CHAPTER

Addiction: A dysregulation of
satiety and inflammatory
processes
Rivona Harricharan*,1, Oualid Abboussi*, William M.U. Daniels*,†
3
*University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa
†
School of Physiology, University of Witwatersrand, Johannesburg, South Africa
1
Corresponding author: Tel.: +27-813325612, e-mail address: rivonah3@gmail.com

Abstract
Over the years, drug addiction has proven to be a perplexing conundrum for scientists.
In attempts to decipher the components of the puzzle, multiple theories of addiction have
been proposed. While these theories have assisted in providing essential fundamental infor-
mation, current research recommends that a new theory needs to be presented taking into
consideration the results of recent developments in the fields of neuroimmunology, genetics,
and neuropsychiatry. After extensively examining the published literature, we propose in this
review that neuroinflammation and hypothalamic functioning strongly underpin addictive
behavior.
To substantiate this notion, we typed the search-string “cocaine addiction, hypothalamus,
and inflammation” into PubMed and Google Scholar. 50 and 1280 results were obtained in
PubMed and Google Scholar, respectively. All article abstracts were perused for relevance
to this review and 177 articles were used. Recent studies have purported that both acute
and chronic psychostimulant use can activate specific components of the innate immune
system. Findings such as these provide the scientific evidence supporting a hypothesis that
includes a role for the innate immune system and inflammation in addictive behavior. How-
ever, the pathophysiological mechanisms by which they mediate the development of addiction
have not been clearly delineated. The following review particularly focuses on the lateral
hypothalamus and its functioning in satiety, and how inflammatory processes in the brain
may contribute to addiction.

Keywords
Addiction, Behavior, Hypothalamus, Inflammation, Satiety

Progress in Brain Research, Volume 235, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2017.07.012

© 2017 Elsevier B.V. All rights reserved.
65
66 CHAPTER 3 Dysregulation of satiety and inflammatory processes

1 BACKGROUND
Addiction has severe debilitating effects directly impacting the individual (the loss of
relationships, finances, decreased job opportunities, sporadic changes in behavior,
and increased health-associated complications), as well as the broader community
(crime and violence, trauma, and an overall breakdown of community values). Nu-
merous clinical and preclinical studies have been undertaken to understand why in-
dividuals continue to abuse drugs in the face of its substantial negative consequences.
Despite these investigations, our current understanding of the pathophysiology of ad-
diction and its management remains a concern. It is therefore obvious that a need
exists for a revised view on the etiology of addiction in order to reveal novel targets
for more effective treatment strategies.
Addiction or substance use disorder is a chronic disorder that is characterized by
compulsive drug-seeking and drug-taking behaviors regardless of severe negative
consequences of these behaviors (Feltenstein and See, 2008; Koob, 2009). It has been
described as a cycle of dysregulation of the brain’s reward systems, progressively
increasing compulsive drug use with simultaneous loss of control of drug consump-
tion (Koob and Le Moal, 1997). Progression in drug-taking behaviors from compul-
sivity to impulsivity is represented in addiction by the three-phased cycle: of which
the first phase is the Preoccupation/Anticipation phase, where there is exaggerated
motivation for drug use. This phase is associated with a sensitized brain reward sys-
tem (the mesocorticolimbic dopamine system). The second phase is the Binge/Intox-
ication phase, characterized by the downregulation of positive responses, and a
subsequent increase in the level of drug intake, i.e., more of the addictive substance,
is needed to trigger the brain reward system (Koob and Kreek, 2007). The third and
final phase is the Withdrawal/Negative affect phase where the negative effects of the
addictive substance become the driving factor for continued drug seeking and intake
further escalating craving and drug abuse (Koob and Le Moal, 2008; Fig. 1).
The neurophysiological mechanisms of addiction involved in the various stages
of this addiction cycle have been underpinned by a number of theories that focus on
certain brain circuits and neurochemical changes in the brain. The molecular alter-
ations associated with these circuits have been proposed to explain the changes from
drug taking to drug addiction and the concomitant vulnerability of relapse
(Koob, 2009).

