tmpD2C8 TMP

Nicotine & Tobacco Research Advance Access published February 10, 2015
Nicotine & Tobacco Research, 2015, 114

doi:10.1093/ntr/ntv002
Review
Review
The Reinforcing Effects of Nicotine in Humans

and Nonhuman Primates: AReview of
Intravenous Self-Administration Evidence and
Future Directions for Research
Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015
Amy K.Goodwin PhD, TakatoHiranita PhD, Merle G.Paule PhD

National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR
Corresponding Author: Amy K.Goodwin, PhD, U.S. Food and Drug Administration, National Center for Toxicological
Research, 3900 NCTR Rd/ HFT 132, Jefferson, AR 72079, USA. Telephone: 870-543-7702; Fax: 870-543-7745;
E-mail: Amy.Goodwin@fda.hhs.gov
Abstract
Introduction: C
igarette smoking is largely driven by the reinforcing properties of nicotine.
Intravenous (IV) self-administration procedures are the gold standard for investigating the reinforcing effects of psychoactive drugs. The goal of this review was to examine the results of published investigations of the reinforcing effects of nicotine measured using IV self-administration
procedures in humans and nonhuman primates.
Results: The body of literature using nonhuman primate subjects indicates nicotine functions as a
positive reinforcer when available for self-administration via IV catheters. However, it can also be
difficult to establish IV nicotine self-administration in nonhuman primates and sometimes supplemental strategies have been required (e.g., priming injections or food deprivation) before subjects
acquire the behavior. Although the body of literature using human subjects is limited, the evidence
indicates nicotine functions as a reinforcer via the IV route of administration in adult cigarette
smokers. Rates of nicotine self-injection can be variable across subjects and responding is sometimes inconsistent across sessions in both humans and nonhuman primates.
Conclusions: The Family Smoking Prevention and Tobacco Control Act, enacted in 2009, gave the
Food and Drug Administration regulatory authority over the manufacture, marketing, and distribution of tobacco products. Research examining the threshold reinforcing doses for initiation and
maintenance of nicotine self-administration, comparisons of the reinforcing effects of nicotine in
adolescent versus adult subjects, investigations of gender differences in the reinforcing effects of
nicotine, and studies of the abuse liability of non-nicotine tobacco product constituents and their
ability to alter the reinforcing effects of nicotine will inform potential tobacco regulatory actions.
Introduction
The Centers for Disease Control and Prevention (CDC) reported
that 18% of adults in the United States were cigarette smokers in
2012.1 Among adult smokers, the CDC estimates nearly 90% began
smoking before the age of 18.2 Compared to people who have
never smoked, life expectancy for cigarette smokers is decreased by
at least one decade3 and more than 480,000 Americans die from
smoking related illnesses every year, making tobacco use the largest
preventable cause of death and disease in the United States.4 From
20092012, at least $133 billion was spent on direct medical care
related to cigarette smoking, and lost productivity costing $156 billion was attributed to cigarette smoking.1 With the passage of the
Family Smoking Prevention and Tobacco Control Act in 2009, the
U.S. Food and Drug Administration (FDA) was given authorization
Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2015.
This work is written by (a) US Government employee(s) and is in the public domain in theUS.
Nicotine & Tobacco Research, 2015, Vol. 00, No. 00
Results
IV Self-Administration of Nicotine in Nonhuman
Primates
Table 1 summarizes the methods and results from studies of the
reinforcing effects of IV nicotine in nonhuman primates. One of the
first attempts to establish nicotine self-administration in a nonhuman primate species was carried out by Deneau and Inoki in 1967.31
Initially, nicotine was available for self-injection in seven nave
rhesus monkeys (unspecified gender and age). When spontaneous
nicotine self-administration did not occur, a response-independent
injection (i.e., priming injection) was delivered every hour. When
nicotine self-administration was still not established following two
months of hourly priming injections, the automatic injections ceased
and the nicotine dose was increased and spontaneous nicotine selfadministration occurred in two subjects. Following additional automatic nicotine injections over 210days, nicotine self-administration
was initiated in the remaining five subjects (i.e., priming injections
were required). The average daily total intake of nicotine self-administered was variable and ranged from 0.7 to 1.7mg/kg. The dose
of nicotine per injection was then increased each month until selfadministration ceased. Of the six monkeys tested in this fashion, one
stopped at 0.05mg/kg/injection, two stopped at 0.1mg/kg/injection,
one stopped at 0.5mg/kg/injection, one stopped at 1.0mg/kg/injection, and one continued to self-administer at the highest dose tested
(2.0mg/kg/injection). At the 2.0mg/kg/injection dose, the subject
self-administered an average daily dose of 9.6mg/kg. Unfortunately,
details about the number of injections, and pattern and rate of
responding across sessions and subjects were not provided. Thus,
we cannot determine if the results from these studies satisfy any currently acceptable criteria for determining if a drug functions as a
reinforcer (i.e., dose-dependent changes in responding, comparison
to responding for vehicle injections). In addition, many methodological details were not reported (e.g., injection volume, duration of
injection, time-out periods). Nonetheless, the authors concluded
that under the conditions employed in their study, nicotine was selfadministered intravenously in rhesus monkeys without a prior history of operant conditioning using drug or food reinforcement.31
The importance of a subjects experimental history and the duration of access to the test compound (e.g., session duration) was evident in another early nicotine self-administration study by Yanagita32
(see also Yanagita etal.33). Given 24-hr access to nicotine injections,
six out of six rhesus monkeys (unspecified gender and age) described
as self-administration experienced by the authors, self-injected at
least one dose of nicotine relative to saline injections. Only four out
of seven experimentally nave subjects did so when nicotine was substituted for saline. The average total daily intake of nicotine ranged
from 0.22.0mg/kg.33 Importantly, nicotine injections consistently
maintained responding above vehicle levels. When access was limited to 4hr, however, nicotine was not self-administered in experienced monkeys when it was substituted for a psychostimulant
(lefetamine) that was already maintaining self-administration. It has
been well-established that experimental history and session duration
can influence self-administration behavior.19,34 Yanagita32 was the
first to report nicotine maintained responding above vehicle levels in
an old world nonhuman primate species.
Another key factor related to pattern of drug self-administration is the timeout period following a self-injection. In adult male
baboons (Papio anubis and Papio hamadryas) previously trained to
lever press for food or other drugs as reinforcers, Griffiths et al.35
reported that nicotine failed to maintain responding above vehicle
levels during 24-hr sessions of nicotine availability with concurrent
to regulate the manufacture, marketing, and distribution of tobacco

products.5 The FDAs Center for Tobacco Products has three public
health goals: prevent youth initiation of tobacco use, lower the harm
and addictiveness of tobacco products, and encourage cessation of
tobacco use.6
Cigarette smoking appears to be largely driven by the reinforcing
properties of nicotine.710 According to Henningfield and Goldberg,11
the behavioral and physiological effects of smoking tobacco were
described as early as the 1920s and nicotine was identified as the
principal pharmacologic component in tobacco by biomedical
researchers ArmstrongJones in 1927 and Lewin in 1931. The addictive properties of nicotine were acknowledged in internal tobacco
industry communications in the 1950s, with cigarettes being
described as an ideal nicotine delivery device.9 The scientific consensus that nicotine plays a primary role in initiating and maintaining
smoking behavior was first described in the 1964 Surgeon Generals
report12 and confirmed in subsequent reports.2,7,13 The average daily
intake of nicotine via cigarette smoke is difficult to estimate given
differences in behavior amongst smokers and the variable nicotine
content across cigarette brands. Cigarettes may contain 114mg of
nicotine, with 0.011.5mg of nicotine being absorbed from smoking
a single cigarette.1418
There is generally excellent correspondence between drugs that
are abused by humans and those that are self-administered by laboratory animals. Unlike other behavioral paradigms that may be used
to indirectly examine the reinforcing effects of a drug (e.g., conditioned place preference), self-administration procedures provide
direct measures of behavior (e.g., lever pressing) that is maintained
by the reinforcing effects of a drug. Accordingly, the self-administration paradigm is the gold standard for assessing the reinforcing
effects of psychoactive compounds.1923 In addition, the role of other
variables (e.g., dose, schedule of reinforcement, volume and duration
of injections, and prior drug and training experience) in mediating
the reinforcing effects of drugs can be systematically investigated
using self-administration procedures.
Many early attempts to demonstrate the reinforcing effects of
nicotine using intravenous (IV) self-administration procedures in
rodents were unsuccessful.24,25 Several factors may have contributed to these initial negative findings including the age and strain of
rat, injection speeds, limited duration of catheter patency, drug and
training histories, and the reinforcement schedule used. Nonetheless,
more recent studies have reported reliable and robust nicotine selfadministration in rats.2530 In addition to contributing to the overall understanding of the reinforcing effects of nicotine, results from
rodent studies are exceptionally useful for informing investigations
in nonhuman primates and humans. Moreover, since nicotine is not
scheduled according to the Controlled Substances Act and is freely
available for human consumption via tobacco products and other
nicotine delivery devices, the reinforcing effects of IV self-administered nicotine have also been evaluated in humans. Areview of all
data related to the reinforcing effects of nicotine is beyond the scope
of this review, which focuses on investigations of the reinforcing
effects of IV nicotine in humans and nonhuman primates. Indeed,
a December 2014 PubMed search using the relatively specific term
nicotine self-administration returned over 1,400 related references. Thus, one aim of this review is to describe the history and
progress of research focused on assessing the reinforcing effects of
IV nicotine in nonhuman primates and humans. A second aim is
to review specific research areas related to the reinforcing effects of
tobacco product constituents that will provide empirical data and
inform the FDA in its mission to promote public health through the
regulation of tobacco products.
Griffiths etal.35
Goldberg etal.37
Dougherty etal.40
Goldberg and Spealman38
Spealman and Goldberg39
Ator and Griffiths36
Slifer41
Slifer and Balster42
De La Garza and Johanson43 rhesus
Sannerud etal.60
Wakasa etal.
1979
1981
1981
1982
1982
1983
1983
1985
1987
1994
1995
47
rhesus
Yanagita32,33
1977e
not described (n=3)

drug SA (n=1); nave
(n=2)
drug SA (n=3); nave
(n=1)
drug SA (n=1); nave
(n=2)
cocaine SA (n=4)
drug SA (n=8)
rhesus
squirrel
rhesus
drug and food SA (n=3);

nave (n=1)
nave (n=1)
cocaine SA (n=2); food SA

(n=2); nave (n=1)
nave (n=2);
drug SA (n=3)
drug and food SA (n=15)

