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4. PSYCHOPHARMACOLOGY OF DEPENDENCE FOR DIFFERENT DRUG CLASSES

dependence-producing ability of tobacco. However, other neuronal systems
related to substance dependence, such as opioid, glutamate, serotonin and
glucocorticoid systems may also be modulated by nicotine (Dani & De Biasi,
2001; Kenny & Markou, 2001; Malin, 2001) and may be of importance to
specific aspects of substance dependence.

Tolerance and withdrawal
Exposure to nicotine results in a high degree of tolerance, which appears to
be mediated by several mechanisms, and which includes acute and long-
term components (Swedberg, Henningfield & Goldberg, 1990; Perkins et al.,
1993). Tolerance to some effects may be related to the upregulation of nicotine
receptors in the central nervous system, but genetic factors also modulate
the effects of nicotine including the development of tolerance (Collins
&Marks, 1989). This may account for some individual differences in nicotine
dependence (see Chapter 5).
Tolerance rapidly develops to the subjective effects of nicotine during the
course of the day. Smokers generally consider that the first cigarette in the
morning is more rewarding, which may be due to tolerance or to the relief
from the withdrawal that develops overnight. Receptor desensitization (loss
of sensitivity) may explain some of the behavioural effects of nicotine, acute
and/or chronic tolerance, and relapse (Rosecrans & Karan, 1993).
Withdrawal from smoking may be accompanied by symptoms such as
irritability, hostility, anxiety, dysphoric and depressed mood, decreased
heart rate and increased appetite. The urge to smoke correlates with low
blood nicotine levels (Russell, 1987), suggesting that smoking occurs to
maintain a certain concentration of nicotine in the blood in order to avoid
withdrawal symptoms. Thus, the continuity of tobacco use would be
explained by both the positive and negative reinforcement of nicotine.
Termination of prolonged nicotine administration to animals induces
behaviours that suggest depression and increased anxiety, changes in
trained behaviours, as well as weight gain. Reduction of locomotion, and
decreased dopamine content and release in limbic structures, nucleus
accumbens and striatum during nicotine withdrawal have been described
in animal models, and may be correlated with behavioural changes due
to nicotine withdrawal (Malin, 2001). Therefore, animal models for
nicotine withdrawal have some external validity and are used in preclinical
studies, mainly to describe possible future treatments for nicotine
dependence.
The signs and symptoms of tobacco withdrawal, including effects on
electrical activity of the brain, cognitive performance, anxiety, and response
to stressful stimuli, can be largely mitigated by administration of pure nicotine
in a variety of forms (e.g. gum, patch, nasal delivery) (Hughes, Higgins &
Hatsukami, 1990; Heishman, Taylor & Henningfield, 1994; Pickworth,
Heishman & Henningfield, 1995; Shiffman, Mason & Henningfield, 1998).

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