Download Chapter 1 - Overview of Nicotine Withdrawal and Negative

C H A P T E R
1
Overview of Nicotine
Withdrawal and Negative
Reinforcement (Preclinical)
O. George1, G.F. Koob1,2,3
1The
Scripps Research Institute, La Jolla, CA, United States; 2National
Institute on Drug Abuse, Baltimore, MD, United States; 3National Institute
on Alcohol Abuse and Alcoholism, Rockville, MD, United States
INTRODUCTION
Studies on the neurobiological substrates of tobacco addiction largely
depend on the availability of suitable animal models. In this review, we
first describe the features of tobacco smoking and nicotine abuse and
dependence in humans and animal models. We then discuss the roles
of positive and negative reinforcement in nicotine use and dependence.
Lastly, we provide an overview of the possible neurobiological mechanisms of nicotine that underlie positive and negative reinforcement.
TOBACCO DEPENDENCE AND NICOTINE
Tobacco smoking is the leading avoidable cause of disease and premature death in the United States, and it is responsible for over 480 000 deaths
annually (Agaku, King, & Dube, 2014) and USD$289 billion in direct
healthcare costs and productivity losses each year. Smoking is implicated
in ∼70% of deaths from lung cancer, ∼80% of deaths from chronic obstructive pulmonary disease, and ∼50% of deaths from respiratory disease
(Agaku et al., 2014). Much evidence indicates that individuals use tobacco
primarily to experience the psychopharmacological properties of nicotine
and that a large proportion of smokers eventually become dependent on
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Negative Affective States and Cognitive Impairments in Nicotine Dependence
http://dx.doi.org/10.1016/B978-0-12-802574-1.00001-6
© 2017 Elsevier Inc. All rights reserved.
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1. OVERVIEW OF NICOTINE WITHDRAWAL AND NEGATIVE REINFORCEMENT
nicotine, significantly contributing to the motivation to smoke (Balfour,
1984; Stolerman, 1991). An estimated 13.7% of the US population age 18
and over smoked every day in the past month (Agaku et al., 2014). Electronic cigarette use has rapidly grown in the general population, further
emphasizing the key role of nicotine in tobacco dependence (Palazzolo,
2013). According to the latest report from Bloomberg Industries, the combined sales of electronic cigarettes have doubled every year for the past
5 years, generating over USD$1 billion in revenue in the United States
in 2014. The sale of electronic cigarettes is predicted to pass that of traditional cigarettes by 2047. Moreover, electronic cigarettes are marketed
and viewed by the general public as safe because they do not produce
compounds other than nicotine. However, considering the high level of
nicotine in electronic cigarette vapor (∼500–750 mg/m3; Goniewicz, Hajek,
& McRobbie, 2014), such nicotine intake likely has profound effects on the
brain that can facilitate the transition to tobacco dependence, particularly
in adolescents. Indeed, preliminary reports demonstrated that high levels
of nicotine vapor exposure alone can lead to increased dependence and
motivation to take nicotine in rodent models (George, Grieder, Cole, &
Koob, 2010; Gilpin et al., 2014). The pervasiveness of tobacco use and the
rapid growth of electronic cigarettes associated with the extensive costs to
smokers and society provide a compelling basis for elucidating the actions
of nicotine within the central nervous system that lead to potential neuroadaptations in the motivational systems that mediate the development of
dependence and withdrawal symptoms.
THEORETICAL FRAMEWORK
Nicotine addiction can be defined as a chronic, relapsing disorder that
has been characterized by a compulsion to seek and take nicotine, loss of
control over nicotine intake, and emergence of a negative emotional state
(eg, dysphoria, anxiety, and/or irritability) that defines a motivational
withdrawal syndrome when access to nicotine is prevented (Koob & Le
Moal, 2008). Addiction has been conceptualized as a three-stage cycle—
binge/intoxication, withdrawal/negative affect, and preoccupation/
anticipation—that worsens over time and involves allostatic changes in
the brain reward and stress systems. Two primary sources of reinforcement, positive and negative reinforcement, have been hypothesized to
play a role in this allostatic process (Fig. 1.1A). The term reinforce means
“to strengthen” and refers to any stimulus (reinforcer) that increases the
probability of a specific response that follows. Positive reinforcement is
defined as the process by which the presentation of a stimulus increases the
probability of a response. Negative reinforcement is defined as the process
by which removal of an aversive stimulus (or aversive state of withdrawal
Theoretical Framework
3
FIGURE 1.1 Motivational mechanisms in nicotine dependence. (A) Change in the relative contribution of positive and negative reinforcement constructs and associated changes
in homeostatic and allostatic set points during the development of nicotine dependence.