cocaine SA (n=3); nave
(n=1)
not described (n=4)
drug SA (n=4)
drug SA (n=6)
nave (n=7)
not described (n=4)
nave (n=7)
Subject history
rhesus
baboon
squirrel
squirrel
rhesus
baboon
squirrel
rhesus
Deneau and Inoki31
Species
1967
Authors
FR 160
second order
FRf
FR 1
FR 1
PR
FR 1
Schedule
0.03
0.010.1c
FR 10
24 hr
FR 5
1hr or 12 injections FR 30
3 hr
FR 10
1 hr
0.010.3c
0.0080.25c
FR 1
1 hr
0.00010.1c
0.00010.1c
FR 1
2hr or 50 injections FI (5min)
0.010.56c
1 hr
2hr or 1012
second orderl
injectionsl
2hr or 50 injections FR 2
0.0030.1c
0.010.32c
subject
dependentj
24 hr
1.5hr or 12
injections
3 hr
4 hr
24 hr
24 hr
24 hr
24 hr
Session duration
0.0030.56c
0.0030.56c
0.0150.27a
0.0013.2c
0.03c
0.00250.64b
0.020.2b
0.020.2b
0.050.2b
0.012.0a
Dose range
(mg/kg/
injection)
15 min
5 min
unspecified
unspecified
unspecified
unspecified
60 s
15 s
13minl
1 min
1 min
unspecified
3 hr
3 min
nicotine substituted for saline;

infusion speed varied as a
manipulation
nicotine substituted for cocaine; w/

vs. w/o food deprivation
nicotine substituted for cocaine
priming injections when

spontaneous SA didnt occur
nicotine substituted for lefetamineg
nicotine substituted for saline
nicotine substituted for saline
nicotine substituted for lefetamineg;
each dose examined for one
24-hr session
priming injections of nicotine
during initial trainingi
training required 29months using
unspecified methods
nicotine substituted for cocaine,
saline, and nicotine baselines
nicotine substituted for cocaine;
FI duration varied as a
manipulation
nicotine SA w/ and w/o concurrent
food pellet SA
nicotine SA w/ and w/o concurrent
food pellet SA
unspecified
unspecified
unspecified
unspecified
unspecified
Methodological strategies
Time out
Year
Table1. Nicotine IV Self-Administration (SA) in Nonhuman Primates
0.03
0.030.056
0.0080.06h
0.010.1
0.010.1
0.030.1
0.010.1h
0.010.1h,m
0.0030.056h
0.010.56h
0.030.56h
0.0150.09h,k
none
0.03h
none
0.020.2h
0.020.2h
0.050.2
0.0252.0
Doses selfadministered
(mg/kg/injection)d

3
Freeman and Woolverton49
Gould etal.48
Mello etal.57
Justinova etal.54
Mascia etal.55
Panlilio etal.56
2009
2011
2011
2011
2011
2012
squirrel
squirrel
squirrel
rhesus
rhesus
rhesus
squirrel
Species
nicotine experienced
(n=4)
nicotine SA (n=3)
nicotine SA (n=4)
cocaine and food

SA and/or drug
discrimination (n=8)
not described (n=5)
drug SA (n=4); no drug

SA (n=1)
nave (n=5)
Subject history
16hr or 2hr w/o

an injections
0.03
0.03
0.03
1 hr
1 hr
1 hr
0.000320.1a 1hr or 20
injections
0.010.1a
1.513hrn
FR 10
FR 10
FR 10
second order
PR
PR
PR
6hr or 0.5hr w/o

a response
0.0030.06a
0.0120.05a
FR 10
Schedule
1 hr
Session duration
0.0030.03a
Dose range
(mg/kg/
injection)
1 min
1 min
1 min
10 s
10 min
30 min
unspecified
1 min
Time out
distinct visual stimulus paired w/

nicotine injections
PR evaluation followed the FR
evaluation; each dose studied
for at least 5 sessions
or saline; also evaluated
nicotine + cocaine mixtures
also evaluated effects of
varenicline on cocaine SA
also evaluated nicotine +
cocaine mixtures
nicotine injections; evaluating
2-arachidonoyglycerol
PPAR- agonists
PPAR- agonists
Methodological strategies
0.03
0.03
0.03
0.00320.01
none
0.0120.05o
0.0030.06
0.0030.03
(mg/kg/injection)d
FI=fixed-interval schedule of reinforcement; FR=fixed-ratio schedule of reinforcement; PR=progressive-ratio schedule of reinforcement.

a
Nicotine dose range expressed as the free base.
b
Basis (salt or free base) of nicotine dose range not described.
c
Nicotine dose range expressed as the salt.
d
Dose range included if nicotine self-administration occurred in at least one subject.
e
The same data, with additional details, was presented in Yanagita etal.33
f
FR value not specified.
g
1-1,2-diphenyl-1-dimethylaminoethan HCL (SPA; lefetamine).
h
The doses self-administered were determined by a general visual inspection of the data presented or statements made by the authors, but statistical analysis to support such conclusions were not presented in the referenced
citation.
i
During initial training, the first response after 5min elapsed produced an injection; if no response occurred within 7min then an automating (priming) injection occurred.
j
Data for 2 subjects were presented; one subject worked on a second order schedule where completion of an FR 4 produced a 0.5-s tone and the completion of a FR 4 after a FI (1min) produced the tone and an injection;
the second subject worked on a tandem FR/FI schedule where the first response after an injection initiated a 16-s interval and the first response after the interval produced an injection.
k
Nicotine SA in 3 out of 4 subjects.
l
Parameters (maximum number of injections, duration of FI, duration of timeout) varied across subjects.
m
Patterns of responding for nicotine injections differed across baseline conditions (cocaine, saline, nicotine) and an inverted u-shaped dose-effect curve was observed in the first 5days of nicotine SA but became flatter as
responding stabilized.
n
Sessions ended after 20 injections or two consecutive 30-min trials without completion of the response requirement; each injection was followed by 30-min timeout.
o
Nicotine self-administered in only one of five subjects and responding was not dose-dependent.
Le Foll etal.50
Authors
2007
Year
Table1. Continued
4
Acomparison of responding under both an FI and the second-order

schedule of reinforcement demonstrated that patterns of responding maintained by nicotine were qualitatively similar to those maintained by cocaine or morphine injections using these schedules of
reinforcement.37,39 Overall rates of responding for nicotine selfinjections were higher under the second-order schedule compared
to the FI schedule and the authors attributed this difference to the
visual stimuli paired with each nicotine injection.37,39 Specifically,
under the FI schedule, one stimulus light indicated injections could
be earned and was extinguished during timeout periods. Under the
second order schedule, however, injections were associated with a
brief change in the color of the stimulus light. Thus, these studies
were the first to demonstrate a meaningful role for the presentation
of unique visual stimuli paired with nicotine self-injection and the
selective sensitivity of the reinforcing effects of nicotine to blockade
by a nicotinic antagonist (mecamylamine) in a new world monkey
species.
Around the same time the Goldberg and Spealman research
group was examining the reinforcing effects of nicotine in squirrel monkeys, others were using rhesus monkeys. Compared to
squirrel monkeys,39 similar rates of responding for nicotine injections were reported for rhesus monkeys (gender and age unspecified) when comparable schedules of reinforcement were used.40 The
highest total nicotine intake self-administered during 3-hr sessions,
according to the data for the two subjects shown, appears to have
ranged from approximately 213mg/kg under a slow substitution
regimen. Dougherty and colleagues40 compared responding during
two dose-change procedures. In the rapid procedure, the nicotine
dose was changed daily (progressive increase and then a progressive decrease over daily sessions), while in the slow procedure the
nicotine dose was changed every 510 sessions. The data presented
for two subjects indicate higher response rates, more injections, and
a greater amount of nicotine was self-administered using the slow
procedure. Thus, Dougherty etal.40 was the first to demonstrate the
importance of the substitution procedures chosen for assessing the
reinforcing effects of nicotine. This has become an area of interest as
a possible strategy for lowering the abuse liability and harm from
tobacco products (see below Future Directions).
Other studies in adult male rhesus monkeys used FR schedules of
reinforcement and sought to determine if concurrent responding for
food41,42 or food deprivation43 would alter nicotine self-administration. When food pellets were available under an FI schedule on one
lever, and injections of nicotine were available under an FR schedule on a different lever, higher rates of responding for nicotine were
found when compared to a no food condition.41,42 While nicotine
maintained self-administration under both food deprivation and
satiation conditions in three adult rhesus monkeys, nicotine intake
was higher under food deprivation conditions in one of three subjects.43 Asecond subject showed a similar trend but the shift was not
statistically significant. These results suggest that food deprivation
may affect the potency and effectiveness of nicotine as a reinforcer.
Another variable that may impact self-administration behavior is the duration of nicotine infusions.4446 Durations of injections and rates of nicotine infusion for studies that provided such
information, or included enough information to estimate infusion
rates, are shown in Table2. The impact of rate of infusion (0.0003
0.0052mg/s) on nicotine self-administration in male and female
rhesus monkeys, and the corresponding time-course of nicotine
plasma levels, was examined in a study by Wakasa et al.47 They
reported that as the time to infuse a fixed nicotine dose (0.03mg/kg/
unlimited food access. A3-hr timeout period followed each nicotine

