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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

& Clarke, 1996; Vidal, 1996; Paterson & Nordberg, 2000). Acute doses can
produce alteration of mood, although daily users are substantially less
sensitive to such effects than non-users, suggesting that tolerance develops
to some of the effects (Soria et al., 1996; Taylor, 1996; Foulds et al., 1997; US
DHHS, 1988). In brief, nicotine produces dose-related psychoactive effects
in humans that are similar to those of stimulants, and it elevates scores on
standardized tests for liking and euphoria that are relied upon by WHO for
assessing dependence potential (Henningfield, Mizasato & Jasinsk, 1985; US
DHHS, 1988; Jones, Garrett & Griffiths, 1999; Royal College of Physicians,
2000).
The potential for dependence associated with smoking seems to equal or
surpass that of other psychoactive substances. In animal models, nicotine
can serve as a potent and powerful reinforcer, it induces intravenous self-
administration, facilitates intracranial self-stimulation and conditioned place
preference and has discriminative stimulus properties (Goldberg et al., 1983;
Goldberg & Henningfield, 1988; Corrigall, 1999; Di Chiara, 2000). Patterns of
self-administration are more similar to those of stimulants than of other drug
classes (Griffiths, Bigelow & Henningfield, 1980).

Mechanism of action
At the cellular level, nicotine binds to nicotinic acetylcholine receptors
(nAChRs). There are a variety of subtypes of neuronal nAChRs. Cloning
techniques have revealed several different neuronal nAChR subunits in
mammals (Lukas et al., 1999). The receptors are composed of five subunits
around an ion channel. Agonist (e.g. nicotine) binding causes the resting
conformation of the subunits to change to the open conformation and allows
sodium ion inflow, which causes cell depolarization (Miyazawa et al., 1999;
Corringer, Le Novere & Changeux, 2000).
In the brain, nicotinic receptors are situated mainly in presynaptic
terminals and modulate neurotransmitter release; therefore, nicotine effects
may be related to various neurotransmitter systems (reviewed in Dani & De
Biasi, 2001; Kenny & Markou, 2001; Malin, 2001). Nicotine is known to
promote dopamine synthesis by increasing tyrosine hydroxylase expression
and release through activation of somatodendritic nAChRs in both
nigrostriatal and mesolimbic dopamine pathways (Clarke & Pert , 1985;
Panagis et al., 2000).
Nicotine increases dopamine output in the nucleus accumbens, and
blocking dopamine release reduces nicotine self-administration in rats
(Schilstrom et al., 1998; Dani & De Biasi, 2001). Nicotine stimulates dopamine
transmission in specific brain areas and in particular, in the shell of the
nucleus accumbens and in areas of the extended amygdala, which have been
related to drug dependence for most drugs (see Chapter 3). Therefore,
nicotine depends on dopamine for the behavioural effects that are most
relevant for its reinforcing properties; this is likely to be the basis of the

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