(B) Constructs associated with positive and negative reinforcement.
in the case of addiction) increases the probability of a response. In the case
of nicotine use and dependence, nicotine is the positive reinforcer, and the
negative affective state of nicotine withdrawal is the negative reinforcer
(Fig. 1.1B).
Nicotine acts as a positive reinforcer in only a very narrow dose range
in both humans and rodents. Moderate to high doses of nicotine can be
aversive, particularly in nondependent subjects, producing conditioned
place aversion and leading to decreases in nicotine self-administration
(Fowler & Kenny, 2014). From an experimental psychology perspective, at a high dose, nicotine can be considered an aversive stimulus that
produces punishing effects that lead to a decrease in the probability of
nicotine self-administration (Goldberg & Spealman, 1983; Koffarnus &
Winger, 2015). The roles of positive reinforcement, negative reinforcement, and punishment are key to understanding nicotine use and the
development of nicotine addiction. This review mainly focuses on
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1. OVERVIEW OF NICOTINE WITHDRAWAL AND NEGATIVE REINFORCEMENT
positive and negative reinforcement, but emerging work on the punishing effects of nicotine has recently suggested that it may be an important
factor in excessive nicotine intake in dependent subjects (Fowler, Lu,
Johnson, Marks, & Kenny, 2011).
POSITIVE REINFORCEMENT ASSOCIATED WITH
NICOTINE USE
Although many components in cigarette smoke may contribute to
smoking, much evidence indicates that individuals use tobacco primarily to experience the psychopharmacological properties of nicotine. A large proportion of smokers eventually become dependent on
nicotine (Balfour, 1984; Stolerman, 1991). Nicotine acts as a positive
reinforcer and will support intravenous self-administration in various species, including humans, nonhuman primates, and rodents (Fig.
1.2), even at doses and regimens that do not lead to a withdrawal syndrome (Corrigall & Coen, 1989; Donny, Caggiula, Knopf, & Brown,
1995; Goldberg & Henningfield, 1988; Goldberg & Spealman, 1982;
FIGURE 1.2 Pattern of nicotine self-administration in humans and rats. Vertical lines
indicate a single nicotine self-administration. Notice the similarity in the pattern of nicotine
self-administration in humans and rats. The unit dose for each subject is indicated on the
right side of each record. Letters and numbers on the left axis are the initials (humans) or
number of subjects (rats). Human data are reproduced from Henningfield, J. E., Miyasato, K., Jasinski,
D. R. (1983). Cigarette smokers self-administer intravenous nicotine. Pharmacology, Biochemistry,
and Behavior, 19, 887–890. Rat data are from George et al. (unpublished results).
