Definitions health implications/dangers (Caggiula-et-al.,-2002;-APA,-2013). Nicotine stimulates nicotinic acetylcholine receptors

of addiction vary considerably across published sources, and are constantly
being reviewed and re-evaluated to improve diagnostic accuracy, clinical
treatment and prevention. The American Psychiatric Association (APA), defines substance-dependence
as maladaptive patterns of substance use resulting in clinically significant health
impairment or distress, associated with loss of control of substance-taking
behaviour, tolerance to the drug’s effects, and withdrawal symptoms experienced
in its absence (APA,-2013).

In order to effectively
understand the development and maintenance of substance addiction, with
specific focus on our tobacco-dependent subject; John, it is imperative to understand
(based on currently accepted models), the relationships/interactions between
pharmacological and physiological effects of the drug, external factors and
associative learning phenomena responsible for compulsion, patterns of
abstinence and relapse, and the critical behavioural features by which
substance addiction can be identified.

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Pharmacological Effects of Nicotine

Recreational drug use is attributed to
reliable precipitation of pleasant feelings, which stem from a complex array of
physiological and neurochemical reward responses in the user (O’Brien-et-al.,-1998),
however, only a small minority are susceptible to addiction.

In tobacco, nicotine is the main
psychoactive constituent responsible for the behavioural and motivational
changes which maintain use and addiction (Stolerman-&-Jarvis,-1995). However, while it’s reliable,
rewarding, pharmacological effects positively reinforce continued use (Hogarth,-2017;-O’Brien-et-al.,-1998), they are insufficient to account for
high levels of self-administration exhibited in users, especially in
particular environments or despite knowledge of health implications/dangers (Caggiula-et-al.,-2002;-APA,-2013).

Nicotine stimulates nicotinic acetylcholine receptors (nAChRs) and dopamine (DA)
release, enhancing cognition and providing a reward response respectively (Hogarth,-2017;-Dani-&-Harris,-2005). Incessant DA release in the
hippocampus increases synaptic strength (Collingridge-&-Bliss,-1993;-Malenka,-&-Nicoll,-1999), linking
it to behavioural
long-term potentiation (LTP) and behavioural reinforcement (McGehee,-2009).

This is the
primary mechanistic model to explain the way in which subconscious associations
between environment and successful/rewarding behavioural sequences are established
and to which learning and memory are attributed to within the brain (Frey,-1997;-Tang-&-Dani,-2009;-Everitt-et-al.,-2001;-Schultz-et-al.,-1997;-Packard-&-Knowlton,-2002), both generally, and in a
drug-context, whereby drug-associated memory can be developed (Winder-et-al.,-2002;-Kauer,-2004;-Tang-&-Dani,-2009;-Kelley,-2004), perpetuating
drug-use, hence initiating addiction (Tang-&-Dani,-2009). This corresponds
to the idea that memories linked to addictive
behaviours contribute to the motivation of continued drug use. (Bonson-et-al.,-2002;-Dani-&-Montague,-2007;-Everitt-et-al.,-2001;-Kenny-&-Markou,-2005;-Kilts-et-al.,-2001).

Pavlovian-Instrumental Interactions

Pavlovian Conditioning

One of the most significant models in
behavioural adaptation is Pavlovian conditioning,
which elucidates the way in which organisms can learn to anticipate a
biological event (unconditioned stimulus (US)), from a previously neutral
stimulus (conditioned stimulus (CS)) that reliably predicts this event, and
anticipation of the US evokes a cascade of physiological changes which
behaviourally adapt the organism in preparation for the US itself.(Rescorla-&-Wagner,-1972;-Hogarth,-2017)


(Operant) Conditioning

Instrumental (a.k.a. Operant) Conditioning is concerned with how
individuals can take voluntary action to or in anticipation of,
acquiring/achieving desired outcomes (US), based on a combination of their
knowledge of the causal relationship
between the response & the outcome, and the current value of the outcome & is
acquired because it ultimately leads to the US. (Thorndike)