2 BRIEF SUMMARIES OF SELECTED THEORIES OF ADDICTION

2.1 THE HEDONIC THEORY
The hedonic theory is defined as the pursuit of personal pleasure and self-indulgence
which, in the context of addiction, is phrased as pleasure seeking. This theory pos-
tulates that an individual consumes the addictive substance initially for the apparent
pleasurable consequences of that substance. However with drug withdrawal, severe
 2 Brief summaries of selected theories of addiction 67

Preoccupation
anticipation
Preoccupation with obtaining Persistent desire
persistent physical/ larger amounts taken
psychological problems than expected

Addiction

ne
Wi tive

n
ga
thd aff

ica e
tio
int Bing
raw ect

ox
al
Tolerance withdrawal
compromised social, occupational,
or recreational activities
FIG. 1
Illustration of the three-phased addiction cycle (Koob and Le Moal, 2008).

unwanted symptoms are experienced so that substance use now becomes a method of
alleviating these nasty symptoms. Dependence subsequently develops as a function
of this recurrent and reoccurring drive for pleasure, alternated by the need to get rid of
the unpleasant experiences during withdrawal (Feltenstein and See, 2008). This theory
suggests that addiction develops in relation to the positive properties of drugs and the
negative properties of drug withdrawal, therefore proposing a process of hedonic ho-
meostasis dysregulation (Chao and Nestler, 2004; Koob and Le Moal, 1997).
Although this theory provides an explanation for the initiation and maintenance of
drug use, one of its major shortcomings is that it fails to account for the aspects of drug
abuse involving relapse following prolonged abstinence (Feltenstein and See, 2008).

2.2 SENSITIZATION
Repeated use of some drugs often leads to tolerance, with increasing doses of the
drug required to achieve the initial hedonic effects of the drug. With other drugs,
especially psychostimulants, sensitization may occur where the repeated administra-
tion of the same dose of the drug may evoke heightened effects compared to those
initially experienced (Kalivas and Stewart, 1991). For example, the repeated injec-
tions of morphine into rats resulted in increased locomotor activity in these animals
(Vezina and Stewart, 1987).

2.3 COUNTERADAPTATION
While the above two mentioned theories address important aspects of the addiction
cycle, they do not explain how relapse occurs even after a substantial period of
drug abstinence. The counteradaptation theory has been postulated, suggesting that
68 CHAPTER 3 Dysregulation of satiety and inflammatory processes

long-term use of drugs leads to a number of neuroanatomical and neurochemical ad-

aptations in the brain. The ability of the brain to counter these neuroadaptations fails,
resulting in a state of disequilibrium that lasts for an extended time period. The brain
subsequently remains vulnerable to the effects of drugs and hence the phenomenon
of relapse (Koob and Le Moal, 1997).

2.4 ABNORMAL BEHAVIORAL CONTROL AND DECISION MAKING

Animal and human studies have implicated abnormal functioning of the prefrontal
cortex in the development of the addictive state (Goldstein and Volkow, 2002;
Schoenbaum et al., 2006). The prefrontal cortex is involved in higher order brain
functions such as cognitive control, decision making, attribution of salience to stim-
uli, and impulse control (Clark and Noudoost, 2014; Moorman et al., 2015; Sebastian
et al., 2014). Since impairments in these functions resemble addictive behavior, some
scientists have argued that the prefrontal cortex plays a central role in addiction
(Fattore and Diana, 2016; Koob and Volkow, 2016).

2.5 MALADAPTIVE ASSOCIATIVE LEARNING

Milton and Everitt (2012) proposed that the inability of drug addicts to obtain full
recovery even after a long period of no drug consumption is due to the formation
of maladapted drug-associated memories. These memories may be formed in a clas-
sical Pavlovian manner. The drug user forms these memories linking the positive
effects of the drug to the environment in which the drug was taken. In so doing, neu-
tral cues become strong precipitating factors for further drug seeking and/or relapse.

2.6 DOPAMINE-MEDIATED REWARD PREDICTION ERRORS

The reward prediction error theory is based on the observations that unexpected re-
wards result in significant increases in the firing rate of midbrain dopaminergic neu-
rons, while anticipated rewards produce insignificant responses in dopaminergic
neurons (Keiflin and Janak, 2015). It therefore seems that dopaminergic neurons
do not drive the reward response, but rather indicate the difference between the
expected reward and the actual reward experienced. To overcome this discrepancy,
the individual learns cues that predict good reward such that the difference between
expectation and actual diminishes. This phenomenon relates to the reinforcement
properties of substances, impacts on decision making, and promotes drug-seeking
behavior.
While each of these theories provides useful insights, none of them explain the
full cycle of addictive behavior. Nevertheless, they have provided useful platforms
for other research conducted to unravel the underlying neuronal mechanisms that un-
derpin the development of substance abuse (Everitt and Robbins, 2016; Nestler et al.,
2016; Volkow et al., 2015). The outcomes of this research have undoubtedly been
impressive in offering detailed accounts of the pathways and mechanisms that are
 3 Brain circuitry and areas involved in addiction 69

imperative in conceptualizing addictive processes and brain circuits. However, these

approaches have been highly mesocorticolimbic systems oriented. Of note is the rel-
atively under exploration of the involvement of inflammatory processes that are ini-
tiated following drug exposure, in the development of addiction. Here, we wish to
address this shortcoming and expand on the role of the immune system in addictive
behavior. In addition, we wish to provide a rationale, suggesting that the pathophys-
iology of addiction may also include a dysregulation of the hypothalamus-dependent
satiety system of the body.