Positive Reinforcement Associated With Nicotine Use
5
Goldberg, Spealman, & Goldberg, 1981; Goldberg, Spealman, Risner,
& Henningfield, 1983; Goodwin, Hiranita, & Paule, 2015; Watkins,
Epping-Jordan, Koob, & Markou, 1999). For example, nicotine-containing cigarettes support higher breakpoints on a progressive-ratio
schedule of reinforcement than denicotinized cigarettes in humans
(Rusted, Mackee, Williams, & Willner, 1998; Shahan, Bickel, Badger,
& Giordano, 2001; Shahan, Bickel, Madden, & Badger, 1999). The positive reinforcing effects of nicotine are generally attributed to its acute
effects on mood and cognition. In humans, nicotine acutely produces
positive rewarding effects, including mild euphoria (Pomerleau &
Pomerleau, 1992), increased energy, and heightened arousal (Benowitz,
1996; Stolerman & Jarvis, 1995). Smoking cigarettes produces arousal,
particularly with the first cigarette of the day, and relaxation when
under stress (Benowitz, 1988). In animals, intravenous nicotine selfadministration has been reliably demonstrated in numerous strains of
rodents and different laboratories (Corrigall, 1999; Donny et al., 1995;
Rose & Corrigall, 1997; Watkins et al., 1999). Systemic injections of
the competitive nicotinic receptor antagonist dihydro-β-erythroidine
and noncompetitive antagonist mecamylamine decrease intravenous
nicotine self-administration in rats with limited access to nicotine
(1 h/day; Corrigall & Coen, 1989; Watkins et al., 1999). Moreover, nicotine increases attentional processes (Kaye et al., 2014; Young et al.,
2004; Young, Meves, & Geyer, 2013), lowers brain reward thresholds
(Epping-Jordan, Watkins, Koob, & Markou, 1998), increases wakefulness (Salin-Pascual, Moro-Lopez, Gonzalez-Sanchez, & BlancoCenturion, 1999), and increases learning and memory (Davis, Kenney, &
Gould, 2007; Gould & Leach, 2014) in rodents and humans. The similar effects of nicotine on mood and cognition reported in humans
and rodents provide a behavioral mechanism of action for the positive reinforcing effects of nicotine. However, preclinical studies have
found that nicotine is a weak reinforcer. The reinforcing effectiveness
of nicotine is approximately 10 times lower than that of cocaine in a
progressive-ratio schedule of reinforcement (Risner & Goldberg, 1983).
Although the acute positive reinforcing effects of nicotine are important in establishing self-administration behavior and may be sufficient
to maintain nicotine self-administration in nondependent subjects, they
do not appear to be sufficient to explain the intense craving for nicotine
that is observed in dependent subjects and the escalation of nicotine
intake during the transition from initial nicotine use to nicotine dependence and after relapse (Cohen, Koob, & George, 2012). Our hypothesis
is that during the transition from nicotine use to nicotine dependence,
there is a switch in the neurobiological mechanisms that underlie the
motivation for nicotine self-administration that reflects a transition
from positive to negative reinforcement mechanisms (Fig. 1.1).
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1. OVERVIEW OF NICOTINE WITHDRAWAL AND NEGATIVE REINFORCEMENT
NEGATIVE REINFORCEMENT ASSOCIATED WITH
NICOTINE USE
A nicotine withdrawal or abstinence syndrome after chronic nicotine
exposure has been characterized in both humans (Hughes, Gust, Skoog,
Keenan, & Fenwick, 1991; Shiffman & Jarvik, 1976) and animals (EppingJordan et al., 1998; Hildebrand, Nomikos, Bondjers, Nisell, & Svensson,
1997; Malin et al., 1994, 1992; Malin, Lake, Carter, Cunningham, & Wilson,
1993; Watkins, Koob, & Markou, 2000) and has both somatic and affective components. In humans, acute nicotine withdrawal is characterized
by affective symptoms, including depressed mood, dysphoria, irritability, anxiety, frustration, increased reactivity to environmental stimuli, and
difficulty concentrating, as well as somatic symptoms, such as bradycardia, gastrointestinal discomfort, and increased appetite that leads to
weight gain (American Psychiatric Association, 2000; Hughes et al., 1991).
The enduring symptoms of nicotine withdrawal (protracted abstinence)
include continued affective changes, such as depressed mood, irritability, sleep disturbances, and stress responsivity (Hughes et al., 1991), with
abstinent smokers often reporting powerful cravings for tobacco (Hughes
et al., 1984). Although the somatic symptoms of withdrawal from drugs
of abuse are unpleasant and annoying, it has been hypothesized that
avoidance of the affective components of drug withdrawal, including
those associated with nicotine withdrawal (negative reinforcement), play
a more important role in the maintenance of nicotine dependence than
the somatic symptoms of withdrawal (Koob, Markou, Weiss, & Schulteis,
1993; Markou, Kosten, & Koob, 1998).