injection, limiting the number of injections to 8 per 24-hr session. In
a follow-up study, Ator and Griffiths36 used shortened sessions (2hr)
and brief timeout periods (15 or 60 s) and reported that nicotine
was self-administered significantly above saline levels in three out
of three subjects. Other methodological differences between the two
studies included the response requirement and substitution procedures. In the Griffiths et al.35 study, a fixed ratio (FR) schedule of
reinforcement was used and nicotine was substituted for cocaine, but
nicotine was not self-administered above vehicle levels. In the Ator
and Griffiths36 study, results from two experiments were presented.
In one, an FR schedule (15-s timeout) was used to examine nicotine
self-administration during 2-hr sessions. Nicotine self-administration was variable in this experiment, with patterns of responding
for nicotine injections differing across baseline conditions (cocaine,
saline, and nicotine baselines) and with higher rates of nicotine selfadministration occurring during the first 5 days of nicotine access
compared to the last 5days. In the second experiment, a fixed interval (FI) schedule (60-s timeout) was used and nicotine was substituted for a cocaine baseline. Responding was less variable compared
to the first experiment and the number of nicotine injections was
higher than that of saline injections.36 The highest total mean intake
of nicotine per 2-hr session ranged between 1.02.8mg/kg across
subjects. Thus, in addition to differences in session duration and
timeout periods, the schedule of reinforcement also differed between
the two studies. The FI schedule produced less variable response rates
for nicotine injections across time when compared to the FR schedule.36 The authors also noted that even when responding for nicotine
injections was higher than for vehicle injections, the overall response
rates for nicotine injections were relatively low when compared to
rates maintained by other drugs (e.g., cocaine). Importantly, the Ator
and Griffiths36 study was the first to demonstrate an inverted-Ushaped dose-response curve for nicotine self-administration in nonhuman primates.
Goldberg etal.37 first demonstrated that high rates of behavior
could be maintained by nicotine self-injections in adult male squirrel
monkeys (Saimiri sciureus) using an unlimited food access condition.
Goldberg and colleagues used a second-order schedule of reinforcement under which completion of an FR requirement following a FI
of time resulted in changes in the color of a stimulus light; completion of an additional FR requirement then initiated a nicotine injection that was paired with another change in the color of the stimulus
light.37 Response rates during experimental sessions were characterized by the authors as consistently high and averaged between
0.81 and 1.58 responses per second. When saline injections were
substituted for nicotine injections, response rates fell to very low
levels (actual number not given). Since experimental sessions ended
after the 12th timeout period (or 90min elapsed), the maximum
number of nicotine injections that could be earned was 12. Using an
average squirrel monkey body weight of 0.8kg, the maximum total
nicotine intake that could have been self-administered would have
been approximately 0.36mg/kg. Pretreatment with mecamylamine,
a nicotinic antagonist, resulted in lowered rates of responding for
nicotine injections. Subsequent studies reported full nicotine doseresponse curves in adult male squirrel monkeys.38,39 In all three of
these squirrel monkey studies, automatic (i.e., priming) injections of
nicotine were used to help establish nicotine self-administration in
some monkeys. During the initial training, the first response after
5min produced an injection of nicotine. However, if no response
occurred within 7min, an automatic injection of nicotine occurred.
6
Table2. Infusion Rates in Nicotine IV Self-Administration (SA) Studies
Year
1977d
Authors
Yanagita32,33
Species
rhesus
Infusion Infusion rate

duration (s)
(ml/s)
46e
Griffiths etal.35
Goldberg and Spealman38
Spealman and Goldberg39
baboon
squirrel
squirrel
1983
Ator and Griffiths35
baboon
1983
1983
1983
1985
Henningfield etal.62
Henningfiled and Goldberg63,64
Slifer41
Slifer and Balster42
human
human
rhesus
rhesus
1987
1994
1995
De La Garza and Johanson43

Sannerud etal.60
Wakasa etal.47
rhesus
squirrel
rhesus
2003
Rose etal.65
human
2004
2007
2008
2009
2010
Harvey etal.66
Le Foll etal.50
Sofuoglu etal.67
Freeman and Woolverton49
Rose etal.68
human
squirrel
human
rhesus
human
10
0.2i
30
10
180510j
2011
2011
2011
2011
2012
Gould etal.48
Mello etal.57
Justinova etal.54
Mascia etal.55
Panlilio etal.56
rhesus
rhesus
squirrel
squirrel
squirrel
10
1
0.2
0.2
0.2
1/23
0.000430.11e
Injection
volume
Dose range
SA?
0.25ml/kg
0.0250.64b mg/kg/injection
no
0.020.2b mg/kg/injection
0.0013.2c mg/kg/injection
0.753.0a mg/injection
0.753.0b mg/injection
0.03b mg/kg/injection
individualizeda,h
(0.040.15mg/injection)
0.0030.06a mg/kg/injection
individualizeda,h
(0.050.21mg)
0.03mg/kg/injection
0.03mg/kg/injection
0.03mg/kg/injection
yes
no
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
1/23
10/120
0.2/0.2
0.2/0.2
0.2/0.2
1/5
1/5
1/10
1/9.2
1/10
1/10
1/10
1/10
0.2/0.2
1/23
1/23
1/23
not described
0.00300.030 0.25ml/kg
0.000170.53e
10mlg
e
0.0122.20
0.2 ml
0.0122.20e
0.2 ml
0.0120.40e
0.2 ml
0.0501.60e
1 ml
0.0502.80e
1 ml
0.0750.30e
1 ml
0.0820.33e
1 ml
0.00080.08e
1 ml
0.00080.08e
1 ml
0.0080.24e
1 ml
0.00640.20e
1mle
0.0400.40e
0.2 ml
0.0052
0.25ml/kg
0.0013
1ml/kg
0.0003
4ml/kg
0.020.075 not described
1/10
0.2/0.2
5/30
not described
not described
0.0750.30
1 ml
0.040e
0.2mli
0.00330.023
5 ml
0.0120.050e not described
0.601.90j not described
1.5/10
0.1/1
0.2/0.2
0.2/0.2
0.2/0.2
0.00800.08e
0.00260.80e
0.12e
0.12e
0.12e
1.5 ml
0.1 ml
0.2 ml
0.2 ml
0.2 ml
yes
yes
yes
yes
yes
no
yes
yes
yes
yes
Nicotine dose range expressed as the free base.

c
d
The same data, with additional details, were presented in Yanagita etal.33
e
Calculation(s) based on other information provided by the authors and/or using estimated mean body weights (e.g., 610kg for rhesus monkeys, 2025kg for
baboons, 0.8kg for squirrel monkeys, 7580kg for humans).
f
Griffiths etal.35 describe the injection duration as occurring within a 2-min period (p168).
g
5-ml drug solution followed by 5-ml vehicle.
h
Doses of nicotine that were administered were individualized and calculated to be equal to a puff on the usual brand of cigarette during a baseline session.
i
The duration and volume of injection for 0.01mg/kg/injections of nicotine; other doses were achieved by varying the duration and volume of injections.
j
Set to be equal to each individuals rate of intake during cigarette smoking.
a
injection) was increased (slower infusion speed), the average rates of

nicotine self-administration decreased. In addition, plasma concentrations of nicotine were positively correlated with infusion speeds
in mg/s: the faster the injections, the higher the plasma nicotine levels. These data suggest that the rate of infusion may affect responding for injections of nicotine. In contrast, the Griffiths etal.35 study
in adult male baboons reported that nicotine (0.0013.2mg/kg/
injection) did not maintain responding above vehicle levels using
infusion rates up to approximately 100-fold faster than that of
Wakasa etal.47 (i.e., infusion rates of 0.000170.53mg/s as calculated using 20kg as the mean baboon body weight). Asubsequent
study in adult male baboons36 reported clear inverted U-shaped
dose-response curves for nicotine self-administration (0.010.1mg/
kg/injection) using infusion rates of approximately 0.051.6mg/s.
The FR-160 schedule of reinforcement used by Griffiths et al.,35
however, was a much higher response requirement than the FR-5
schedule used by Wakasa et al.47 and the FR-2 schedule used by

Ator and Griffiths.36 Thus, the lack of a demonstration of nicotine
self-administration in the Griffiths etal.35 study may have been due
to the relatively high FR requirement. Indeed, a more recent study
reported nicotine failed to maintain responding above saline levels
when substituted for cocaine under a progressive ratio schedule
of reinforcement in adult male rhesus monkeys.48 Specifically, the
final ratio completed (i.e., breakpoint) was less than 100 for nicotine injections, compared to more than 900 for cocaine.48 Asimilar
study reported that nicotine maintained self-administration above
vehicle levels in only one of five adult male rhesus monkeys under
a progressive ratio schedule.49 The maximal infusion rates of IV
nicotine in the studies of Freeman and Woolverton49 and Gould
et al.48 were much faster than that used in the study of Wakasa
etal.47 Thus, though one study indicated that lower infusion rates
decreased nicotine self-administration,47 the body of data shown
1979
1982
1982
46
120f
0.2
0.2
0.2
5
5
10
9.2
10
10
10
10
0.2e
33e
130e
567e
2
e
Infusion rate
(mg/s)
self-administration behavior via smoking. Thus, it is possible that

nicotine self-administration would be more easily acquired and/
or consistent in the presence of other tobacco product constituents. Indeed, examinations of non-nicotine tobacco product constituents are essential areas of study for future assessments of the
reinforcing effects of nicotine (see below Future Directions).
IV Self-Administration of Nicotine inHumans

