DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Conditioned tolerance (situation-specific tolerance) develops
when environmental cues such as sights, smells, or situations consistently
are paired with the administration of a drug. When a drug affects
homeostatic balance by producing sedation and changes in blood pressure,
pulse rate, gut activity, and so on, there is usually a reflexive counteraction
or adaptation in the direction of maintaining the status quo. If
a drug always is taken in the presence of specific environmental cues
(e.g., smell of drug preparation and sight of syringe), these cues begin
to predict the effects of the drug, and the adaptations begin to occur
even before the drug reaches its sites of action. If the drug always is preceded
by the same cues, the adaptive response to the drug will be
learned, and this will prevent the full manifestation of the drug’s effects
(tolerance). This mechanism of conditioned tolerance production follows
classical (pavlovian) principles of learning and results in drug tolerance
under circumstances where the drug is “expected.” When the
drug is received under novel or “unexpected” circumstances, conditioned
tolerance does not occur, and drug effects are enhanced.
The term acute tolerance refers to rapid tolerance developing
with repeated use on a single occasion, such as in a “binge.” For
example, cocaine often is used in a binge, with repeated doses over
one to several hours, sometimes longer, producing a decrease in
response to subsequent doses of cocaine during the binge. This is
the opposite of sensitization, observed with an intermittent dosing
schedule, described in the next section.
Sensitization. With stimulants such as cocaine or amphetamine,
reverse tolerance, or sensitization, can occur. This refers to an increase
in response with repetition of the same dose of the drug. Sensitization
results in a shift to the left of the dose-response curve (Figure 24–1).
For example, with repeated daily administration to rats of a dose of
cocaine that produces increased motor activity, the effect increases
over several days, even though the dose remains constant. A conditioned
response also can be a part of sensitization to cocaine. Simply
putting a rat into a cage where cocaine is expected or giving a placebo
injection after several days of receiving cocaine under the same circumstances
produces an increase in motor activity as though cocaine
actually were given, i.e., a conditioned response. Sensitization, in contrast
to acute tolerance during a binge, requires a longer interval
between doses, usually ~1 day.
Sensitization has been studied in rats equipped with microdialysis
cannulas for monitoring extracellular DA (Kalivas and Duffy,
1990) (Figure 24–2). The initial response to 10 mg/kg of cocaine
administered intraperitoneally is an increase in measured DA levels.
After seven daily injections, the DA increase is significantly greater
than on the first day, and the behavioral response also is greater.
Figure 24–2 also provides an example of a conditioned response
(learned drug effect): injection of saline produced both an increase in
DA levels and an increase in behavioral activity when administered
3 days after cocaine injections had stopped. Little research on sensitization
has been conducted in human subjects, but the results suggest
that the phenomenon can occur. It has been postulated that stimulant
psychosis results from a sensitized response after long intermittent
periods of use.
Cross-tolerance occurs when repeated use of a drug in a given
category confers tolerance not only to that drug but also to other drugs
in the same structural and mechanistic category. Understanding crosstolerance
is important in the medical management of persons
dependent on any drug. Detoxification is a form of treatment for drug
Dopamine Release
(% of control)
300
250
200
150
100
COCAINE
day 1 of treatment
day 7 of treatment
SALINE
injected before cocaine
injected 3 days
after cocaine
treatment stopped
0 40 80 120 180
Time (minutes)
Figure 24–2. Cocaine-induced changes in CNS dopamine release.
Dopamine was measured in the extracellular fluid of the nucleus
accumbens of rats after daily injections of cocaine (10 mg/kg,
i.p.). The first injection of cocaine produced a modest increase
and the last, after 7 days, produced a much greater increase in
dopamine release. The first saline injection produced no effect on
dopamine levels, whereas the second, given 3 days after 7 days of
cocaine injections, produced a significant rise in dopamine, presumably
due to conditioning. (Adapted from Kalivas and
Duffy, 1990.)
dependence that involves giving gradually decreasing doses of the
drug to prevent withdrawal symptoms, thereby weaning the patient
from the drug of dependence (see “Detoxification” later in the chapter).
Detoxification can be accomplished with any medication in the same
category as the initial drug of dependence. For example, users of
heroin also are tolerant to other opioids. Thus, the detoxification of
heroin-dependent patients can be accomplished with any medication
that activates opioid receptors.
Physical Dependence
Physical dependence is a state that develops as a result
of the adaptation (tolerance) produced by a resetting of
homeostatic mechanisms in response to repeated drug
use. Drugs can affect numerous systems that previously
were in equilibrium; these systems find a new balance in
the presence of inhibition or stimulation by a specific
drug. A person in this adapted or physically dependent
state requires continued administration of the drug to
maintain normal function. If administration of the drug
is stopped abruptly, there is another imbalance, and the
affected systems again must go through a process of
readjusting to a new equilibrium without the drug.
Withdrawal Syndrome. The appearance of a withdrawal
syndrome when administration of the drug is terminated
is the only actual evidence of physical dependence.
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CHAPTER 24
DRUG ADDICTION