Abrupt abstinence from chronic nicotine administration also leads
to a withdrawal syndrome in rodents (Malin et al., 1992) that has somatic
and motivational components. Both spontaneous and antagonistprecipitated nicotine withdrawal produce various somatic signs (eg, eye
blinks, body shakes, chewing, gasping, writhing, ptosis, and teeth chattering) and motivational effects (eg, elevated reward thresholds, anxietylike responses, and conditioned place aversion; Epping-Jordan et al.,
1998; Ghozland, Zorrilla, Parsons, & Koob, 2004; Stinus, Cador, Zorrilla, &
Koob, 2005; Watkins, Stinus, Koob, & Markou, 2000). Several groups
have established that rats will self-administer nicotine when given chronic
extended access to the drug (Fu, Matta, Kane, & Sharp, 2003; LeSage, Keyler,
Collins, & Pentel, 2003; O’Dell et al., 2007; Paterson & Markou, 2004;
Valentine, Hokanson, Matta, & Sharp, 1997). Passive nicotine administration decreases nicotine self-administration in chronic self-administration
paradigms (LeSage et al., 2003), and mecamylamine increases nicotine selfadministration (O’Dell et al., 2007). Rats that are dependent on nicotine
show anxiogenic-like effects during spontaneous withdrawal (Pandey,
Roy, Xu, & Mittal, 2001; Slawecki, Thorsell, Khoury, Mathe, & Ehlers, 2005)
Negative Reinforcement Associated With Nicotine Use
7
and mecamylamine-precipitated anxiety-like responses in the elevated
plus maze (George et al., 2007). Rats that self-administer nicotine when
given limited access to it (1 h/day, 5 days/week) show very limited, if
any, signs of somatic or motivational withdrawal (Paterson & Markou,
2004) and do not exhibit the escalation of nicotine intake after abstinence
(Cohen et al., 2012, 2015; George et al., 2007), suggesting that nicotine selfadministration is mostly driven by positive reinforcement mechanisms in
this model. However, rats that are given extended access to nicotine selfadministration with days of deprivation between each session (23/day,
every 24–48 h) show the escalation of nicotine intake (Fig. 1.3C) and emergence of somatic and motivational signs of withdrawal, including anxietylike behavior and hyperalgesia (Fig. 1.3D and E; Cohen et al., 2012, 2015)
that predict the magnitude of nicotine intake after abstinence, suggesting that
nicotine self-administration in this model is mainly driven by negative
reinforcement.
One hypothesis to explain the increased self-administration of nicotine during 23 h access, particularly after periods of deprivation, is that
nicotine self-administration becomes more heavily motivated by negative
reinforcement mechanisms that are driven by recruitment of brain systems that are involved in anxiety-like symptoms and dysphoria (Koob &
Le Moal, 2005, 2006). Recent work has confirmed this hypothesis by demonstrating that 2 days of nicotine abstinence was sufficient to increase nicotine self-administration when access to nicotine resumed (Cohen et al.,
2012). Moreover, this nicotine deprivation effect was observed even after
6 weeks of abstinence (Fig. 1.3B) and was only observed in dependent rats
with extended access to nicotine and not limited access (George et al.,
2007). The reinforcing effects of nicotine can also be measured by using a
progressive-ratio schedule of reinforcement, in which the responses that
are required to obtain a discrete dose of nicotine increase after each trial
until the animal stops responding (breakpoint). Both increasing doses of
nicotine and nicotine withdrawal increase breakpoints under a progressive-ratio schedule (Cohen et al., 2012, 2015), demonstrating that the reinforcing effects of nicotine are dose- and withdrawal-dependent. Moreover,
repeated periods of 2–3 days of abstinence lead to the escalation of nicotine
self-administration with increased responding under a progressive-ratio
schedule (Cohen et al., 2012). Again, only dependent rats with extended
access to nicotine self-administration were sensitive to the effect of abstinence and showed the escalation of intake. We also recently showed that
abstinence-induced anxiety-like behavior and hyperalgesia predicted
subsequent nicotine self-administration when access to nicotine resumed
(Fig. 1.3D and E; Cohen et al., 2015), suggesting that the removal of an
aversive state that is characterized by increased anxiety-like behavior and
pain is a key driving force behind excessive nicotine intake in dependent
subjects (Fig. 1.1).