While the reinforcing effects of nicotine have been designated as the
primary factors in the maintenance of cigarette smoking, relatively
little research in humans has specifically examined the reinforcing
effects of nicotine outside of the context of smoking. Table3 summarizes the results from investigations of IV nicotine self-administration studies in adult cigarette smokers. In 1983, Henningfield and
colleagues62 examined IV nicotine self-administration in adult male
smokers. The total nicotine intake was described for each subject
for one dose (1.5mg/injection) during one session and ranged from
0.0180.027mg/kg. While neither the number of injections nor the
rate of responding across nicotine doses and saline were described,
the authors concluded that nicotine was, indeed, self-administered
and that when compared to saline, nicotine response patterns were
less variable and didnt decrease across sessions while saline injections did.62 In a second study,63 both nicotine self-administration and
avoidance of nicotine administration were evaluated in male smokers. The authors reported that nicotine maintained higher rates of
responding when compared to saline in some subjects (i.e., positive reinforcing effects maintained self-administration behavior) but
in other subjects, lower rates of responding were observed when
compared to saline (i.e., aversive effects of nicotine suppressed selfadministration behavior). Interestingly, subjects reported adverse
effects of nicotine (e.g., nausea, fear, coughing, and pain at injection
site) regardless of whether nicotine was maintaining or suppressing
self-administration behavior. In a subsequent experiment, subjects
that did not self-administer nicotine during initial sessions participated in sessions where they could respond to avoid nicotine injections and/or respond to self-inject nicotine. Programmed nicotine
injections occurred at specific intervals, but responding on one lever
prior to the injection turned off a stimulus light and canceled the
next injection (avoidance). Responding on another lever produced a
nicotine injection (self-administration). All three subjects that were
tested responded to avoid nearly all of the nicotine injections and
never responded to self-inject nicotine. Henningfield and his colleagues6264 were the first to demonstrate nicotine self-administration
in humans using an IV route of administration, but also that some
smokers would respond to avoid nicotine injections.
Rose and colleagues65 investigated the effects of pretreatment
with mecamylamine on IV nicotine self-administration in male and
female smokers. The doses per injection were individualized so that
they were comparable to the per-puff nicotine doses that subjects
obtained when freely smoking their usual cigarette brand during
baseline sessions. The study did not include a vehicle control condition for comparison of response rates to nicotine self-administration rates. When no mecamylamine was given, a mean of 3.4mg
(SD = 3.52) nicotine was self-administered. When mecamylamine
was given, a mean of 4.3mg (SD=3.17) nicotine was self-administered. The authors concluded that nicotinic receptors played a role
in the reinforcing effects of nicotine.65
Harvey and colleagues66 used a vehicle control condition in their
investigations of IV nicotine self-administration in male smokers and
clearly demonstrated nicotine-maintained responding above vehicle
in Table2 does not provide clear evidence that the rate of infusion
predicts the likelihood of IV nicotine self-administration in nonhuman primates.
In 2007, adult nave male squirrel monkeys with no prior
operant behavioral training, no food deprivation or concurrent
food self-administration, with no automatic (i.e., priming) injections of nicotine, but with the use of associated auditory and
visual stimuli, engaged in high rates of nicotine self-administration.50 Since rodent studies had suggested that the reinforcing effects of nicotine were, in part, due to its enhancing the
reinforcing effectiveness of environmental stimuli, 5153 a colored
stimulus light was paired with nicotine injections and a different colored light was paired with completion of the FR requirement on a second inactive lever. Responding on each lever
was compared to ascertain if nicotine injections were affected
by the presentation of the different stimuli. Subjects responded
significantly more on the lever associated with the nicotinepaired visual stimulus than on the lever paired with only a
visual stimulus. Thus, in the absence of behavioral and drug
histories and without employing facilitatory conditions (e.g.,
priming injections, food deprivation), nicotine was an effective
positive reinforcer in adult male squirrel monkeys. The ability
of IV nicotine injections to reinforce behavior in experimentally
nave subjects was shown to be similar to that of cocaine. 46 The
highest nicotine intake appears to have been approximately
0.35mg/kg during 1hr sessions. Later studies conducted by the
same research group reported an approximate average nicotine
intake of 1.5mg/kg during 1-hr sessions in adult male squirrel
monkeys. 5456 At this point, however, it is unknown whether IV
nicotine injections are reinforcing in the absence of changes in
associated visual and auditory stimuli in experimentally nave
nonhuman primate subjects.
Additional studies in nonhuman primates have focused on
assessing the preclinical efficacy of various pharmacological interventions to decrease or stop nicotine self-administration (e.g.,
medications development). For example, after demonstrating
that nicotine, cocaine, and combinations of nicotine and cocaine
maintained responding above vehicle levels in rhesus monkeys,57
the effects of chronic treatment with buspirone58 and varenicline59
on self-administration were examined. The effects of clofibrate,56
WY14643 and methOEA,55 and sertraline60 on nicotine self-administration have also been examined. As discussed below (Future
Directions), the reinforcing effects of non-nicotine tobacco product constituents (e.g., anatabine) are also being investigated in
squirrel monkeys.61
Thus, the body of literature in nonhuman primates confirms
that nicotine functions as a positive reinforcer when available
for self-administration via IV catheters (Table 1). Nicotine is
self-administered in multiple nonhuman primate species, in both
experienced and nave subjects, and across multiple experimental conditions (e.g., various schedules of reinforcement, timeout
periods, and duration of infusions). Nicotine self-administration,
however, can also be difficult to establish in nonhuman primates,
sometimes requiring supplemental strategies (e.g., priming injections or food deprivation) before subjects acquire the behavior.
Rates of nicotine self-injection can also be variable across subjects and inconsistent across sessions within a study. It has been
suggested that non-nicotine tobacco product constituents may
enhance the reinforcing effects of nicotine, or have reinforcing
effects on their own that contribute to maintaining nicotine
Thus, the body of literature examining the reinforcing effects of

nicotine in humans is limited. All studies in humans, however, have
reported that nicotine maintained self-injection behavior, indicating nicotine functions as a positive reinforcer via the IV route of
administration in adult cigarette smokers. Like studies in nonhuman
primates, however, the consistency of nicotine self-injection across
subjects and sessions can be variable and one study reported that
subjects responded to avoid nicotine injections.64 While the nonhuman primate data indicate nicotine is self-administered across
various experimental conditions (e.g., various schedules of reinforcement and timeout periods), the conditions under which nicotine is
self-injected by humans has been limited to the use of FR schedules
and choice procedures, and the use of short timeout periods. Like in
nonhuman primates, the infusion duration does not seem to play a
crucial role in maintaining nicotine self-injection in humans. While
the nonhuman primate data indicate environmental variables (e.g.,
stimulus lights) that are paired with nicotine injections may play a
critical role in maintaining nicotine self-injection, this has not been
examined in human subjects. In addition, the reinforcing effects of
nicotine are unknown in nave human subjects and only one study has
examined the effects of non-nicotine tobacco product constituents in
humans. Interestingly, the dose range of nicotine that functioned as
a positive reinforcer in humans (0.753.0mg/injection; translates to
0.00940.034mg/kg/injection in an 80kg subject) is similar to the
general dose range found to maintain nicotine self-administration in
nonhuman primates (general range of 0.0030.056mg/kg/injection).
The similarities between humans and nonhuman primates on measures of the reinforcing effects of IV self-administered nicotine suggest that nonhuman primate subjects are an especially useful model
for future investigations.
Future Directions
Threshold Reinforcing Doses of IV Nicotine
Reducing nicotine levels in tobacco products has been suggested as
a strategy for lowering the abuse liability and harm associated with
tobacco products.6974 The effects of both gradual and immediate
methods of nicotine dose reduction on nicotine self-administration
have been studied in rodents. For example, two schedules of nicotine dose reduction and their effects on maintenance of established
self-administration have been compared in rats.75 A gradual
reduction approach (nicotine doses were systematically lowered by
half approximately every 10 sessions after self-administration was
established) was compared with an immediate reduction approach
(nicotine doses were immediately lowered across sessions after selfadministration was established) and the results suggested similar
behavioral changes occurred with both methods. Both schedules
of nicotine dose reduction produced significant decreases in selfadministration behavior, accompanied by some temporary compensatory behavior.75 Thus, it is possible that lowering nicotine levels in
tobacco products may result in decreased exposure to nicotine and
other tobacco product constituents, and/or elimination of exposure
altogether via an extinction of smoking behavior, in a significant proportion of tobacco users. Indeed, the introduction of denicotinized
cigarettes to cigarette smokers in controlled laboratory conditions
resulted in decreased smoking behavior.76
There are two distinct phases of nicotine self-administration
(acquisition and maintenance) that may be used to investigate the
role of a threshold reinforcing nicotine dose. Reports in rodents generally indicate that higher unit doses of nicotine are required for
levels. Under a concurrent FR schedule of reinforcement, responding on one lever resulted in a nicotine injection and responding on
a different lever resulted in a saline injection.66 The number of injections was significantly greater for nicotine than for saline, though
there was a dose-dependent decrease in the number of nicotine injections at the highest dose tested. In addition, the effect of different FR
values (101600) and timeout length (120min) on lever responding were evaluated in some subjects. At the four upper FR values
(200, 400, 800, and 1600), nicotine maintained responding above
saline levels. No significant changes in response rate were associated
with the changes in timeout length. Harvey etal.66 were the first to
demonstrate a clear inverted-U dose-response curve for IV nicotine
self-administration and responding under a high FR requirement in
cigarette smokers.
IV nicotine self-administration was also compared to a vehicle
control condition in smokers in a study conducted by Sofuoglu and
colleagues.67 They were interested in doses of nicotine that resembled those expected to be delivered in a typical cigarette puff. During
experimental sessions, sample injections from each of two syringes
(saline and nicotine) were given, and subjects were then allowed to
choose between the two syringes (six choice opportunities/session).
The two highest doses of nicotine tested (0.4 and 0.7mg/injection)
were chosen more than saline.67
Preference for IV nicotine was compared to IV saline and to puffs
of denicotinized cigarette smoke and sham puffs by Rose and colleagues68 in smokers. Abaseline smoking session was used to identify the average nicotine dose smoked for each participant, followed
by two training sessions in which participants were trained to discriminate between IV nicotine or saline, and then between puffs of
denicotinized smoke and sham puffs. Lastly, four experimental sessions occurred in which choice behavior was characterized during
choice components of the sessions that followed satiation components. The four possible satiation conditions (one per session) were:
denicotinized cigarette puffs + IV nicotine injections; denicotinized
cigarette puffs + IV saline injections; sham puffs + IV nicotine injections; and sham puffs + IV saline injections. Satiation components
consisted of programmed administration of puffs and injections
based on each subjects unlimited smoking during baseline sessions.
During experimental sessions, the first component was a satiation
component, followed by a choice component, then a second satiation
component, a second choice component, a third satiation component, and then finally a third choice component. The first two choice
components provided a choice between only two alternatives: IV
nicotine versus IV saline or cigarette puffs versus sham puffs. The
third choice component provided all four alternatives. During choice
components, subjects controlled the number of puffs and injections.
Satiation components were 60min in duration and choice periods
were 10min in duration. When IV nicotine and IV saline injections
were available during either of the first two choice periods, participants demonstrated a significant preference for IV nicotine injections.
Denicotinized puffs were selected significantly more than sham puffs
during the first two choice conditions. When all four alternatives were
available, participants had a significant preference for denicotinized
cigarette puffs when compared to sham puffs, nicotine injections, and
saline injections. Thus, Rose etal.68 was the first study to compare the
reinforcing effects of non-nicotine tobacco components to those of
nicotine in humans. While denicotinized cigarette puffs were chosen
most often, this may be due to sensory cues associated with smoking
behavior (e.g., smell) or other pharmacologically active non-nicotine
tobacco product constituents (e.g., acetaldehyde).
Table3. Nicotine IV Self-Administration (SA) in Human Cigarette Smokers

Session
duration
Schedule
Time out
(mg/injection)
1983 Henningfield etal.62 male (n=6)
0.753.0a
3 hr
FR 10
1 min
unspecifiedd
1983 Henningfield and

