152 Tobacco Dependence
effects of dopamine in mediating CPP induced by other
drugs of abuse such as cocaine, amphetamine, and morphine
(Hoffman, 1989; Schechter & Calcagnetti, 1993). Various
aspects of validity as related to the PC paradigm are sum-
marized in Table 7.1.
Preclinical Genetic Models: Insights into
Individual Differences in Nicotine-Induced Behavior
Animal studies using inbred strains have indicated that there
are potential strain differences providing some insight as to
why there are individual differences in the development of
nicotine addiction in humans. Indeed, when inbred strains of
mice are provided with a choice of nicotine or vehicle solu-
tions, the strains differ dramatically in their self-selection of
nicotine (Crawley et al., 1997; Meliska, Bartke, McGlacken,
& Jensen, 1995; S. Robinson, Marks, & Collins, 1996).
Across the different strains, the higher the preference for the
nicotine solution, the lower the sensitivity to nicotine-induced
seizures (S. Robinson et al., 1996). Thus, the negative toxic
actions of nicotine limit nicotine consumption in mice. There
are also differences in SA of nicotine by inbred strains of mice,
where nicotine can serve as a positive reinforcer in c75BL/6
mice but not in DBA/2 mice (Stolerman et al., 1999).
Genetically altered mice with certain targeted gene muta-
tions are also becoming important tools in studying the
molecular nature of nicotine addiction (Mohammed, 2000;
Picciotto et al., 1998). These •knock outŽ mice are mutant
mice lacking genetic information encoding speci“c nACHR
subunits. Because the 2 subunit is widely expressed in the
central nervous system and is found in the mesocorticolimbic
dopamine system, the reinforcing effects of nicotine have
been examined in 2-knockout mice (Picciotto et al., 1998).
Picciotto et al. (1998) report that nicotine-induced dopamine
release in the ventral striatum is only observed in wild-type
mice and not in 2-knockout mice. Furthermore, mesen-
cephalic dopamine neurons are no longer responsive in
2-knockout mice. Similar to their wild-type counterparts,
2-knockout mice learned to self-administer cocaine. How-
ever, when nicotine was substituted for cocaine, nicotine SA
was attenuated in the 2-knockout mice relative to wild-
types. These “ndings suggest that the 2 receptor subtype
plays a crucial role in the reinforcing effects of nicotine.
Studies using mutant mice provide some insight as to indi-
vidual differences in tobacco smoking. For example, differ-
ent expression of nACHR subtypes (i.e., by knocking out
various nACHR subunits in animals) can partially account
for differences in nicotine effects. Although genetic knockout
mice are a powerful tool, research using this technique
has not yet reached its full potential. Thus far, the gene of
interest is knocked out prior to birth, possibly resulting in
compensatory changes in the developing central nervous
system of the animal. For a “ner assessment of the role of
various nACHR subtypes, mutant mice that undergo gene-
speci“c mutations in certain brain regions at a precise time in
their adult life are needed. Eventually, this line of research
will provide identi“cation of molecular sites that modulate
nicotine addiction facilitating medication development for
the treatment of tobacco dependence in human smokers.Relevance of Preclinical Studies to Understanding
Tobacco DependenceAnimal models, such as the SA and PC paradigms (discussed
previously), provide a unique contribution toward our under-
standing of tobacco dependence in humans. These models
allow the examination of the reinforcing effects of nicotine
that are highly relevant to tobacco dependence in humans,
and that cannot be easily studied in human subjects mainly
for ethical reasons. In animals, potential behavioral effects
of pharmacological agents can be more fully characterized.
Furthermore, these animal models allow the investigation of
the basic underlying neurochemical mechanisms that are rel-
evant to nicotine addiction.
Animal models also can be used to study environmental
factors in initiation and maintenance of nicotine addiction.
Smokers report that environmental factors such as stress in-
duce smoking behavior and that smoking helps to alleviate
stress (McKennell, 1970; USDHHS, 1988). Preclinical stud-
ies have shown that environmental stressors can increase cor-
ticosterone levels and in turn can alter behavioral responses to
administration of drugs of abuse. For example, prenatal stress
(Deminiere et al., 1992), isolation (Alexander, Coambs, &
Hadaway, 1978; Schenk, Lacelle, Gorman, & Amit, 1987),
foot-shocks (Goeders & Guerin, 1994), and exposure to social
defeat stress (Miczek & Mutschler, 1996) can activate as well
as facilitate SA of psychomotor stimulants and opioids. In
addition, exposure to intermittent foot-shock can reinstate
heroin (Shaham & Stewart, 1995), cocaine (Ahmed & Koob,
1997; Erb, Shaham, & Stewart, 1996), alcohol (Lê et al.,
1998), and nicotine (Buczek, Lê, Stewart, & Shaham, 1999)
drug-seeking behavior following extinction and an extended
period of abstinence. However, the role of environmental
stressors in eliciting nicotine reinforcement using animal
models has not been characterized thoroughly. These ex-
periments will lead to the development of animal models of
gene-environment interactions in nicotine addiction. Future
experiments will provide us with clues as to whether the inter-
actions can be demonstrated, the magnitude of their effect, and
the conditions under which the interactions vary in strength.