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1. OVERVIEW OF NICOTINE WITHDRAWAL AND NEGATIVE REINFORCEMENT
Active
Inactive
*
*
*
*
*
*
*
*
*
*
1 2 3 4 5 6 7 8 910 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4
2.4
2.1
1.8
1.5
1.2
0.9
0.6
0.3
0.0
(B)
Post-ND intake
(mg/Kg)
Responses
70
60
50
40
30
20
10
0
mg/Kg
(A) 80
60
Nicotine infusions
#
*
50
#
*
#
*
#
*
#
*
#
*
#
*
1.6
*
1.4
*
*
*
1.2
1.0
0.8
0.6
0.1
Baseline ND ND ND ND
1
2
3
4
Sessions
(C)
1.8
1
10
100 1000 10000
Duration of Abstinence (h)
LgA 48 h intermittent
40
30
50
45
40
35
30
25
20
15
10
5
0
21
18
15
9
Baseline
(E)
2
R = 0.2779
P < 0.05
0
0.2 0.4 0.6 0.8
1
1.2 1.4
% time in open arms (normalized)
Number of injections (FR1)
Number of injections (FR1)
(D)
12
ShA 48 h intermittent
0
6
LgA daily
10
3
20
40
35
30
25
20
15
10
5
0
30
R2 = 0.4171
P < 0.05
40
50
60
70
80
Paw withdrawal thresold
90
FIGURE 1.3 Evidence of negative reinforcement in rats given extended access to
nicotine self-administration. (A) 72 h of nicotine deprivation (ND1-4) produces a robust
increase in nicotine intake in rats with access to nicotine self-administration for 23 h/
day. (B) Abstinence-induced increase in nicotine intake is observed after acute (24 h)
and protracted (6 weeks) abstinence. (C) Repeated periods of abstinence (48 h) between
each session produce a robust and sustained escalation of nicotine intake only in rats
with long access (LgA) but not short access (ShA). (D) Abstinence-induced anxiety-like
behavior (low percentage time on open arms) predicts high nicotine intake when access
to nicotine resumes. (E) Abstinence-induced hyperalgesia (low withdrawal threshold)
predicts high nicotine intake when access to nicotine resumes. Reproduced from (A and B)
George, O., Ghozland, S., Azar, M. R., Cottone, P., Zorrilla, E. P., Parsons L. H., et al. (2007).
CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proceedings of the National Academy of Sciences of the
USA, 104, 17198–17203; (C) Cohen, A., Koob, G. F., George, O. (2012). Robust escalation of
nicotine intake with extended access to nicotine self-administration and intermittent periods of
abstinence. Neuropsychopharmacology, 37, 2153–2160; (D and E) Cohen, A., Treweek, J.,
Edwards, S., Leão, R. M., Schulteis, G., Koob, G. F., et al. (2015). Extended access to nicotine
leads to a CRF1 receptor dependent increase in anxiety-like behavior and hyperalgesia in rats.
Addiction Biology, 20, 56–68.
Neurobiological Mechanisms of Positive Reinforcement
9
There is significant face validity of the deprivation model to the human
condition. The nicotine deprivation effect in rats is similar to the human
condition, in which one observes an increase in smoking after abstinence
(ie, an increase in the number and duration of puffs) followed by a titration period of nicotine intake (Benowitz & Jacob, 1984; Isaac & Rand, 1972;
Madden & Bickel, 1999; Nil, Woodson, & Battig, 1987; Rusted et al., 1998).