Goldberg63,64
0.753.0b
3 hr
FR 10
1 min
unspecifiede
individualizeda,f
(0.040.15)
4 hr
FR 1
unspecified
unspecifiedg
0.753.0a
3 hr
FR 101600
120 min
0.753.0
0.10.7a
1.5 hr
choiceh
15 min
0.4, 0.7
individualizeda,f
(0.050.21)
3.5 hr
FR 1
nonei
Year
Authors
2003 Rose etal.65
2004 Harvey etal.66
2008 Sofuoglu etal.67
2010 Rose etal.68
Subjects
Subject history
smokers; previous drug

use (opioids, stimulants,
sedatives)
male (n=6)
use (social drinking,
polydrug use and
dependence)
male (n=7)
smokers; no other details
female (n=9)
about drug history
provided
male (n=8)
use (opioids, stimulants,
hallucinogens,
marijuana)
male (n=6)
smokers; participants had
female (n=4)
never met criteria for
abuse or dependence of
substances other than
nicotine
male (n=6)
smokers; no other details
female (n=10)
about drug history
provided
unspecified
Nicotine dose range expressed as the freebase.

c
d
Only select data were presented but the authors conclude that nicotine was self-administered in patterns that were related to the unit dose of nicotine and less
variable than saline.
e
Only select data were presented; nicotine maintained responding in some subjects in some experiments and responding to avoid nicotine injections was illustrated
in a separate experiment.
f
Doses of nicotine that were administered were individualized and calculated to be equal to a puff on the usual brand of cigarette during a baseline session.
g
No baseline condition (e.g., vehicle) was used for comparison to nicotine; authors were comparing pretreatment with a nicotinic acetylcholine channel antagonist
(mecamylamine) with placebo.
h
Choice of syringe (nicotine or saline) following samples of each.
i
Subjects were able to freely self-administer nicotine.
a
initiation/acquisition of IV nicotine self-administration relative to

doses that maintain self-administration once acquired (for review
see Donny et al.70). That is, there appears to be a lower reinforcement threshold for maintenance of nicotine self-administration in
rats trained with nicotine than for the acquisition of nicotine selfadministration in rats with no history of nicotine reinforcement.
Thus, it is possible that lowering nicotine levels in tobacco products
may result in fewer people initiating the behavior of nicotine selfadministration (e.g., smoking).
The effects of possible nicotine dose-reduction strategies on nicotine self-administration initiation and maintenance behavior have
not been characterized in nonhuman primates. It would be unethical
to study the threshold nicotine dose associated with initiation of nicotine self-administration in humans. It would be possible, however,
to examine the threshold reinforcing doses required to maintain IV
nicotine self-administration, along with the effectiveness of immediate and gradual nicotine reduction on IV nicotine self-administration. The design of these kinds of studies in humans would benefit
greatly from data obtained from a nonhuman primate species. In
addition, results from rodent and nonhuman primate studies would
be especially useful for informing human studies examining the
threshold reinforcing doses of nicotine required to maintain smoking
behavior in and out of a controlled laboratory setting, and the effects

of gradual and immediate reduction of nicotine content in cigarettes
on subsequent smoking behavior. Thus, addressing the following
experimental questions using human and nonhuman primate subjects may provide useful information for potential regulatory actions
regarding nicotine levels in tobacco products:
What is the threshold reinforcing dose of nicotine for acquisition
of IV self-administration in a nonhuman primate?
What is the threshold reinforcing dose of nicotine for the maintenance of IV self-administration in nonhuman and humans?
Are immediate or gradual nicotine dose reduction schedules
more effective at decreasing IV nicotine self-administration in
humans and nonhuman primates?
The IV Reinforcing Effects of Nicotine in Adolescents

Adolescence appears to be a particularly important and susceptible
developmental period regarding the initiation of substance abuse
and tobacco product use specifically. The initiation of tobacco product use occurs most often during adolescence77,78 and adult smokers
who began smoking during adolescence are significantly more likely
to become nicotine dependent than those who did not begin smoking
Dose range
(mg/injection)
10
Are there differences in the rates of acquisition of IV nicotine

self-administration in adolescent versus adult subjects?
Are there differences in response rates, patterns of responding,
or total number of injections across IV nicotine doses during
ongoing nicotine self-administration in adolescent versus adult
subjects?
Are there differences in threshold reinforcing doses of nicotine
during the acquisition and/or maintenance of IV nicotine selfadministration in adolescent versus adult subjects?
Are other outcome measures (e.g., pharmacokinetic outcomes)
correlated with behavioral differences in the acquisition and/or
maintenance of IV nicotine self-administration in adolescent versus adult subjects?
Non-Nicotine Tobacco Product Constituents

Of the thousands of compounds that can be found in tobacco products, nicotine is the primary alkaloid, accounting for approximately
96%98% of the total alkaloid content in tobacco.88 The remaining
2%4% is comprised of nornicotine, anabasine, anatabine, cotinine,
and myosmine.88 In addition, other tobacco constituents include
several aldehyde compounds (e.g., acetaldehyde, formaldehyde)89,90
and compounds that may act as monoamine oxidase inhibitors
(e.g., famesylacetone, harmane, norharmane).9193 The FDA has
established a list of harmful and potentially harmful constituents
(HPHCs) that are contained in tobacco products.95 The HPHC list
includes constituents that are banned from foods (applies only to
smokeless tobacco products), have been identified as known, probably or possible human carcinogens, produce adverse respiratory or
cardiac effects, produce developmental toxicity, or result in abuse
liability.94 The abuse potential of a constituent may be evidenced by
at least two of the following measures: central nervous system activity, animal drug discrimination, conditioned place preference, animal
self-administration, drug liking, or signs of withdrawal.94
There are currently 93 tobacco product constituents included on

the HPHC list, with four of those compounds designated as having abuse liability (acetaldehyde, anabasine, nicotine, and nornicotine). Acetaldehyde, which is also a metabolite of ethanol (and
has been studied in this context), maintains IV self-administration
in nave, adult, male rats.9599 One study has examined nornicotine
and reported it also maintained responding above vehicle levels in
experimentally nave adult male rats.100 Additionally, the reinforcing
effects of nicotine alone have been compared to those of nicotine in
combination with a mixture of other tobacco alkaloids (anabasine,
nornicotine, anatabine, cotinine and myosmine) in rodents. Adult
male rats receiving combinations of nicotine plus an alkaloid mixture responded significantly more when compared to those receiving
nicotine alone and to those receiving saline in combination with the
alkaloid mixture.101 Both nicotine groups (nicotine alone and nicotine with the alkaloid mixture) responded significantly more than the
saline group and the saline with the alkaloid mixture group. Since
the alkaloids were not tested individually, the interpretation of these
data is problematic. Cigarette smoke extract (CSE) was recently
reported to be more effective in both initiating and maintaining
self-administration when compared to nicotine alone in adult male
rats.102 However, the CSE-induced enhancement of the reinforcing effects of nicotine was dependent on the schedule of reinforcement since CSE was comparable to nicotine alone in maintaining
responding under a progressive-ratio schedule of reinforcement. In
addition, nornicotine (but not anabasine nor anatabine), was selfadministered above saline levels by adult male rats when substituted
for nicotine.103 Pre-treatment with each of these three alkaloids
dose-dependently decreased responding maintained by a range of
nicotine doses, and all three produced a nicotine-like discriminativestimulus effects in adult male mice.103 Only one study has evaluated
the reinforcing effects of a non-nicotine tobacco product constituent in nonhuman primates.61 In that study, a range of anatabine
doses (0.00320.32mg/kg/injection) was substituted for nicotine
(0.01mg/kg/injection) to examine its abuse potential and its efficacy
as a pretreatment for nicotine self-administration in adult rhesus
monkeys. Mello et al.61 reported that anatabine failed to maintain
responding above vehicle levels when substituted for nicotine in
nicotine-experienced animals. When given as a pretreatment, anatabine dose-dependently decreased responding maintained by a range
of nicotine self-injections (0.0010.01mg/kg/injection). Anatabine
pretreatment, however, also decreased food-maintained responding.
Despite the non-specific decreases in responding maintained by nicotine injections or food presentations, the authors concluded that the
data suggest anatabine may be useful for the treatment of nicotine
addiction.61 Nonetheless it is notable that the tobacco alkaloids are
not always nicotine-like or enhancers of the reinforcing effects of
nicotine.
There is additional evidence of the abuse liability of nonnicotine tobacco constituents using other behavioral procedures.
Conditioned place preference and drug discrimination procedures
in rodents indicate that acetaldehyde and nornicotine have considerable abuse potential (for review see Hoffman etal.104). In addition,
studies using drug discrimination procedures indicate the stimulus
effects produced by anabasine and cotinine dose-dependently substituted for the discriminative-stimulus effects of nicotine in adult
male rats trained to discriminate nicotine from saline.105,106 Only
one previous study has evaluated the nicotine-like discriminativestimulus effects of non-nicotine tobacco product constituents in nonhuman primates.107 Nornicotine and cotinine produced nicotine-like
until adulthood.7982 There is little evidence of initiation of tobacco

product use after the age of 24.77 Though the period of adolescence
in rats is relatively short (post-natal days 2855),83,84 some investigators have shown age-related susceptibility to the initiation of nicotine
self-administration in rats. More specifically, adolescent rats appear
to self-administer a wider range of nicotine doses significantly above
vehicle levels compared to adult rats regardless of gender.27,79,85,86
Additionally, peri-adolescent exposure to nicotine has been shown
to result in increased nicotine self-administration in adulthood when
compared to rats lacking such exposure.87 Thus, in rodents, it is possible that exposure to nicotine during adolescence may enhance the
subsequent rewarding/reinforcing effects of nicotine when exposure
occurs in adulthood. Comparisons of nicotine self-administration
between adolescents and adults have not been made in nonhuman
primates. Anonhuman primate species that experiences an extended
adolescent period (similar to humans) would be the more ideal species for comparisons of the effects of nicotine self-administration in
adolescent and adult subjects. Moreover, given the long life span of
nonhuman primates, studies on the long-term consequences of adolescent exposure to nicotine can more readily be undertaken using
nonhuman primate species. It would be unethical to administer nicotine to adolescent human subjects. Thus, addressing the following
experimental questions using nonhuman primate subjects will provide useful information for understanding the role of developmental
period in the initiation and continued use of tobacco products into
adulthood:

