Definitionsof addiction vary considerably across published sources, and are constantlybeing reviewed and re-evaluated to improve diagnostic accuracy, clinicaltreatment and prevention.

The American Psychiatric Association (APA), defines substance-dependenceas maladaptive patterns of substance use resulting in clinically significant healthimpairment or distress, associated with loss of control of substance-takingbehaviour, tolerance to the drug’s effects, and withdrawal symptoms experiencedin its absence (APA,-2013).In order to effectivelyunderstand the development and maintenance of substance addiction, withspecific focus on our tobacco-dependent subject; John, it is imperative to understand(based on currently accepted models), the relationships/interactions betweenpharmacological and physiological effects of the drug, external factors andassociative learning phenomena responsible for compulsion, patterns ofabstinence and relapse, and the critical behavioural features by whichsubstance addiction can be identified. Pharmacological Effects of NicotineRecreational drug use is attributed toreliable precipitation of pleasant feelings, which stem from a complex array ofphysiological 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 mainpsychoactive constituent responsible for the behavioural and motivationalchanges 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 forhigh levels of self-administration exhibited in users, especially inparticular 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 thehippocampus increases synaptic strength (Collingridge-&-Bliss,-1993;-Malenka,-&-Nicoll,-1999), linkingit to behaviourallong-term potentiation (LTP) and behavioural reinforcement (McGehee,-2009).This is theprimary mechanistic model to explain the way in which subconscious associationsbetween environment and successful/rewarding behavioural sequences are establishedand 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 adrug-context, whereby drug-associated memory can be developed (Winder-et-al.,-2002;-Kauer,-2004;-Tang-&-Dani,-2009;-Kelley,-2004), perpetuatingdrug-use, hence initiating addiction (Tang-&-Dani,-2009). This correspondsto the idea that memories linked to addictivebehaviours 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 InteractionsPavlovian ConditioningOne of the most significant models inbehavioural adaptation is Pavlovian conditioning,which elucidates the way in which organisms can learn to anticipate abiological event (unconditioned stimulus (US)), from a previously neutralstimulus (conditioned stimulus (CS)) that reliably predicts this event, andanticipation of the US evokes a cascade of physiological changes whichbehaviourally adapt the organism in preparation for the US itself.(Rescorla-&-Wagner,-1972;-Hogarth,-2017) Instrumental(Operant) ConditioningInstrumental (a.

k.a. Operant) Conditioning is concerned with howindividuals can take voluntary action to or in anticipation of,acquiring/achieving desired outcomes (US), based on a combination of theirknowledge of the causal relationshipbetween the response & the outcome, and the current value of the outcome & isacquired because it ultimately leads to the US. (Thorndike)Pavlovian-InstrumentalTransfer (PIT): Inconjunction 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 expectationof the drug effect of tobacco (US). This not only elicits an involuntarycascade of physiological reflexes in anticipation of taking the drug (UR), but alsovoluntary instrumental; drug-seeking responses (R)(e.

g. going to buy or ask forcigarettes), leading to consumption of the drug. (Rescorla-&-Solomon,-1967)(evidence in rats?)  Case: JohnIn John’scase, CS include environments of alcohol consumption, stress, or with “hismates”, with which he associates smoking, and thereby retrieves positive expectationsof the effects of nicotine (US), he describes as “enjoyable” and “pleasant.”This elicits a learnt series of physiological and neurochemical changes, andvoluntary behavioural sequences learnt (possibly from his smoker friends) to successfullyacquire cigarettes (R), to achieve the desired action of smoking; “sharing acigarette with friends” or “taking a smoke break” (UR).

Hence, drugcues can produce conditioned drug-like responses, such as euphoria, whichpositively reinforce and thereby further motivate drug taking (Stewart-et-al.,-1984), i.e. drug use is driven by thepleasurable anticipation of drug effects produced by drug-like conditionedresponses. (O’Brien-et-al.,-1998) ToleranceUponingestion, drugs shift the user’s physiological state away from its biologicalhomeostatic set-point, initiating a series of compensatory “drug-opposite”responses (via complex biological negative feedback mechanisms), tore-establish homeostasis (Hogarth,-2017;-DiFranza-&-Wellman,-2005;-Siegel,-1979)(See-Figure-2.).Following chronic exposure, sensitivity to the drug reducesby mechanisms which lower receptor-drug affinity (desensitisation), and decreasing the number of receptors (down-regulation), reducing excitatory or inhibitory effects of neurotransmitterrelease or drug presence on the cell, thereby preventing super-optimal receptorbinding 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-oppositeeffect,’ provides tolerance to the drug, which upon abstinence or abrupttermination, can be identified by withdrawal syndrome. Conditioned ToleranceThroughPavlovian conditioning, these physiological compensatory responses grow throughrepeated association of external/environmental cues with drug use (Siegel,-1979).