A critical point is that rats with 23 h access (without an abstinence period)
show, as in humans, stable nicotine intake for months, and the nicotine
deprivation effect is a short-lasting phenomenon that allows one to unveil
and investigate the neural basis of the motivation to take nicotine under a
negative reinforcement framework. Additionally, the similarity in blood nicotine levels in dependent humans and rats in a chronic access/deprivation
model supports the relevance of this model to human addiction. Blood nicotine levels range between 10 and 25 ng/ml over the course of 24 h in humans
who smoke at least one pack of cigarettes per day and reach 15 ng/ml after
one cigarette (Benowitz & Jacob, 1984; Benowitz, Porchet, Sheiner, & Jacob,
1988). In previous studies, we measured blood nicotine levels in rats (O’Dell
et al., 2006) and found that 1.0 mg/kg/day of nicotine via a minipump produced blood levels of 22 ng/ml. The rats in our self-administration studies
self-administer 0.8–1.2 mg/kg/day using a unit dose of 0.03 mg/kg (Cohen
et al., 2012; George et al., 2007; O’Dell et al., 2007). In actual measurements
after an infusion of nicotine at the dose used for self-administration, nicotine levels ranged from 10 to 30 ng/ml (see Guillem et al., 2005, from our
laboratory, and LeSage et al., 2002). These results suggest that under certain
conditions, intravenous nicotine self-administration in rodents reaches levels well beyond those that are required to produce dependence as defined
by the manifestation of a withdrawal syndrome during abstinence.
Altogether, these results suggest that extended access to nicotine itself
can lead to the escalation of intake and dependence (as measured by
withdrawal when nicotine is removed or nicotinic receptors are blocked).
Dependence appears to be manifested by a negative emotional state, and
negative reinforcement processes drive escalation. Thus, the transition
from nicotine use to nicotine dependence is hypothesized to involve neuroadaptations within brain reward and stress circuitries and neuroadaptations (Koob & Le Moal, 2005) that contribute to negative emotional states
that drive negative reinforcement (Koob & Bloom, 1988).
NEUROBIOLOGICAL MECHANISMS OF POSITIVE
REINFORCEMENT
The neurobiological mechanisms that are involved in the acute reinforcing effects of nicotine have largely focused on the mesocorticolimbic
dopamine system, a system that is heavily implicated in the reinforcing
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1. OVERVIEW OF NICOTINE WITHDRAWAL AND NEGATIVE REINFORCEMENT
effects of indirect sympathomimetics, such as cocaine and amphetamine
(Koob, Sanna, & Bloom, 1998). Nicotine is an agonist at nicotinic acetylcholine receptors (Lindstrom, 1997), and nicotinic acetylcholine receptors
have been shown to be localized on cell bodies and dendrites of dopamine
neurons in the ventral tegmental area and terminal fields of the mesocorticolimbic dopamine system, such as the nucleus accumbens (Clarke
& Pert, 1985; Swanson, Simmons, Whiting, & Lindstrom, 1987). Systemic
nicotine administration also increases extracellular dopamine levels in the
shell of the nucleus accumbens, an effect that is observed with other major
drugs of abuse (Nisell, Marcus, Nomikos, & Svensson, 1997; Pontieri,
Passarelli, Calo, & Caronti, 1998; Pontieri, Tanda, Orzi, & Di Chiara, 1996).
Neurochemical in vivo microdialysis studies have shown that nicotine
can release dopamine via actions at both sites, with more evidence for the
actions of nicotine at the level of the ventral tegmental area (Corrigall &
Coen, 1991; Corrigall, Coen, & Adamson, 1994; Corrigall, Franklin, Coen, &
Clarke, 1992; Enrico et al., 2013; Nisell, Nomikos, & Svensson, 1994; Panin,
Lintas, & Diana, 2014). The recruitment of dopamine and γ-aminobutyric
acid (GABA) neurons in the ventral tegmental area through the activation
of α4β2*, α6β2*, and α5* but not α7* subunit-containing receptors appears
to be critical for the positive reinforcing effects of nicotine (Maskos et al.,
2005; Morel et al., 2014; Orejarena et al., 2012; Pons et al., 2008; Tolu et al.,
2013). Other neuropharmacological systems that are implicated in the
positive reinforcing effects of nicotine include cholinergic (Azam, WinzerSerhan, Chen, & Leslie, 2002; Oakman, Faris, Kerr, Cozzari, & Hartman,
1995; Tago, McGeer, McGeer, Akiyama, & Hersh, 1989), serotonergic
(Carboni, Acquas, Leone, & Di Chiara, 1989), glutamatergic (McGehee,
Heath, Gelber, Devay, & Role, 1995; Schilstrom, Nomikos, Nisell, Hertel, &
Svensson, 1998), GABAergic (Corrigall, Coen, Adamson, Chow, & Zhang,
2000; Corrigall, Coen, Zhang, & Adamson, 2001; Dewey et al., 1999), and
opioidergic (Houdi, Pierzchala, Marson, Palkovits, & Van Loon, 1991;
Pomerleau & Pomerleau, 1984) systems.
