Animal Models of Nicotine Addiction 149region and axons of many important neurotransmitter
systems; stimulation of these receptors can in”uence the re-
lease of other neurotransmitters such as dopamine, norepi-
nephrine, acetylcholine, GABA, and glutamate, leading to
behavioral changes associated with arousal, mood, and
cognition function (for review, see Clementi et al., 2000;
Paterson & Nordberg, 2000).
Similar to other drugs of abuse, nicotine is hypothesized to
produce its reinforcing effects by activating the mesocorticol-
imbic dopamine system (for reviews, see Di Chiara, 2000;
Stolerman & Shoaib, 1991; Watkins, Koob, & Markou, 2000).
This pathway originates in the ventral tegmental area (VTA)
and projects to the nucleus accumbens (NAc) and other corti-
cal target areas. Nicotine depolarizes dopaminergic neurons
in the VTAin vitro,and stimulates the release of dopamine in
the NAcin vivo(Calabresi, Lacey, & North, 1989; Imperato,
Mulas, & Di Chiara, 1986). In humans, functional magnetic
resonance imaging reveals that an acute nicotine injection re-
sults in an increase in neuronal activity in limbic and cortical
brain regions such as the amygdala, NAc, cingulate, and
frontal cortical lobes (Stein et al., 1998). This increase is ac-
companied by increases in behavioral measures of feelings
such as •rush,Ž • high,Žand drug liking (Stein et al., 1998). In
animals, intravenous (i.v.) nicotine self-administration in
the rat produces regional brain activation in the NAc, medial
prefrontal cortex, and medial caudate area, as assessed by
c-Fos and Fos-related protein expression (Pagliusi, Tessari,
DeVevey, Chiamulera, & Pich, 1996; Pich et al., 1997).
Variability in the metabolism of nicotine across indi-
viduals might contribute to nicotine•s addictive potential. For
example, •slowŽ metabolizers of nicotine may be more sub-
ject to the aversive properties of nicotine because of the
higher levels of untransformed nicotine per unit time and,
consequently, may use less tobacco. Conversely, •fastŽ me-
tabolizers of nicotine may be less subject to nicotine toxicity
because of lower levels of nicotine and, consequently, need to
use more tobacco per unit time to maintain suf“cient levels of
nicotine. It has been suggested that the nicotine metabolism
pathway may be altered via genetic polymorphisms (Idle,
1990). Studies have examined genetic variation of enzymes
involved in the metabolism of nicotine, however, the out-
comes are not conclusive and warrant further investigation.
Understanding of individual differences in nicotine metabo-
lism and their relationship to susceptibility for becoming
and/or remaining a regular tobacco user is in the early stages.
Increased information is needed on the full array of genes in-
volved in the various metabolic processes, the extent of indi-
vidual variation in the genetic substrate, along with a better
appreciation of how these differences in”uence susceptibility
to become addicted to nicotine.
ANIMAL MODELS OF NICOTINE ADDICTIONAnimal models examining the reinforcing effects of nicotine
have been used to assess the various contributing factors of
tobacco dependence as observed in the human population.
The extent to which animal models can be used to interpret
the underlying nature of dependence in humans depends
mainly on the validity of the model. Animal models have
been evaluated based on predictive, face, and construct valid-
ity (Willner, 1991). Predictive validity of an animal model is
de“ned as •performance in the test predicts performance in
the condition being modeled.Ž For example, valid animal
models of drug reward can differentiate between drugs that
are abused by humans and those that are not and can therefore
be used to evaluate whether a novel drug possesses abuse li-
ability as well as to detect potential candidate medications for
prevention of drug addiction. Face validity is an indication of
whether the •behavioral and pharmacological qualitiesŽ of an
animal model are similar in nature to those seen in the human
condition. Construct validity is assessed by determining
whether there is a •sound theoretical rationaleŽ between
the animal model and the human condition being modeled
(Willner, 1991). Table 7.1 addresses the questions that assess
the validity of each animal model discussed next as related to
nicotine addiction.
Several animal models have been used to examine the
reinforcing effects of nicotine. In the following paragraphs,
we discuss methodology, “ndings directly related to nico-
tine addiction, and validity (see Table 7.1) of two frequently
used animal models, the self-administration and the place-
conditioning paradigms.Self-AdministrationThe self-administration (SA) paradigm provides a measure
of the reinforcing effects of drugs. The animal learns the re-
lationship of its behavior such as pressing a lever or a nose-
poke and a reinforcer such as an i.v. injection of a drug. If
the relationship between the animal•s behavior and the re-
sponse is reinforcing, the probability of the animal continu-
ing the behavior is increased. It has taken 10 to 15 years of
research with animals to map out the conditions that will
support reliable SA of nicotine. Nicotine SA has been demon-
strated in nonhuman primates (Goldberg, Spealman, & Gold-
berg, 1981), rats (Corrigall & Coen, 1989; Donny, Caggiula,
Knopf, & Brown, 1995), and mice (Picciotto et al., 1998;
Stolerman, Naylor, Elmer, & Goldberg, 1999). The role of
the mesocorticolimbic dopamine system in mediating nico-
tine SA has also been examined. For example, lesions
of dopaminergic neurons in the NAc, and administration of