3 BRAIN CIRCUITRY AND AREAS INVOLVED IN ADDICTION

Although a variety of activities (gambling, internet use) and substances (cocaine, al-
cohol) can lead to addictive behavior, the common feature they possess is a modu-
lation of the reward system of the brain. In essence, this means an escalation in
dopamine activity in the mesocorticolimbic system (Feltenstein and See, 2008). Cen-
tral to the reward system are the dopamine projections from cell bodies in the ventral
tegmental area (VTA) in the midbrain to the striatum, specifically the nucleus
accumbens (NAc) and dorsal striatum. The NAc has been closely linked to the he-
donic experience following substance intake (liking) and the subsequent motivation
to pursue further intake (wanting) (Castro et al., 2015), while the dorsal striatum par-
ticipates in the regulation of locomotor activity (Clark et al., 2015). There are also
dopaminergic projections from the VTA to cortical structures (mesocortical system)
and in particular the prefrontal, orbitofrontal, and anterior cingulate cortices. In the
addicted individual, abnormalities in prefrontal cortex functioning have been sug-
gested to be responsible for poor decision making and working memory
(Sebastian et al., 2014), and the loss of control of intake has been ascribed to mal-
functioning of the orbitofrontal cortex (Schoenbaum and Shaham, 2008). The meso-
limbic pathway consists of dopaminergic projections from the ventral tegmental area
to limbic areas, including the hippocampus and amygdala (Feltenstein and See,
2008). These limbic structures are involved in learning and memory and have been
proposed to play a role in linking the rewarding properties of drugs to the context in
which the drug is consumed (Goodman and Packard, 2016; Kutlu and Gould, 2016;
Luo et al., 2013). As such the hippocampus and amygdala have been associated with
learned addictive behaviors and cue-induced relapse in drug use.
Interestingly, dopaminergic producing neurons in the VTA can be divided into two
distinct groups based on the destination of their axons. Projections that form the meso-
cortical pathway and terminate in the prefrontal cortex originate from a subset of VTA
neurons that are different to those that give rise to the mesolimbic pathway and project
to the NAc and limbic areas (Cooper et al., 2017). The purpose of this subspecialization
in circuitry apparently relates to differential functioning with activation of neurons
forming the mesolimbic pathway being associated with pleasant outcomes, while stim-
ulation of neurons forming the mesocortical pathway often results from aversive stim-
uli (Lammel et al., 2014; Morales and Margolis, 2017).
70 CHAPTER 3 Dysregulation of satiety and inflammatory processes

Besides the dopaminergic efferent projections, there are also reciprocal glutama-
tergic projections which extend from the prefrontal cortex and limbic areas back to
the VTA. These projections form a feedback loop so that the firing of dopaminergic
neurons in the VTA, stimulated following drug consumption, can be modulated by
afferent projections (Cooper et al., 2017).
In summary the NAc and ventral pallidum appear to be the brain areas intimately
involved in the reinforcing effects of drugs of abuse, while the prefrontal, orbitofrontal,
and anterior cingulate cortices modulate emotional responses, cognitive control, and
executive functions (Volkow et al., 1993, 2003). The amygdala and hippocampus,
on the other hand, are involved in conditioned learning (Mahan et al., 2012; See,
2005). All these brain areas are reflective of the symptomology of the addict’s
pathophysiological state. For instance, cue-related relapse is generated within the lim-
bic structures, while euphoria, feelings of ecstasy, impulsivity, and lack of control
combined with inadequate decision making occur in the prefrontal cortex.

4 DRUG-INDUCED ALTERATIONS IN DOPAMINE

NEUROTRANSMISSION
Over the past few decades, researchers in the field of addiction have been captivated
by the allure of the dopamine theory; however, viable treatments stemming from this
theory have not been completely successful (Nutt et al., 2015). Because of this ob-
servation, scientists have realized that it is unlikely that addiction is the result of a
dysregulation in one specific neurotransmitter system (Nutt et al., 2015). Neverthe-
less the mechanism of action of many drugs of abuse entails primarily an interference
in dopaminergic neurotransmission. Drugs are therefore able to manipulate the re-
ward pathway by either directly influencing the action of dopamine within the sys-
tem or indirectly by altering the activity of other neurotransmitters (Tomkins and
Sellers, 2001). Motivation, concentration, and the ability for one to experience plea-
sure are all emotional states that have been linked to dopamine-containing circuits
within the central nervous system (CNS) (Coppen, 1967). The constant increase
in synaptic dopamine concentrations, evoked by the repetitive use of drugs of abuse,
led some researchers to believe that addiction is in fact characterized by diminished
dopamine neurotransmission. The reduced dopamine activity has been suggested to
result from exhaustion of dopamine stores in presynaptic neurons, leading to de-
creased release and subsequent impaired signal transduction due to changes in recep-
tor numbers or altered intercellular signaling (Dunlop and Nemeroff, 2007).
Knowledge of dopamine neurochemistry therefore appears to be fundamental to
our understanding of addiction.
Dopamine is a neurotransmitter synthesized from the precursor tyrosine, in the
cytoplasm of presynaptic neurons. It is stored in vesicles that are transported to
the presynaptic terminal of dopaminergic neurons (Dunlop and Nemeroff, 2007).
It is released into the synaptic cleft following action potentials arriving at the
 5 Changes in dopamine signaling may mediate addictive behavior 71