NEUROBIOLOGICAL MECHANISMS OF NEGATIVE
REINFORCEMENT
The neurobiological substrates for the dependence-inducing effects of
nicotine are beginning to be elucidated. Neurotransmitter systems that
are implicated in nicotine withdrawal include decreases in dopamine and
opioid peptide system activity, increases in corticotropin-releasing factor (CRF), dynorphin, and norepinephrine activity, and changes in serotonin activity (Cohen & George, 2013; Tejeda, Natividad, Orfila, Torres, &
O’Dell, 2012; Watkins, Koob, et al., 2000). Decreases in the extracellular
levels of dopamine in the nucleus accumbens and central nucleus of the
Neurobiological Mechanisms of Negative Reinforcement
11
amygdala, but not the prefrontal cortex, have been observed during nicotine withdrawal (Hildebrand, Nomikos, Hertel, Schilstrom, & Svensson,
1998; Panagis, Hildebrand, Svensson, & Nomikos, 2000), with decreased
tonic activity of ventral tegmental area dopamine neurons (Grieder et al.,
2012). Decreases in serotonin synthesis have also been observed during
chronic nicotine exposure (Benwell & Balfour, 1979). Increases in CRF have
been observed in the central nucleus of the amygdala during withdrawal
(George et al., 2007). The somatic and affective/aversive signs of nicotine
withdrawal have also been precipitated by the opioid receptor antagonist
naloxone and nicotinic receptor antagonist mecamylamine, and opioid
and nicotinic receptor agonists can reverse the somatic signs of nicotine
withdrawal (Hildebrand et al., 1997; Malin et al., 1993). Moreover, nicotinic receptor blockade in the ventral tegmental area and interpeduncular nucleus produces somatic and motivational withdrawal (anxiety-like
behavior) in nicotine-dependent rats (Hildebrand, Panagis, Svensson, &
Nomikos, 1999; Zhao-Shea et al., 2015), possibly through the blockade of
α7 nicotinic receptors (Nomikos, Hildebrand, Panagis, & Svensson, 1999).
Acute nicotine administration has also been shown to activate hormonal and neurotransmitter stress responses (Faraday, Blakeman, &
Grunberg, 2005; Matta, Beyer, McAllen, & Sharp, 1987; Okada, Shimizu, &
Yokotani, 2003; Sharp & Matta, 1993), and such activation is dose dependent (Mendelson, Sholar, Goletiani, Siegel, & Mello, 2005). Nicotine not
only acutely activates the hypothalamic-pituitary-adrenal (HPA) axis
(Matta et al., 1987) but also activates CRF neurons extrahypothalamically
(Matta, Valentine, & Sharp, 1997). Withdrawal from chronic nicotine elevates CRF in the basal forebrain (Slawecki et al., 2005), and a CRF receptor
antagonist that was injected intracerebroventricularly blocked the anxiogenic-like effects of withdrawal from bolus injections of nicotine (Tucci,
Cheeta, Seth, & File, 2003). The hypothesis that CRF is activated during
nicotine withdrawal (Bruijnzeel & Gold, 2005) is based on the observation that acute withdrawal from nicotine can increase circulating corticosterone, and extracellular CRF has been shown to be increased in the
central nucleus of the amygdala during withdrawal from chronic nicotine
(George et al., 2007) as well as during withdrawal from chronic administration of other major drugs of abuse (Koob et al., 1998). The anxiogeniclike effects of precipitated nicotine withdrawal were blocked by a CRF1
receptor antagonist, and local infusion of CRF in the central nucleus of the
amygdala produced anxiety-like behavior (George et al., 2007). Nicotine
also enhanced norepinephrine release in the paraventricular nucleus of
the hypothalamus (Sharp & Matta, 1993). However, activation of the HPA
axis showed a subsensitive response during withdrawal from chronic
nicotine administration (Matta, Fu, Valentine, & Sharp, 1998; Mendelson
et al., 2005; Semba, Wakuta, Maeda, & Suhara, 2004). Chronic selfadministration increases norepinephrine release in the paraventricular
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1. OVERVIEW OF NICOTINE WITHDRAWAL AND NEGATIVE REINFORCEMENT
nucleus of the hypothalamus (Fu, Matta, Brower, & Sharp, 2001) and
amygdala (Fu et al., 2003). The blockade of noradrenergic α1 receptors can
decrease nicotine self-administration and nicotine reinstatement (Forget
et al., 2010). Given that norepinephrine, CRF, and glucocorticoids interact
in the basal forebrain in a feedforward system, in which each system
enhances the release of the other neurotransmitters (Koob, 1999; Vendruscolo
et al., 2012), these results would be consistent with the hypothesis that
chronic nicotine activates extrahypothalamic CRF systems during the
development of dependence. From a developmental perspective, increased
CRF-like immunoreactivity was observed in adult rats that were exposed
to nicotine during adolescence and has been linked to an anxiety-like
phenotype (Slawecki et al., 2005).
