TOPIC

7: WITHDRAWAL AND TOLERANCE

DIAGNOSTIC DEFINITION (DSM-5)

th
• Diagnostic and Statistical Manual of Mental Disorders 5 Edition (APA, 2013) DSM-5
o Handbook for the standardisation of psychiatric diagnosis and classification
o Treatment providers/researchers use to identify individuals who cross the boundary
(from normality) to be diagnosed with a particular mental disorder
• Substance use disorders: alcohol, sedatives, cannabis, stimulants, tobacco, hallucinogens,
opioids
• 11 symptoms of substance use (generally)
1. Susbtance is often taken in larger amounts or over a longer period than was
intended
2. Persistent desire or unsuccessful efforts to cut down or control substance use
3. Significant time spent trying to obtain the substance, or recovering from its effects
4. Craving, or a strong desire/urge to use the substance
5. Recurrent substance use resulting in a failure to fulfil major role obligations
6. Continued substance use despite recurrent social or interpersonal problems caused
or related to the substance
7. Important social, occupational, or recreational activities are given up or reduced
because of substance use
8. Recurrent substance use in situations in which it is physically hazardous
9. Continuing substance use despite knowledge that it is likely to cause or exacerbate
a physical or psychological problem
10. Tolerance
a. A need to incease substance does to achieve intoxication or desired effect
b. A diminished effect with the same amount of the substance
11. Withdrawal
a. Having experienced the characteristic withdrawal syndrome for the
substance
b. The substance (or related substance) is taken to relieve or avoid withdrawal
symptoms

TOLERANCE
RECEPTOR DESENSITISATION AND DOWN-REGULATION
• To remain healthy, neurons need to fire with a certain frequency
o Too frequent/infrequent firing can result in neurotoxicity
§ Cellular mechanisms exist to modify various states to balance firing
rate/synaptic communication within optimal limits
• Drugs of abuse cause super-optimal states of synaptic communicatin which can lead to cell
death
o If the drug acts on inhibitory receptors, the cell will under-fire
o If the drug acts on excitatory receptors, the cell will over-fire
• Two mechanisms neurons employ to protect themselves from super-optimal receptor binding
resulting from chronic drug exposure are receptor desensitisation and down-regulation
o Desensitisation: the number of receptors on the cell membrane remains constant but
the associated ion channelsbecome insensitive such that binding to the receptor has
no impact on the excitation or inhibition of the cel
o Down-regulation: is where there is a decrease in the number of receptors such that
neurotransmitter release or drug presence has less effect on the excitation or
inhibition of the cell

BEHAVIOURAL TOLERANCE
• As a result of desensitisation and down-regulation there is a reduction in the response to the
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drug
• Tolerance is represented as a shift to the right in the dose-response curve
o A larger dose is required ot achieve the same effect
o The same dose yields a smaller effect
o Lower maximum response to the drug because the upper limit of the cells firing rate
is capped by desensitisation and down-regulation

WITHDRAWAL
• Receptor desensitisation and down-regulation occur to optimise the level of binding when a
drug is chronically present
• As a consequence, abstinence from the drug will result in the opposite problem: supra-
optimal (low) level of binding
• Supra optimal binding will occur in the same neurotransmitter systems to which the drug
binds
• Thus, withdrawal will produce the opposite responses to acute drug administration

ALCOHOL
• Alcohol acts upon various neurotransmitter systems, (acute column) to collectively produce a
broad state of relaxation and euphoria. By contrast the adaptation to chronic alcohol
exposure (chronic column) shows the opposite psychologic effects, over-excitation and
dysphoria

• The over-excitation of brain activity resulting from decreased GABA (less inhibition) and
increased glutamate (more excitation) following alcohol withdrawal can be life-threatening
and neurotoxic in its own right, so treatments for alcohol dependence are increasingly using
self-paced control reduction programs to negate these harms prior to full abstinence (Craig
et al. Plos one, 6, e22994)
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STIMULANTS: COCAINE AND METHAMPHETAMINE