discriminative-stimulus effects in adult male squirrel monkeys.107
In contrast anabasine dose-dependently, but only partially (up to
approximately 50%), produced nicotine-like discriminative-stimulus
effects.107 Overall, given the vast number of constituents found in
tobacco products, very little research has examined the abuse potential of tobacco product constituents other than nicotine. Results
from rodent models should be used to inform future studies in nonhuman primates. Additionally, it is likely that non-nicotine tobacco
product constituents may alter the reinforcing effects of nicotine.
Since very few studies have examined the abuse potential or
behavioral effects of IV administered behaviorally active doses of
the vast majority of non-nicotine tobacco product constituents, it
would be unethical to examine such things in humans until data
from rodent and nonhuman primate studies have been reported.
Experimental questions about the abuse potential of non-nicotine
tobacco product constituents and their ability to alter the IV reinforcing effects of nicotine include:
11
Are there gender differences in the threshold dose of nicotine
required to maintain IV self-administration in adult humans and
nonhuman primates?
Are there gender differences during the initiation and or maintenance of IV nicotine self-administration in adolescent nonhuman
primates?
Are there gender differences in the correlation of other outcome
measures (e.g., pharmacokinetic outcomes) with IV nicotine selfadministration in adolescent and adult nonhuman primates and
humans?
Are there gender differences in the abuse potential of non-nicotine tobacco product constituents in adult and adolescent nonhuman primates?
Do individual non-nicotine tobacco product constituents alter
the reinforcing effects of nicotine differentially in adolescent and
adult male and female nonhuman primates?
Gender Differences
There is some evidence of gender differences in the reinforcing effects
of nicotine in laboratory animals and human smokers (for reviews
see Perkins etal.108 and Fattore etal.109). Female rats more quickly
acquired nicotine self-administration at lower doses and earned more
injections of nicotine on a progressive-ratio schedule compared to
male rats.110 In addition, increased nicotine self-administration was
more pronounced in male adolescent rats than in adolescent female
rats (compared to adult males and females), though the effect was
more persistent over time in females.27,79,85,111 In other studies, female
rats had higher rates of responding for presentations of a visual discriminative-stimulus without nicotine injections compared to male
rats.112,113 While a few nonhuman primate studies have used females
as subjects,33,47,59 no study has systematically compared females and
males on measures of the reinforcing effects of IV nicotine. Similarly,
human studies have sometimes included female subjects,67,68,114 but
a systematic comparison of the reinforcing effects of IV nicotine in
male and female subjects has not beendone.
Some gender comparisons of smoking behavior have been
reported. In female cigarette smokers, changes in the nicotine dose
contained in cigarettes had less of an effect on the reinforcing
properties of smoking when compared to male smokers,115 indicating female smokers may be less sensitive to the reinforcing effects
of nicotine in cigarettes. Conversely, female rodents110 and female
smokers116,117 may be more sensitive to non-pharmacological stimuli
associated with nicotine administration.
Thus, addressing all of the experimental questions posed
throughout the Future Directions section in male and female nonhuman primate and human subjects would provide useful information
for understanding the role of gender in the initiation and continued
use of tobacco products. More specifically:
Are there gender differences in the threshold dose of nicotine
required for the initiation of IV nicotine self-administration in
adult nonhuman primates?
In addition to the specific areas identified above using IV self-administration procedures in humans (i.e., threshold reinforcing dose
required to maintain IV nicotine self-administration, gender differences in the maintenance of IV nicotine self-administration, gender
differences in the correlation of other outcomes measures with IV
nicotine self-administration), there are other potentially useful areas
that may be applicable to human subjects including:
What is the threshold reinforcing dose of IV nicotine that maintains smoking behavior in humans under controlled laboratory
settings versus naturalistic conditions?
Are immediate or gradual IV nicotine dose reduction schedules
more effective at decreasing smoking behavior in humans?
As noted above, the effects of behaviorally active doses of the vast
majority of non-nicotine tobacco product constituents are not known
and these compounds, at behaviorally active doses, should not be
examined in humans in the absence of data from animal studies. Also
described previously, however, one study compared denicotinized cigarettes to IV nicotine in humans,68 allowing the reinforcing effects of a
combination of non-nicotine tobacco product components to be examined in humans. Recently, the reinforcing effects of cigarette smoke
extract have been examined in rodents102 and future studies in humans
(and nonhuman primates) may find this approach useful for comparing the reinforcing effects of IV nicotine with cigarette smoke extract.
Summary
In summary, studies of IV nicotine self-administration procedures in
nonhuman primates and humans are particularly useful for addressing several relevant research questions aimed at providing an empirical basis for informing tobacco product regulation. The body of
literature indicates that nicotine functions as a positive reinforcer
when available for self-injection in nonhuman primates and human
cigarette smokers. Further research using nonhuman primates examining the threshold reinforcing doses of IV nicotine that are required
to initiate and maintain self-administration, comparing the reinforcing effects of nicotine in adolescent versus adult subjects and male
versus female subjects, investigating the abuse potential of non-nicotine tobacco product constituents, and evaluating the effects that
non-nicotine tobacco product constituents may have on the reinforcing effects of nicotine will inform the FDA in its mission to promote
public health through the regulation of tobacco products.
Human Studies of the Reinforcing Effects of Nicotine

Do individual non-nicotine tobacco product constituents have IV
reinforcing effects (i.e., are they self-administered) in nonhuman
primate subjects?
Do individual non-nicotine tobacco product constituents alter the
reinforcing effects of IV nicotine in nonhuman primate subjects?
12
Funding
U.S. Food and Drug Administration/Center for Tobacco Products (NCTR
Protocol E07537-01).
Declaration of Interests
None declared.
Acknowledgments
The information in these materials is not a formal dissemination of information by the FDA and does not represent agency position or policy.
References
Service, U.S. Department of Health, Education, and Welfare; 1974. http://

profiles.nlm.nih.gov/NN/B/B/Q/N/. Accessed December 22, 2014.
14. Benowitz NL, Jacob P III. Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther. 1984;35:499504.

15. Benowitz NL, Jacob P III. Intravenous nicotine replacement suppresses nicotine intake from cigarette smoking. J Pharmacol Exp Ther.
1990;254:10001005. http://jpet.aspetjournals.org/content/254/3/1000.
long. Accessed December 22, 2014.
16. Hukkanen J, Jacob P III, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 2005;57:79115.
17. Kozlowski LT, Mehta NY, Sweeney CT, etal. Filter ventilation and nicotine content of tobacco in cigarettes from Canada, the United Kingdom,
and the United States. Tob Control. 1998;7:369375.
18. Matta SG, Balfour DJ, Benowitz NL, etal. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl). 2007;190:269319.
19. Ator NA, Griffiths RR. Principles of drug abuse liability assessment in
laboratory animals. Drug Alcohol Depend. 2003;70:S5572.
20. Carter LP, Stitzer ML, Henningfield JE, OConnor RJ, Cummings KM,
Hatsukami DK. Abuse liability assessment of tobacco products including
potential reduced exposure products. Cancer Epidemiol Biomarkers Prev.
2009;18:32413262.
21. Haney M, Spealman R. Controversies in translational research: drug selfadministration. Psychopharmacology (Berl). 2008;199:403419.

22. Horton DB, Potter DM, Mead AN. A translational pharmacology
approach to understanding the predictive value of abuse potential assessments. Behav Pharmacol. 2013;24:410436.
23. Le Foll B, Goldberg SR. Effects of nicotine in experimental animals and
humans: an update on addictive properties. Handb Exp Pharmacol.
2009;192:335367. doi: 10.1007/978-3-540-69248-5_12.
24. Dar R, Frenk H. Nicotine self-administration in animals: a reevaluation.
Addict Res Theory. 2002;10:545579.
25. Caille S, Clemens K, Stinus L, Cador M. Modeling nicotine addiction in
rats. Methods Mol Biol. 2012;829:243256.
26. LeSage MG, Perry JL, Kotz CM, Shelley D, Corrigall WA. Nicotine selfadministration in the rat: effects of hypocretin antagonists and changes in
hypocretin mRNA. Psychopharmacology (Berl). 2010;209:203212.
27. Levin ED, Slade S, Wells C, et al. Threshold of adulthood for the onset
of nicotine self-administration in male and female rats. Behav Brain Res.
2011;225:473481.
28. Liu X. Positive allosteric modulation of alpha4beta2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from
a rat model of nicotine self-administration. Psychopharmacology (Berl).
2013;230:203213.

29.
Liu X, Caggiula AR, Yee SK, et al. Mecamylamine attenuates
cue-induced reinstatement of nicotine-seeking behavior in rats.
Neuropsychopharmacology. 2007;32:710718.
30. ODell LE, Khroyan TV. Rodent models of nicotine reward: what do
they tell us about tobacco abuse in humans? Pharmacol Biochem Behav.
2009;91:481488.
31. Deneau GA, Inoki R. Nicotine self-administration in monkeys. Ann N Y
Acad Sci. 1967;142:277279.
32. Yanagita T. Brief review on the use of self-administration techniques for
predicting drug dependence potential. In: Thompson T, Unna KR, eds.
Predicting Dependence Liability of Stimulant and Depressant Drugs.
Baltimore, MD: University Park Press; 1977:231242.
33. Yanagita T, Ando K, Kato S, Takada K. Psychopharmacological studies on
nicotine and tobacco smoking in rhesus monkeys. Psychopharmacol Bull.
1983;19:409412.
34. Meisch RA, Lemaire GA. Drug self-administration. In: Van Haaren F, ed.
Methods in Behavioral Pharmacology. Vol 10. New York, NY: Elsevier;
1993:257293.
35. Griffiths RR, Brady JV, Bradford LD. Predicting the abuse liability of drugs
with animal drug self-administration procedures: psychomotor stimulants
and hallucinogens. In: Thompson T, Dews PB, eds. Advances in behavioral
pharmacology. Vol 2. New York, NY: Academic Press; 1979:163208.
1. Centers for Disease Control and Prevention. Smoking & Tobacco Use,
Data and Statistics, Fact Sheets. 2012. http://www.cdc.gov/tobacco/data_
statistics/fact_sheets/index.htm. Accessed December 22, 2014.

