, known as b-process.
This b- process would constitute the compensa-
tory response to the drug. In the case of ethanol
consumption, the a-process is the effect of intake
that, for example, could be the decrease in body
temperature caused by administration of ethanol.
The b-process, following the same example,
would be an increase in body temperature. The
model also included two more tenets: the
a-process magnitude is maintained with the same
dose of a drug; however, the b-process gets
stronger with repeated intake of the drug (Baker
and Tiffany 1985). Because of the strengthening
of the b-process in each drug intake experience,
subjects become more tolerant. That is, the com-
pensatory responses become more effective to
compensate the disturbance of the drug. In the
example, this translates into maintaining the
body temperature constant, reducing the hypo-
thermic effect of ethanol.
One caveat of the model is that it cannot
explain why sometimes chronic tolerance is
observed and why sometimes it is not. More spe-
cifically, it cannot explain the situational specific-
ity of drug tolerance, that is, why tolerance is
observed only in the presence of environmental
and contextual cues that are related to drug
administration.
A model based on associative learning postu-
lated by Siegel (1975, 2001) states that chronic
tolerance is at least partially the result of associa-
tions between the drug (or its effects on the organ-
ism) and cues present during administration
or consumption. The internal disruption in
homeostasis caused by the drug is considered an
unconditioned stimulus (US), which causes the
organism to emit an unconditioned response
which maintains the homeostasis. The responses
involved in acute tolerance constitute the uncon-
ditioned response in this model. The stimuli that
are typically present at the time of drug adminis-
tration signal the onset of the drug, and thus work
as conditioned stimuli (CS). When the CSs are
present they prepare the organism for the effect of
the drug by allowing it to anticipate the homeo-
static responses which compensate for the drug
effects (i.e., conditioned compensatory response;
CCR). This model, (e.g., Siegel 1975; Siegel et al.
2000) emphasizes the role of compensatory con-
ditioned responses as the basis of drug tolerance:
according to the model, these conditioned com-
pensatory responses are the main cause behind the
reduction in the effect of a drug (US). Further-
more, Siegel’s model can also explain the occur-
rence of withdrawal symptoms. If the cues
associated with a drug are present in the absence
of its effect (i.e., with no consumption), the elic-
itation of compensatory responses would have
nothing to compensate for and will produce an
aversive motivational state. This phenomenon
would be at least in part responsible for the man-
ifestation of cravings (Siegel 2001).
Consider a subject who habitually drinks or
takes a drug in a certain place regularly (e.g., a
bar). In such a situation, the subject associates
features of the place (e.g., physical settings,
friends, vision of the drink, taste) with the effects
of acute tolerance. This “bar context” elicits com-
pensatory responses that prepare the individual
for the effect of the drug. If one night the person
exposes himself to the bar, but does not drink, in
this situation, the compensatory responses would
be elicited in absence of any drug perturbation to
compensate, causing cravings. These cravings
will cease if the person consumes, as the drug
would return the body to the original homeostatic
state. If another night the same person goes to a
new place, the compensatory responses will not
manifest and the subject will not show tolerance
after consumption and the full effect of the drug
would be expressed.
Siegel’s model of drug tolerance has received
much empirical support. It helps explain the
acquisition and development of drug tolerance,
the manifestation of withdrawal symptoms, and
the motivational aspects of drug abuse and
Tolerance
dependence, while also contributing to the devel-
opment of potential treatments from the perspec-
tive of Pavlovian conditioning. For example,
following Pavlovian principles, researchers have
focused on extinction learning as a Pavlovian
model for cue exposure therapy (e.g., González
et al. 2016), which can be used to decrease toler-
ance and withdrawal symptoms and thus help in
removing some of the elements that maintain drug
consumption (Siegel et al. 2000).
Pharmacodynamics and
Pharmacokinetics of Tolerance
At a pharmacodynamic level tolerance involves
several processes that result in impaired excitation
of the drug receptor. For example, a drug con-
stantly binding with the receptor may desensitize
it (Bespalov et al. 2016), reduce its receptor den-
sity in the neuron (Chavkin and Goldstein 1984),
or trigger processes that modify the firing rate of
the action potential (Allouche et al. 2014).
At a pharmacokinetic level (i.e., dispositional
tolerance) tolerance involves processes that lead
to a smaller amount of the substance at the site it
affects. This may be caused by metabolism (e.g., a
decrement in enzymes that make a drug active),
absorption, distribution, and excretion of drugs.
Compensatory Responses to Nondrug
Stimuli
Conditioned compensatory responses involved
in tolerance have been found in different types
of drugs, including commonly abused drugs
such as opiates, ethanol, and caffeine. This pro-
cess applies to drugs due to the disrupting effects
of such stimuli, but also it applies to non-
pharmacological stimuli that produce strong
physiological reactions. In general, compensatory
responses are present whenever the organism
needs to adapt to new stimuli (Siegel 2008). For
instance, compensatory responses to chromatic
stimuli produce adaptation. Continued presenta-
tion of a color over a period of some minutes
causes it to appear desaturated. The adaptation to
3
color involves a chromatic CCR, analogous to
those responsible for drug tolerance. For example,
cues associated to a green color produce a percep-
tion of magenta when they are presented as ach-
romatic test stimuli. This kind of CCR can also be
seen in the adaptation to hypothermic stimulation,
in which a reduction in the induced-coldness of
the body is observed over the course of repeated
applications of cold water. Similarly, signals asso-
ciated to the immersion cause a CCR of hyper-
thermia. CCRs are involved in ingestion as well,
for example, insulin is sometimes released in
anticipation to food intake. Cues for the taste or
smell of the food can trigger the release of insulin
long before the food is ingested. This mechanism
allows the organism to be prepared for the sugar
arrival, allowing its adaptation. All these exam-
ples support tolerance as a mechanism that can be
applied to several different situations. These situ-
ations include drug use, but also the reaction to
different kind of stimulation, and consequently, it
seems to be a general mechanism to adapt to
disrupting stimuli.
Cross-References
▶ Associative Learning
▶ Classical Conditioning
▶ Habituation
▶ Homeostasis
▶ Withdrawal
References
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4 Tolerance
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