• Stimulants (cocaine, amphetamine, etc.) increase the activity of dopamine (reward) and
serotonin (positive mood), producing a state of motivation, euphoria and confidence.
Accordingly, the withdrawal syndrome is marked by a loss of motivation, depression and
anxiety
• Givent that stimulants activate mesolimbic dopamine neurons, withdrawal should be
characterised by a decrease in activity in these cells
o Ackerman and White (1992) recorded the number of dopamine cells within the VTA
that were spontaneously active during the recording period
o Compared rats that had been withdrawn for 10-14 days following 2 weeks of
repeated treatment with either cocaine or saline – the number of cells found to be
active was reduced by 49% in the cocaine withdrawn animals
o Reduced dopamine activity throught to contribute to cocaine withdrawal syndrome, in
particular, the loss of motivation
• In humans, withdrawal from methamphetamine is similarly marked by a loss of dopamine
activity in the mesolimbic pathway
o Volkow et al (2001): meth users underwent brain imaging following 1 and 14 months
abstinence
§ Compared to normal control, meth abusers showed reduced dopamine
activity (red colour) at one month abstinence but showed some recovery by
14 months abstinence
§ Note, the level of recovery was less in meth abusers with a longer history of
meth abuse, suggesting a persistent desensitisation or down regulation of
dopamine receptors with longer drug use

OPIATES
• Opiates primarily act on the endorphin and dopamine systems to produce analgesia,
euphoria and reward
• The withdrawal syndrome is correspondingly characterised by pain, dysphoria and loss of
motivation

• Opiate withdrawal increases rapidly following abstinence peaking around Day 2 and then
declines. But withdrawal is not fully abated by 10 days post-abstinence
o Some have suggested that negative mood or depression is a permanent, or very
persistent, psychological condition of ex-opiate addicts, presumably resulting from
irreversible desensitisation or down-regulation of opiate and/or dopamine receptors
(Koob and Le Moal 2011)
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CANNABIS
• THC binds to the CB1 receptor
o Breivogel et al 1999: pretreated rats with
THC for 21 days and found desensitisation
and down regulation of CB1 in the
cerebellum, hippocambus and striatum
o Note that the S shaped function relating
dose of the drug to the amount of receptor
binding is both shifted to the right and has
a lower maximum (tolerance)
• Endocannabinoid system is involved in retrograde
inhibition of neurotransmission, damping synaptic
communication broadly across the brain and
creating a sense of calm
o Withdrawal is marked by anger, anxiety and
sleep disturbance
o In heavy marijuana users, withdrawal
symptoms last around 27 days, peaking at
1 week after abstinence

NICOTINE
• Nicotine primarily acts upon acetylcholine receptors (cognitive enhancement) and dopamine
(reward)
• Nicotine withdrawal syndrome is characterised by impaired cognition, depression and anxiety
• Jacobsen et al 2005: compared somkers and non-smokers performance on a ‘2-back task’
which assesses sustained attention and memory
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o Smokers generally performed worse than non-smokers, consistent with pe-existing

cognitive impairment or toxic damage.
o Importantly, abstinence increased this cognitive impairiment in smokers, suggesting
that nicotine withdrawal is characterised by a cognitive deficit, compared to the
acute cognitive enhancing effects of nicotine

CONDITIONED WITHDRAWAL
• Abraham Wikler: withdrawal represented a significant barrier to abstinence promoting relapse
to drug use – cycle of abstinence-withdrawal-relapse
o Articulated this idea with reference to instrumental learning – an individual learns to
perform a particular acion (drug use) in order to pre-emptively avoid an expected
withdrawal syndrome or terminate a current withdrawal syndrome
o Recreational drug use maintained by rewaeding properties of the drug (positive
reinforcement)
§ Addiction driven by the manifestation of the withdrawal syndrome, and
learning to take the drug in order to negate this withdrawal syndrome
(negative reinforcement)
• Why does relapse occur adter withdrawal when the probability of another withdrawal is
unlikely?
o Wilker argued that environmental cues that predicted withdrawal could come to elicit
a conditioned withdrawal state, through the process of Pavlovian conditioning
§ i.e. an addict has undergone withdrawal in a particular environment (e.g.
bedroom), that environment (CS) may elicit a conditioned withdrawal state
(CR) when encountered in the duture, which would motivate a relapse to drug
use via negative reinforcement
• O’Brien (1977): studied conditioned withdrawal in opiate addicts maintained on methadone
o Baseline: skin temperature measured whilst subjects were placed in a room and
injected with saline
o Conditioning: subjects were placed in the same room with a sound and a peppermint
odour added, and injected with naloxone (opiate antagonist) to produce a withdrawal
state (indexed by reduced skin temperature)
o Test: subjects were placed in the some room with the sound and peppermint odour,
but injected with saline
§ There was a conditioned decrese in skin temperature akin to that produced
by naloxone precipitated withdrawal but which was not seen with saline prior
to conditioning
o Environmental cues can produce conditioned withdrawal, which may promote relapse