2. Centers for Disease Control and Prevention. Preventing Tobacco Use
Among Young and Young Adults: A Report of the Surgeon General.
Atlanta, GA: U.S. Department of Health and Human Services, Centers
for Disease Control and Prevention, National Center for Chronic Disease
Prevention and Health Promotion, Office on Smonking and Health; 2012.
http://www.surgeongeneral.gov/library/reports/preventing-youth-tobaccouse/. Accessed December 22, 2014.
3. Jha P, Ramasundarahettige C, Landsman V, etal. 21st-century hazards of
smoking and benefits of cessation in the United States. N Engl J Med.
2013;368:341350.
4. Centers for Disease Control and Prevention. The Health Consequences of
Smoking: 50 Years of Progress. AReport of the Surgeon General. Atlanta,
GA: U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention, National Center for Chronic Disease Prevention
and Health Promotion, Office on Smoking and Health; 2014. http://
www.surgeongeneral.gov/library/reports/50-years-of-progress/. Accessed
December 22, 2014.
5. Family Smoking Prevention and Tobacco Control Act, Pub. L.No. 111
31; 2009. http://www.gpo.gov/fdsys/pkg/PLAW-111publ31/pdf/PLAW111publ31.pdf. Accessed December 22, 2014.
6. Ashley DL, Backinger CL. The Food and Drug Administrations regulation
of tobacco: the Center for Tobacco Products Office of Science. Am J Prev
Med. 2012;43(suppl 3):S255263.
7. Centers for Disease Control and Prevention. The Health Consequences of
Smoking: Nicotine Addiction. Rockville, MD: US Department of Health
and Human Services Centers for Disease Control, Office on Smoking
and Health; 1988. http://profiles.nlm.nih.gov/ps/access/NNBBZD.pdf.
Accessed December 22, 2014.
8. Henningfield JE, Heishman SJ. The addictive role of nicotine in tobacco
use. Psychopharmacology (Berl). 1995;117:1113.
9. Hurt RD, Robertson CR. Prying open the door to the tobacco industrys secrets about nicotine: the Minnesota Tobacco Trial. JAMA.
1998;280:11731181.
10. Stolerman IP, Shoaib M. The neurobiology of tobacco addiction. Trends
Pharmacol Sci. 1991;12:467473.
11. Henningfield JE, Goldberg SR. Progress in understanding the relationship between the pharmacological effects of nicotine and human tobacco
dependence. Pharmacol Biochem Behav. 1988;30:217220.
12. Centers for Disease Control and Prevention. Smoking and Health: Report
of the Advisory Committee to the Surgeon General of the Public Health
Service. Washington, DC: Public Health Service, U.S. Department of
Health, Education, and Welfare; 1964. http://profiles.nlm.nih.gov/NN/B/
B/M/Q/. Accessed December 22, 2014.
13. Centers for Disease Control and Prevention. The Health Consequences
of Smoking. Washington, DC: Center for Disease Control, Public Health
59. Mello NK, Fivel PA, Kohut SJ, Carroll FI. Effects of chronic varenicline
treatment on nicotine, cocaine, and concurrent nicotine+cocaine selfadministration. Neuropsychopharmacology. 2014;39:12221231.
60. Sannerud CA, Prada J, Goldberg DM, Goldberg SR. The effects of sertraline on nicotine self-administration and food-maintained responding in
squirrel monkeys. Eur J Pharmacol. 1994;271:461469.
61. Mello NK, Fivel PA, Kohut SJ, Caine SB. Anatabine significantly decreases
nicotine self-administration. Exp Clin Psychopharmacol. 2014;22:18.
62. Henningfield JE, Miyasato K, Jasinski DR. Cigarette smokers self-administer intravenous nicotine. Pharmacol Biochem Behav. 1983;19:887890.

63. Henningfield JE, Goldberg SR. Control of behavior by intravenous
nicotine injections in human subjects. Pharmacol Biochem Behav.
1983;19:10211026.
64. Henningfield JE, Goldberg SR. Nicotine as a reinforcer in human subjects
and laboratory animals. Pharmacol Biochem Behav. 1983;19:989992.
65. Rose JE, Behm FM, Westman EC, et al. PET studies of the influences
of nicotine on neural systems in cigarette smokers. Am J Psychiatry.
2003;160:323333.
66. Harvey DM, Yasar S, Heishman SJ, Panlilio LV, Henningfield JE, Goldberg SR.
Nicotine serves as an effective reinforcer of intravenous drug-taking behavior
in human cigarette smokers. Psychopharmacology (Berl). 2004;175:134142.
67. Sofuoglu M, Yoo S, Hill KP, Mooney M. Self-administration of intravenous
nicotine in male and female cigarette smokers. Neuropsychopharmacology.
2008;33:715720.

68. Rose JE, Salley A, Behm FM, Bates JE, Westman EC. Reinforcing
effects of nicotine and non-nicotine components of cigarette smoke.
Psychopharmacology (Berl). 2010;210:112.
69. Benowitz NL, Henningfield JE. Reducing the nicotine content to make
cigarettes less addictive. Tob Control. 2013;22(suppl 1):i1417.
70. Donny EC, Taylor TG, LeSage MG, etal. Impact of tobacco regulation on
animal research: new perspectives and opportunities. Nicotine Tob Res.
2012;14:13191338.
71. Gray N, Henningfield JE, Benowitz NL, et al. Toward a comprehensive
long term nicotine policy. Tob Control. 2005;14:161165.
72. Hatsukami DK, Perkins KA, Lesage MG, etal. Nicotine reduction revisited: science and future directions. Tob Control. 2010;19:e110.
73. Hatsukami DK, Benowitz NL, Donny E, Henningfield J, Zeller M. Nicotine
reduction: strategic research plan. Nicotine Tob Res. 2013;15:10031013.
74. Sofuoglu M, LeSage MG. The reinforcement threshold for nicotine as a
target for tobacco control. Drug Alcohol Depend. 2012;125:17.
75. Smith TT, Levin ME, Schassburger RL, Buffalari DM, Sved AF, Donny
EC. Gradual and immediate nicotine reduction result in similar low-dose
nicotine self-administration. Nicotine Tob Res. 2013;15:19181925.
76. Donny EC, Houtsmuller E, Stitzer ML. Smoking in the absence of nicotine:
behavioral, subjective and physiological effects over 11days. Addiction.
2007;102:324334.
77. Pierce JP, White VM, Emery SL. What public health strategies are needed
to reduce smoking initiation? Tob Control. 2012;21:258264.
78. Substance Abuse and Mental Health Services Administration. Results
from the 2010 National Survey on Drug Use and and Health: Summary
of National Findings. In: HHS, ed. Vol NSDUH Series H-41. Rockville,
MD: Substance Abuse and Mental Health Services Administration; 2010.
http://atforum.com/documents/NSDUH2010.pdf. Accessed December
22, 2014.
79. Levin ED, Lawrence SS, Petro A, etal. Adolescent vs. adult-onset nicotine
self-administration in male rats: duration of effect and differential nicotinic receptor correlates. Neurotoxicol Teratol. 2007;29:458465.
80. Kendler KS, Myers J, Damaj MI, Chen X. Early smoking onset and risk
for subsequent nicotine dependence: a monozygotic co-twin control study.
Am J Psychiatry. 2013;170:408413.
81. Moolchan ET, Ernst M, Henningfield JE. A review of tobacco smoking in
adolescents: treatment implications. J Am Acad Child Adolesc Psychiatry.
2000;39:682693.
82. Riggs NR, Chou CP, Li C, Pentz MA. Adolescent to emerging adulthood smoking trajectories: when do smoking trajectories diverge, and do they predict
early adulthood nicotine dependence? Nicotine Tob Res. 2007;9:11471154.

36.
Ator NA, Griffiths RR. Nicotine self-administration in baboons.
Pharmacol Biochem Behav. 1983;19:9931003.
37. Goldberg SR, Spealman RD, Goldberg DM. Persistent behavior at high
rates maintained by intravenous self-administration of nicotine. Science.
1981;214:573575. http://www.sciencemag.org/content/214/4520/573.
long. Accessed December 22, 2014.

38. Goldberg SR, Spealman RD. Maintenance and suppression of behavior by intravenous nicotine injections in squirrel monkeys. Fed Proc.
1982;41:216220.
39. Spealman RD, Goldberg SR. Maintenance of schedule-controlled behavior
by intravenous injections of nicotine in squirrel monkeys. J Pharmacol Exp
Ther. 1982;223:402408. http://jpet.aspetjournals.org/content/223/2/402.
full.pdf+html. Accessed December 22, 2014.
40. Dougherty J, Miller D, Todd G, Kostenbauder HB. Reinforcing and other
behavioral effects of nicotine. Neurosci Biobehav Rev. 1981;5:487495.
41. Slifer BL. Schedule-induction of nicotine self-administration. Pharmacol
Biochem Behav. 1983;19:10051009.
42. Slifer BL, Balster RL. Intravenous self-administration of nicotine: with and
without schedule-induction. Pharmacol Biochem Behav. 1985;22:6169.
43. de la Garza R, Johanson CE. The effects of food deprivation on the
self-administration of psychoactive drugs. Drug Alcohol Depend.
1987;19:1727.
44. Balster RL, Schuster CR. Fixed-interval schedule of cocaine reinforcement:
effect of dose and infusion duration. J Exp Anal Behav. 1973;20:119129.
45. Beardsley PM, Balster RL. The effects of delay of reinforcement and dose
on the self-administration of cocaine and procaine in rhesus monkeys.
Drug Alcohol Depend. 1993;34:3743.
46. Galuska CM, Woods JH. Acquisition of cocaine self-administration with
unsignaled delayed reinforcement in rhesus monkeys. J Exp Anal Behav.
2005;84:269280.
47. Wakasa Y, Takada K, Yanagita T. Reinforcing effect as a function of infusion speed in intravenous self-administration of nicotine in rhesus monkeys. Nihon Shinkei Seishin Yakurigaku Zasshi. 1995;15:5359.
48. Gould RW, Czoty PW, Nader SH, Nader MA. Effects of varenicline on
the reinforcing and discriminative stimulus effects of cocaine in rhesus
monkeys. J Pharmacol Exp Ther. 2011;339:678686.

49. Freeman KB, Woolverton WL. Self-administration of cocaine and
nicotine mixtures by rhesus monkeys. Psychopharmacology (Berl).
2009;207:99106.
50. Le Foll B, Wertheim C, Goldberg SR. High reinforcing efficacy of nicotine
in non-human primates. PLoS One. 2007;2:e230.

51. Caggiula AR, Donny EC, White AR, et al. Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav.
2001;70:515530.
52. Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved
AF. Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav. 2002;77:683687.
53. Donny EC, Chaudhri N, Caggiula AR, etal. Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications
for nicotine self-administration and reinforcement. Psychopharmacology
(Berl). 2003;169:6876.
54. Justinov Z, Yasar S, Redhi GH, Goldberg SR. The endogenous cannabinoid 2-arachidonoylglycerol is intravenously self-administered by squirrel
monkeys. J Neurosci. 2011;31:70437048.
55. Mascia P, Pistis M, Justinova Z, et al. Blockade of nicotine reward and
reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry. 2011;69:633641.
56. Panlilio LV, Justinova Z, Mascia P, et al. Novel use of a lipid-lowering
fibrate medication to prevent nicotine reward and relapse: preclinical findings. Neuropsychopharmacology. 2012;37:18381847.
57. Mello NK, Newman JL. Discriminative and reinforcing stimulus effects of
nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.
Exp Clin Psychopharmacol. 2011;19:203214.