Hence, drug-associated contexts can precipitateconditioned averse responses to the drug effects; (‘drug-opposite effect’)(Hogarth,-2017). Successfulattempts to pre-emptively avoid or alleviate these conditioned withdrawal-likestates further motivate drug-seeking and taking behaviours, negativelyreinforcing the dependence (O’Brien-et-al.,-1998).In heroin-dependent conditioned rats, drug-cue-inducedcompensatory responses enabled them to withstand otherwise potentially fataldosages, compared to those of saline contexts which lacked this same drug-associatedlearning; suffering significantly higher (doubled) mortality rates (Siegel,-1979).WithdrawalDeprivation/abstinencefrom chronic nicotine use provokes this aversive withdrawal state (Kenny-&-Markou,-2001), causing smokers to experience a variety ofsymptoms, of intensity and severity proportional to the extent of nicotine dependence(Fagerstrom,-Heatherton,-&-Kozlowski,-1990;-APA,-2013),and impeding the cessation of drug abuse.

Symptomsmost typically experienced by daily smokers, include, craving, anxiety,irritability, impaired cognitive ability and concentration (APA,-2013), which affect approximately 50% ofcigarette smokers after two or more days of abstinence (Hughes,-2007), but can alsoaffect non-daily smokers (APA,-2013).Conditioned withdrawalWithdrawal may be conditioned intolong-term compulsion (Wikler, 1973;-O’Brien et al., 1998), by repeated pairing with previously neutralenvironmental stimuli. I.e. subsequent reencounters withwithdrawal-associated cues can evoke sensations, memories and/or expectationsof 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 brainreward function, (measured in ratsby 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 themotivation and craving necessary to maintain or promote relapse of persistent drug-seekingand taking behaviours (Kenny-&-Markou,-2001;-Watkins-et-al.,-2000).Additionally,(via operant conditioning), addicts can learn to pre-emptively avoid, orotherwise terminate this aversive withdrawal syndrome, by self-administering thedrug with which it is associated; negatively reinforcing the use of the drug (Hogarth,-2017;-Wikler-&-Pescor,-1967), and hence further motivating relapse, evenlong after abstinence. Nicotine-addictedrats, conditioned to nAChR-antagonists(with no associated somatic effects) paired with hedonically neutral stimuli, demonstratedthat subsequent presentation to withdrawal-associated cues precipitatedconditioned withdrawal (Kenny-&-Markou,-2005), without potential influence ofsomatic effects on conditioning processes (Epping-Jordan-et-al.,-1998).

Similarly,(O’Brien-et-al.,-1977) and(Baldwin-&-Koob,-1993) demonstrated conditioned withdrawal-induced somaticsymptoms, (e.g.

elevated respiration and lowered skin temperature), inopiate-dependent humans and rats respectively.Case: JohnJohn’sdeveloped tolerance to the effects of nicotine has both contributed to, and isresultant of his escalation from a “social-smoker” to a chronic, compulsivesmoker, skewing his natural biological state such that deprivationleads to withdrawal-like states in which he feels “agitated and uncomfortable…if he goes withouta cigarette for more than a few hours.” “Greaterunease and stronger cravings,” experienced in “certain situations, such as when…drinkingalcohol, …out having a beer with…mates,” indicate withdrawal-associatedmemories with these environments, whereby reencounters with these CS induce anaversive conditioned withdrawal state for John, explaining his expresseddifficulty to maintain abstinence in these environments, motivating voluntarycompulsion to take the drug in order to correct this state.

This is consistent with anecdotal reportsfrom addicts that experienced withdrawal-like states upon reencounters withdrug-associated environments (O’Brien-et-al.,-1975).Comorbiditywith AlcoholAdditionally,in combination with one another, nicotine (stimulant) and alcohol (depressant)have counteractive physiological and neurochemical effects. Hence, alcoholincreases the reward threshold for nicotine (Dani & Harris, 2005), corresponding to the fact thatJohn states how he “would consume many more cigarettes…when drinkingalcohol.

..than when he wasn’t.” Conclusion Associativelearning pathways are complexly linked to the regulation of brain reward function(Everitt et al., 2001),heavily implicating them in drug-dependent individuals’ persistent behavioursand the development and maintenance of substance addiction. Social-smokinginitiates chronic use through positive reinforcement by the directpharmacological, physiological and socially rewarding effects of nicotine, leadingto development of tolerance and hence withdrawal in the drugs absence, thusrequiring increased intake to achieve consistent effects.

Environmental factorscan become drug-associated cues when repeatedly paired with these by Pavlovianand operant conditioning processes, by which addicts learn successfulbehaviours to acquire the drug to avoid or alleviate cue-induced aversive withdrawalstates, explaining cycles of abstinence-withdrawal-relapse, via negativereinforcement of compulsive drug-taking behaviour.John demonstratedevidence of all discussed phenomena; exhibiting behaviour consistent with 6 ofthe 11 DSM-5 diagnostic substance-dependence criteria (severe addiction), mostsignificantly, loss of control of use recognised by his desire and difficulty toabstain.Potentially temperamental, environmental,genetic and physiological, culture-related diagnostic issues (APA,-2013)may influence John’s susceptibility/vulnerability to nicotine/substancedependence, but could not be validated from the vignette.