CONDITIONED TOLERANCE
• One problem for Conditioned Withdrawal as a model of addictive behaviour were anecdotal
reports from relapsed addicts which suggested that the cause of their relapse were
cues/contexts (e.g. pubs) that were most strongly associated with drug use in the past, not
those associated with withdrawal
o Conditioned withdrawal predicrts that contexts in which withdrawal had occurred
previously should most effectively promote relapse
§ In order for cues linked to drug use to become conditioned to the withdrawal
state, these cues would have to be stored in memory for hours if not days
until the withdrawal event occurred
§ It is well established that such long ‘trace’ conditioning is less effective than
a short ‘delay’ conditioning. Thus, it seemed unlikely that cues associated
with drug use should elicit conditioned withdrawal
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• Shepard Siegel addressed this criticism and defended the negative reinforcement account –
Siegal’s compensatory response hypothesis:
o Built upon the idea of homeostasis whereby the body seeks to maintain optimal
internal state by possessing an array of detectors which detect whether the current
internal state is greater or less than a ‘set-point’ or optimum
§ E.g. the optimal temperature of the human body is 37 degrees Celsius and
deviations from this are detected by the brain which initiates a cascade of
changes, including sweating, dilating or constricting blood vessels, and
shivering which return the body to the homeostatic set point
• Siegel argued that drugs of abuse shift one’s biological state away from the optimum,
provokimg an array of compensatory responses to return to homeostasis. The figure below
from opponent-process theory (Solomon and Corbit, 1974) depicts this idea
o The top row is the cubjective (conscious) experience of the drug user upon taking the
drug at initialexposure (left) or after many exposures once tolerance has taken place
(right)
o After many exposures, the A state (pleasure/reward) decreases, and the B state
(withdrawal) increases
• Siegel’s insight was that other compensatory responses are mobilised in response to the
drug immediately following ingestion (bottom row)
o The a process is the direct drug effect on receptor binding and its downstream
cascade, whereas the b process is the mobilised compensatory or opponent
(homeostatic) process to correct the imbalance
§ The net product of the underlying a and b process gives rise the the
experienced states A and B (top row)
§ Note, that the underlying b process gets larger after many exposures
o Siegel’s contribution suggested that the growth of the b process (underlying
compensatory response) was due to Pavolovian conditioning of this b process to
exernal cues associated with drug use
§ This implication is that cues associarted with drug use, can elicit a drug-
opposite ‘conditioned tolerance’ effect akin to withdrawal

• Siegel demonstrated support for conditioned tolerance in a variety of paradigms

o Experienced heroin user inject doses that would easily cause overdose in an
inexperienced user – Siegel argued that tolerance to such high doses was partially
mediated by conditioned compensatory responses elicited by drug associated cues;
overdose death can be brough about by the absence of those cues
o Siegel (1982): administered rats with 15 doses of heroin, one does every second day,
and escalated the does from 1mg/kg to 8mg/kg over this period. On the interving
day, rats were administered with saline
o Heroin and saline injections occurred in distinct environments (cages) to allow drug-
context conditioning to take place
o At test, all rats were administered 15mg/kg of heroin (potentiall fatal dose) in either
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the heroin context or the saline context

§ Rats in the heroin context were protected from overdose by a conditioned
compensatory response, whereas rats in the saline context were not,
resulting in a doubling of the mortality rate
o These findings indicate that drug associated cues/contexts can elicit a drug-opposite
response

Theory of conditioned withdrawal was criticised because cues associated with drug use could not be
easily associated with withdrawal events that occurred much later
• Siegel’s demonstration that conditioned compensatory responses are mobilised immediately
following drug ingestion, illustrated hwo cues associated with drug ingesting can elicit a drug-
opposite, compensatory or withdrawal like state
o i.e. when an addict encounters drug associated cues, these cues eleict a withdrawal
like (aversive) state which motivates the addict to take the drug in order to correct
this state
o Thus, Siegel could explain drug-cue precipitated relapse within a negative
reinforcement framework