Animal Models of Nicotine Addiction 151antagonists systemically and directly into the VTA produces
dose-related decreases in nicotine SA (Corrigall & Coen,
1991; Corrigall, Coen, & Adamson, 1994; Corrigall,
Franklin, Coen, & Clarke, 1992). Further evidence for pos-
sible long-term adaptations in the mesocorticolimbic system
stems from research examining activation of immediate early
genes such as the transcription factor c-Fos induced in neu-
rons following various environmental and pharmacological
manipulations. Nicotine SA increases c-Fos-related antigens
expressed in the NAc as well as other regions similar to that
seen with cocaine SA (Pagliusi et al., 1996; Pich et al., 1997).
Thus, nicotine self-administration can result from an action
of nicotine on nACHRs that activate the mesocorticolimbic
dopamine system.
The SA paradigm has high predictive validity since com-
pounds that are deemed addictive in humans will also support
SA. For example, similar to other drugs of abuse such as
cocaine and morphine, animals will self-administer nicotine
(see above). The SA paradigm also possesses a high degree of
face validity. First, similar to human drug intake, animals are
given control over the drug administration and they perform
a required schedule of responses to obtain the drug. Second,
because the current smoking epidemic involves routes of ad-
ministration that allow rapid distribution to brain tissue, the
i.v. route often used in animal SA studies is a route that
closely mimics human drug intake. The degree of construct
validity associated with the SA paradigm is high. In humans,
nicotine becomes addictive in nature partially because it pro-
duces reinforcing interoceptive stimuli or positive subjective
effects. Similarly, a drug is said to maintain SA behavior in
animals because it acts as a positive reinforcer. Thus, the
addictive nature of smoking in humans is assumed to be the
same as that measured by the SA paradigm. With regard to
construct validity, the SA paradigm also provides evidence
for the role of dopamine in mediating the reinforcing effects
of nicotine. The various aspects of validity of the SA model
as a measure for nicotine addiction are summarized in
Table 7.1.
The Place-Conditioning Paradigm
The place-conditioning (PC) paradigm has also been used to
measure the rewarding as well as the aversive properties of
drugs of abuse. The PC paradigm measures the incentive
motivational properties of stimuli that become associated
with drug effects through classical conditioning. The drug is
administered in a distinct environment. After several pair-
ings, the environment becomes associated with the effects of
the drug, thereby acquiring incentive-motivational proper-
ties. Thus, the environment provides cues eliciting either
approach (i.e., conditioned place preference, CPP) or avoid-
ance (i.e., conditioned place aversion, CPA) behaviors de-
pending on whether rewarding or aversive properties of the
drug have been conditioned, respectively.
Nicotine-induced PC has been examined in rodents; how-
ever, similar to nicotine SA, nicotine-induced PC has been
dif“cult to establish (Clarke & Fibiger, 1987). Nicotine-
induced CPP and CPA have been shown in a variety of strains
of rats and mice (Acquas, Carboni, Leone, & Di Chiara, 1989;
Calcagnetti & Schechter, 1994; Fudala, Teoh, & Iwamoto,
1985; Martin & Itzhak, 2000; Schechter, Meehan, &
Schechter, 1995). The role of dopamine in mediating nicotine-
induced CPP has not been extensively studied. In one pub-
lished study, a dopamine receptor antagonist, SCH23390,
prevents acquisition of nicotine-induced CPP (Acquas et al.,
1989). Further studies are needed to clarify the role of
dopamine in mediating the rewarding/aversive effects of
nicotine as measured by the PC paradigm.
The PC paradigm is considered to have a high degree of
predictive validity since drugs that are addictive in humans
also produce CPP in animals. On the other hand, the PC par-
adigm is thought to possess a low degree of face validity
relative to the SA paradigm in regard to the method of drug
delivery. In the PC paradigm, nicotine delivery is passive and
does not depend on the animal•s behavior, whereas with the
SA paradigm the animal actively self-administers nicotine.
However, the PC paradigm possesses a certain level of face
validity since the environment that is paired with effects of
nicotine acquires the status of a conditioned stimulus. Thus,
when the animal is given access to both compartments, and
the resulting effect is a CPP, the environment is said to have
elicited a conditioned response. Conditioned responses also
play an important role in human smoking behavior. Previous
research has shown that drug-associated environments as
well as paraphernalia associated with drug taking (the condi-
tioned stimuli) can evoke both physiological and psycholog-
ical drug-related responses (Ehrman, Robbins, Childress, &
O•Brien, 1992). This parallel seen with human smoking
behavior and the PC paradigm provides evidence for some
degree of face validity with this animal model. The PC para-
digm possesses a high degree of construct validity since it
measures drug-induced reinforcement or incentive motiva-
tion. These theoretical constructs play a fundamental role in
addiction theory (T. Robinson & Berridge, 1993). Similar to
the SA paradigm, “ndings using the PC paradigm also
support the dopamine hypothesis of addiction. Evidence sup-
porting the latter is sparse in regard to nicotine-induced PC
since only one published experiment has examined the ef-
fects of a dopamine antagonist (see Acquas et al., 1989).
However, previous research has thoroughly examined the