58. Mello NK, Fivel PA, Kohut SJ. Effects of chronic buspirone treatment on nicotine and concurrent nicotine+cocaine self-administration.
Neuropsychopharmacology. 2013;38:12641275.
13
14
101. Clemens KJ, Caill S, Stinus L, Cador M. The addition of five minor
tobacco alkaloids increases nicotine-induced hyperactivity, sensitization
and intravenous self-administration in rats. Int J Neuropsychopharmacol.
2009;12:13551366.
102. Costello MR, Reynaga DD, Mojica CY, Zaveri N, Belluzzi JD, Leslie
FM. Comparison of the reinforcing properties of nicotine and cigarette smoke extract in rats [published online ahead of print 2014].
Neuropsychopharmacology. doi: 10.1038/npp.2014.31.

103. Caine SB, Collins GT, Thomsen M, Wright C, Lanier RK, Mello
NK. Nicotine-like behavioral effects of the minor tobacco alkaloids
nornicotine, anabasine, and anatabine in male rodents. Exp Clin
Psychopharmacol. 2014;22:922.

104. Hoffman AC, Evans SE. Abuse potential of non-nicotine tobacco
smoke components: acetaldehyde, nornicotine, cotinine, and anabasine.
Nicotine Tob Res. 2013;15:622632.
105. Brioni JD, Kim DJ, ONeill AB, Williams JE, Decker MW. Clozapine
attenuates the discriminative stimulus properties of (-)-nicotine. Brain
Res. 1994;643:19.
106. Goldberg SR, Risner ME, Stolerman IP, Reavill C, Garcha HS. Nicotine
and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats. Psychopharmacology (Berl).
1989;97:295302.

107. Takada K, Swedberg MD, Goldberg SR, Katz JL. Discriminative
stimulus effects of intravenous l-nicotine and nicotine analogs
or metabolites in squirrel monkeys. Psychopharmacology (Berl).
1989;99:208212.
108. Perkins KA, Donny E, Caggiula AR. Sex differences in nicotine effects
and self-administration: review of human and animal evidence. Nicotine
Tob Res. 1999;1:301315.

109. Fattore L, Altea S, Fratta W. Sex differences in drug addiction: a
review of animal and human studies. Womens Health (Lond Engl).
2008;4:5165.
110. Donny EC, Caggiula AR, Rowell PP, etal. Nicotine self-administration
in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology (Berl). 2000;151:392405.

111. Levin ED, Lawrence S, Petro A, Horton K, Seidler FJ, Slotkin TA.
Increased nicotine self-administration following prenatal exposure in
female rats. Pharmacol Biochem Behav. 2006;85:669674.

112. Chaudhri N, Caggiula AR, Donny EC, et al. Sex differences in
the contribution of nicotine and nonpharmacological stimuli to
nicotine self-administration in rats. Psychopharmacology (Berl).
2005;180:258266.
113. Grebenstein P, Burroughs D, Zhang Y, LeSage MG. Sex differences in
nicotine self-administration in rats during progressive unit dose reduction: implications for nicotine regulation policy. Pharmacol Biochem
Behav. 2013;114115:7081.
114. Rose JE, Behm FM, Westman EC, Bates JE. Mecamylamine acutely
increases human intravenous nicotine self-administration. Pharmacol
Biochem Behav. 2003;76:307313.

115. Perkins KA, Jacobs L, Sanders M, Caggiula AR. Sex differences
in the subjective and reinforcing effects of cigarette nicotine dose.
116. Perkins KA, Gerlach D, Vender J, Grobe J, Meeker J, Hutchison S. Sex
differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine Tob Res. 2001;3:141150.
117. Perkins KA, Doyle T, Ciccocioppo M, Conklin C, Sayette M, Caggiula
A. Sex differences in the influence of nicotine dose instructions on
the reinforcing and self-reported rewarding effects of smoking.
83. Goodwin AK, Lantz-McPeak SM, Robinson BL, Law CD, Ali SF, Ferguson
SA. Effects of adolescent treatment with nicotine, harmane, or norharmane
in male SpragueDawley rats. Neurotoxicol Teratol. 2015;47:2535.
84. Spear LP. The adolescent brain and age-related behavioral manifestations.
Neurosci Biobehav Rev. 2000;24:417463.

85. Levin ED, Rezvani AH, Montoya D, Rose JE, Swartzwelder HS.
Adolescent-onset nicotine self-administration modeled in female rats.
86. Natividad LA, Torres OV, Friedman TC, ODell LE. Adolescence is a
period of development characterized by short- and long-term vulnerability
to the rewarding effects of nicotine and reduced sensitivity to the anorectic
effects of this drug. Behav Brain Res. 2013;257:275285.
87. Adriani W, Spijker S, Deroche-Gamonet V, etal. Evidence for enhanced
neurobehavioral vulnerability to nicotine during periadolescence in
rats. J Neurosci. 2003;23:47124716. http://www.jneurosci.org/content/23/11/4712.long. Accessed December 22, 2014.
88. Huang HY, Hsieh SH. Analyses of tobacco alkaloids by cation-selective
exhaustive injection sweeping microemulsion electrokinetic chromatography. J Chromatogr A. 2007;1164:313319.
89. Houlgate PR, Dhingra KS, Nash SJ, Evans WH. Determination of formaldehyde and acetaldehyde in mainstream cigarette smoke by highperformance liquid chromatography. Analyst. 1989;114:355360.
90. Xie J, Yin J, Sun S, Xie F, Zhang X, Guo Y. Extraction and derivatization
in single drop coupled to MALDI-FTICR-MS for selective determination of small molecule aldehydes in single puff smoke. Anal Chim Acta.
2009;638:198201.
91. Castagnoli K, Steyn SJ, Magnin G, etal. Studies on the interactions of
tobacco leaf and tobacco smoke constituents and monoamine oxidase.
Neurotox Res. 2002;4:151160.
92. Herraiz T, Chaparro C. Human monoamine oxidase is inhibited by
tobacco smoke: beta-carboline alkaloids act as potent and reversible
inhibitors. Biochem Biophys Res Commun. 2005;326:378386.
93.
Poindexter EH Jr, Carpenter RO. The isolation of harmane and
norharmance from tobacco and cigarette smoke. Phytochemistry.
1962;1:215221.
94. U.S. Food and Drug Administration. Harmful and Potentially Harmful
Constituents in Tobacco Products and Tobacco Smoke; Established
List. In: HHS, ed. FDA2012N01432012. U.S. Food and Drug
Administration;
2012.
http://www.fda.gov/tobaccoproducts/guidancecomplianceregulatoryinformation/ucm297786.Htm.
Accessed
December 22, 2014.
95. Myers WD, Ng KT, Singer G. Intravenous self-administration of acetaldehyde in the rat as a function of schedule, food deprivation and photoperiod. Pharmacol Biochem Behav. 1982;17:807811.
96. Myers WD, Ng KT, Singer G. Effects of naloxone and buprenorphine
on intravenous acetaldehyde self-injection in rats. Physiol Behav.
1984;33:449455.
97. Myers WD, Ng KT, Marzuki S, Myers RD, Singer G. Alteration of alcohol drinking in the rat by peripherally self-administered acetaldehyde.
Alcohol. 1984;1:229236.
98. Myers WD, Ng KT, Singer G, Smythe GA, Duncan MW. Dopamine
and salsolinol levels in rat hypothalami and striatum after scheduleinduced self-injection (SISI) of ethanol and acetaldehyde. Brain Res.
1985;358:122128.
99. Takayama S, Uyeno ET. Intravenous self-administration of ethanol and
acetaldehyde by rats. Yakubutsu Seishin Kodo. 1985;5:329334.
100. Bardo MT, Green TA, Crooks PA, Dwoskin LP. Nornicotine is selfadministered intravenously by rats. Psychopharmacology (Berl).
1999;146:290296.

tmpD2C8 TMP

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

tmpD2C8 TMP

Uploaded by

Copyright:

Available Formats

Nicotine & Tobacco Research Advance Access published February 10, 2015

Nicotine & Tobacco Research, 2015, 114

The Reinforcing Effects of Nicotine in Humans

Amy K.Goodwin PhD, TakatoHiranita PhD, Merle G.Paule PhD

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

to regulate the manufacture, marketing, and distribution of tobacco

Goldberg and Spealman38

Spealman and Goldberg39

Ator and Griffiths36

Slifer and Balster42

De La Garza and Johanson43 rhesus

not described (n=3)

drug and food SA (n=3);

cocaine SA (n=2); food SA

drug and food SA (n=15)

Deneau and Inoki31

2hr or 50 injections FI (5min)

2hr or 10 injections FI (5min)

nicotine substituted for saline;

nicotine substituted for cocaine; w/

priming injections when

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

Table1. Nicotine IV Self-Administration (SA) in Nonhuman Primates

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

Freeman and Woolverton49

cocaine and food

drug SA (n=4); no drug

16hr or 2hr w/o

6hr or 0.5hr w/o

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

distinct visual stimulus paired w/

FI=fixed-interval schedule of reinforcement; FR=fixed-ratio schedule of reinforcement; PR=progressive-ratio schedule of reinforcement.

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

Acomparison of responding under both an FI and the second-order

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

unlimited food access. A3-hr timeout period followed each nicotine

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

Infusion Infusion rate

Ator and Griffiths35

De La Garza and Johanson43

Nicotine dose range expressed as the free base.

injection) was increased (slower infusion speed), the average rates of

schedule used by Wakasa et al.47 and the FR-2 schedule used by

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

self-administration behavior via smoking. Thus, it is possible that

IV Self-Administration of Nicotine inHumans

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

Thus, the body of literature examining the reinforcing effects of

Downloaded from http://ntr.oxfordjournals.org/ at FDA Library on February 11, 2015

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

Nicotine & Tobacco Research, 2015, Vol. 00, No. 00

Table3. Nicotine IV Self-Administration (SA) in Human Cigarette Smokers

1983 Henningfield etal.62 male (n=6)

1983 Henningfield and

2003 Rose etal.65

2004 Harvey etal.66

2008 Sofuoglu etal.67

2010 Rose etal.68

smokers; previous drug

Nicotine dose range expressed as the freebase.