Transfer (PIT):

conjunction with one another, arises the current model of Pavlovian-Instrumental Transfer (PIT), whereby conditioned drug-associated cues (CS) (e.g.
environments, anxiety, social pressures, alcohol), can retrieve an expectation
of the drug effect of tobacco (US). This not only elicits an involuntary
cascade of physiological reflexes in anticipation of taking the drug (UR), but also
voluntary instrumental; drug-seeking responses (R)(e.g. going to buy or ask for
cigarettes), leading to consumption of the drug. (Rescorla-&-Solomon,-1967)(evidence in rats?)


Case: John

In John’s
case, CS include environments of alcohol consumption, stress, or with “his
mates”, with which he associates smoking, and thereby retrieves positive expectations
of the effects of nicotine (US), he describes as “enjoyable” and “pleasant.”
This elicits a learnt series of physiological and neurochemical changes, and
voluntary behavioural sequences learnt (possibly from his smoker friends) to successfully
acquire cigarettes (R), to achieve the desired action of smoking; “sharing a
cigarette with friends” or “taking a smoke break” (UR).

Hence, drug
cues can produce conditioned drug-like responses, such as euphoria, which
positively reinforce and thereby further motivate drug taking (Stewart-et-al.,-1984), i.e. drug use is driven by the
pleasurable anticipation of drug effects produced by drug-like conditioned
responses. (O’Brien-et-al.,-1998)



ingestion, drugs shift the user’s physiological state away from its biological
homeostatic set-point, initiating a series of compensatory “drug-opposite”
responses (via complex biological negative feedback mechanisms), to
re-establish homeostasis (Hogarth,-2017;-DiFranza-&-Wellman,-2005;-Siegel,-1979)(See-Figure-2.).

Following chronic exposure, sensitivity to the drug reduces
by mechanisms which lower receptor-drug affinity (desensitisation), and decreasing the number of receptors (down-regulation), reducing excitatory or inhibitory effects of neurotransmitter
release or drug presence on the cell, thereby preventing super-optimal receptor
binding that may lead to neurotoxicity and cell-death(Hogarth,-2017).
Thus, larger doses would be required to attain consistent effects.

Hence this dose-dependent ‘drug-opposite
effect,’ provides tolerance to the drug, which upon abstinence or abrupt
termination, can be identified by withdrawal syndrome.


Conditioned Tolerance

Pavlovian conditioning, these physiological compensatory responses grow through
repeated association of external/environmental cues with drug use (Siegel,-1979). Hence, drug-associated contexts can precipitate
conditioned averse responses to the drug effects; (‘drug-opposite effect’)(Hogarth,-2017).

attempts to pre-emptively avoid or alleviate these conditioned withdrawal-like
states further motivate drug-seeking and taking behaviours, negatively
reinforcing the dependence (O’Brien-et-al.,-1998).

In heroin-dependent conditioned rats, drug-cue-induced
compensatory responses enabled them to withstand otherwise potentially fatal
dosages, compared to those of saline contexts which lacked this same drug-associated
learning; suffering significantly higher (doubled) mortality rates (Siegel,-1979).


from chronic nicotine use provokes this aversive withdrawal state (Kenny-&-Markou,-2001), causing smokers to experience a variety of
symptoms, of intensity and severity proportional to the extent of nicotine dependence
and impeding the cessation of drug abuse.

most typically experienced by daily smokers, include, craving, anxiety,
irritability, impaired cognitive ability and concentration (APA,-2013), which affect approximately 50% of
cigarette smokers after two or more days of abstinence (Hughes,-2007), but can also
affect non-daily smokers (APA,-2013).

Conditioned withdrawal

Withdrawal may be conditioned into
long-term compulsion (Wikler, 1973;-O’Brien et al., 1998), by repeated pairing with previously neutral
environmental stimuli. I.e. subsequent reencounters with
withdrawal-associated cues can evoke sensations, memories and/or expectations
of the drug, inducing a state of conditioned withdrawal (Kenny-&-Markou, 2005),
increasing desire to use and thereby the difficulty of long-term abstinence (Tang-&-Dani,-2009).