Animal models that incorporate aspects of negative reinforcement in
nicotine dependence have unveiled the existence of a novel CRF–CRF1
system in the ventral tegmental area–interpeduncular nucleus pathway.
Indeed, chronic nicotine exposure and withdrawal from nicotine recruit
a population of dopamine–CRF neurons in the ventral tegmental area,
and the activation of such dopamine–CRF neurons produces anxiety-like
behavior and the escalation of nicotine intake (Grieder et al., 2014; ZhaoShea et al., 2015). Moreover, the recruitment of CRF neurons in the ventral
tegmental area during withdrawal is paralleled by a decrease in the tonic
activity of ventral tegmental area dopamine neurons (Grieder et al., 2012),
suggesting that the decrease in dopaminergic tone that is observed in
human smokers may be caused by the recruitment of CRF neurons. Altogether, these reports suggest that downregulation of the dopamine system
in the ventral tegmental area, nucleus accumbens, and central nucleus of
the amygdala, together with the upregulation of CRF and norepinephrine systems in the central nucleus of the amygdala and ventral tegmental
area, may underlie excessive nicotine intake, driven by negative reinforcement in dependent subjects.
TRANSLATIONAL ASPECTS OF THE NEUROBIOLOGY
OF NEGATIVE REINFORCEMENT
Three medications are currently on the market for the treatment of
tobacco addiction: nicotine replacement therapy (gum, lozenge, and patch),
bupropion (Zyban), and varenicline (Chantix). These medications have
actions that can be considered relevant to treating the withdrawal/negative affect stage of the addiction cycle and thus the negative reinforcement
processes associated with nicotine withdrawal. There are a number of neurotransmitter systems that are implicated in the negative reinforcingeffects of
nicotine withdrawal, may contribute to the development of dependence,
and can be targeted to develop new medications for smoking cessation.
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13
The vulnerability to nicotine addiction may be related to initial sensitivity
to the reinforcing effects of nicotine, but recent conceptualizations regarding the development of addiction have introduced the hypothesis that
vulnerability may engage other aspects of the addiction process (Koob &
Le Moal, 1997, 2001, 2005, 2006; Robinson & Berridge, 1993). Under this
framework, incentive salience via a sensitization-like process (Robinson &
Berridge, 1993) may be initially engaged, but compulsive nicotine seeking
and taking likely involve negative reinforcement that is driven by the loss
of reward system activity and recruitment of brain stress system activity (Koob & Le Moal, 2005). The combination of excellent and validated
animal models that incorporate the negative reinforcement processes that
are associated with nicotine withdrawal and a better understanding of
the neurocircuitry and neuropharmacological mechanisms that underlie
nicotine motivational withdrawal has provided viable targets for future
drug development. Human laboratory models of the withdrawal/negative affect stage permit the proof-of-concept testing of potential therapeutics and the clinical validation of relevant pharmacological targets. The
results of such studies can loop back to validate the animal models. Such
a domain approach rather than syndrome approach to drug development
has the potential to reveal pharmacogenetic approaches to drug development and utility, and thus should fit well with new concepts related to
precision medicine.
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