Withdrawal-associated cues reduce brain
reward function, (measured in rats
by elevations of intracranial self-stimulation (ICSS) thresholds (Epping-Jordan-et-al.,-1998)), and these reward deficits,
along with their avoidance and alleviation, are theorised to drive the
motivation and craving necessary to maintain or promote relapse of persistent drug-seeking
and taking behaviours (Kenny-&-Markou,-2001;-Watkins-et-al.,-2000).

(via operant conditioning), addicts can learn to pre-emptively avoid, or
otherwise terminate this aversive withdrawal syndrome, by self-administering the
drug with which it is associated; negatively reinforcing the use of the drug (Hogarth,-2017;-Wikler-&-Pescor,-1967), and hence further motivating relapse, even
long after abstinence.


rats, conditioned to nAChR-antagonists
(with no associated somatic effects) paired with hedonically neutral stimuli, demonstrated
that subsequent presentation to withdrawal-associated cues precipitated
conditioned withdrawal (Kenny-&-Markou,-2005), without potential influence of
somatic effects on conditioning processes (Epping-Jordan-et-al.,-1998). Similarly,
(O’Brien-et-al.,-1977) and
(Baldwin-&-Koob,-1993) demonstrated conditioned withdrawal-induced somatic
symptoms, (e.g. elevated respiration and lowered skin temperature), in
opiate-dependent humans and rats respectively.

Case: John

developed tolerance to the effects of nicotine has both contributed to, and is
resultant of his escalation from a “social-smoker” to a chronic, compulsive
smoker, skewing his natural biological state such that deprivation
leads to withdrawal-like states in which he feels “agitated and uncomfortable…if he goes without
a cigarette for more than a few hours.”

unease and stronger cravings,” experienced in “certain situations, such as when…drinking
alcohol, …out having a beer with…mates,” indicate withdrawal-associated
memories with these environments, whereby reencounters with these CS induce an
aversive conditioned withdrawal state for John, explaining his expressed
difficulty to maintain abstinence in these environments, motivating voluntary
compulsion to take the drug in order to correct this state.

This is consistent with anecdotal reports
from addicts that experienced withdrawal-like states upon reencounters with
drug-associated environments (O’Brien-et-al.,-1975).

with Alcohol

in combination with one another, nicotine (stimulant) and alcohol (depressant)
have counteractive physiological and neurochemical effects. Hence, alcohol
increases the reward threshold for nicotine (Dani & Harris, 2005), corresponding to the fact that
John states how he “would consume many more cigarettes…when drinking
alcohol…than when he wasn’t.”


learning pathways are complexly linked to the regulation of brain reward function
(Everitt et al., 2001),
heavily implicating them in drug-dependent individuals’ persistent behaviours
and the development and maintenance of substance addiction.

initiates chronic use through positive reinforcement by the direct
pharmacological, physiological and socially rewarding effects of nicotine, leading
to development of tolerance and hence withdrawal in the drugs absence, thus
requiring increased intake to achieve consistent effects.

Environmental factors
can become drug-associated cues when repeatedly paired with these by Pavlovian
and operant conditioning processes, by which addicts learn successful
behaviours to acquire the drug to avoid or alleviate cue-induced aversive withdrawal
states, explaining cycles of abstinence-withdrawal-relapse, via negative
reinforcement of compulsive drug-taking behaviour.

John demonstrated
evidence of all discussed phenomena; exhibiting behaviour consistent with 6 of
the 11 DSM-5 diagnostic substance-dependence criteria (severe addiction), most
significantly, loss of control of use recognised by his desire and difficulty to

Potentially temperamental, environmental,
genetic and physiological, culture-related diagnostic issues (APA,-2013)
may influence John’s susceptibility/vulnerability to nicotine/substance
dependence, but could not be validated from the vignette.