presynaptic membrane. At the level of the synaptic cleft, it then interacts with one of
the dopaminergic receptors that are from two main families (D1 and D2) on the post-
synaptic neuron cell surface (Youdim et al., 2006). Structurally all dopamine recep-
tor subtypes conform to the structural model of a G-protein-coupled receptor with
seven-transmembrane-spanning alpha-helices and an extracellular amino terminal
(Dunlop and Nemeroff, 2007).
Drugs of abuse enhance dopamine activity through various mechanisms. These
include (1) blockade of reuptake via the dopamine transporter on the presynaptic
membrane (e.g., cocaine); (2) reversal of the vesicular monoamine transporter
(VMAT2) on presynaptic vesicles causing massive release of dopamine from these
vesicles (e.g., methamphetamine); (3) blocking the inhibitory effects of GABA on
dopamine release (e.g., opioids); or (4) mimicking effects of dopamine by binding
to postsynaptic dopamine receptors (e.g., apomorphine) (Youdim et al., 2006).
The released dopamine serves as the trigger directing behavioral responses toward
motivationally salient stimuli and leads to cellular adaptations that facilitate learning
of associating the stimulus (drug) with the event (consumption of drug) (Jay, 2003).

5 CHANGES IN DOPAMINE SIGNALING MAY MEDIATE

ADDICTIVE BEHAVIOR
Binding of dopamine to D1 receptors activates adenylate cyclase resulting in an in-
creased production of cAMP, while binding to D2 receptors is associated with an
inhibition of cAMP formation. cAMP activates protein kinase A which in turn phos-
phorylates and thereby activates NMDA receptors, allowing the influx of calcium
into the postsynaptic neuron (Clarke and White, 1987). This calcium binds to cal-
modulin and subsequently leads to the activation of the enzyme CaMK II/IV that
phosphorylates the transcription factor CREB (cyclic AMP response-binding pro-
tein). In turn CREB promotes the transcription of immediate early genes, e.g.,
Fos and Jun (Girault and Greengard, 2004). Another important substrate for protein
kinase A is DARPP-32 (DA and cAMP-regulated protein, 32 kDa). DARPP-32 is of-
ten described as an important integrator of DA signaling and determines how post-
synaptic neurons respond to DA (Baik, 2013) by either increasing or decreasing the
activity of the cAMP pathway. Studies have also implicated the ERK (extracellular
signal-regulated kinase) signaling pathway in addiction with DARPP-32 indirectly
modulating ERK activity (Sun et al., 2016).
Persistent drug abuse and withdrawal augment the function of CREB (Self and
Nestler, 1998). The intrinsic excitability of neurons of the NAc shell is enhanced
by increased CREB activity (Dong et al., 2006). This excitability in the NAc shell
neurons may facilitate negative reinforcement methods, promoting motivation to ac-
quire and use cocaine (Carlezon and Thomas, 2009). In support, elevated CREB ac-
tivity in the NAc shell region has been shown to initiate motivation toward cocaine
consumption in self-administering animals (Larson et al., 2011).
72 CHAPTER 3 Dysregulation of satiety and inflammatory processes

The Fos family of proteins is another group of transcription factors that are gen-
erated rapidly and transiently in specific brain regions after acute administration of
many drugs of abuse (Nestler, 2008). Of particular interest is D FosB that is encoded
by the FosB gene and shares homology with other Fos family transcription factors,
which include c-Fos, FosB, Fra1, and Fra2. These Fos family proteins are highly un-
stable though and return to basal levels within hours of drug administration.
Inhibitory receptors (e.g., GABAergic), excitatory receptors (e.g., cholinergic),
or modulatory receptors (e.g., presynaptic mGluR2/3 receptors) influence ERK-
mediated c-Fos promoter activation (Bertran-Gonzalez et al., 2008; Brami-
Cherrier et al., 2005; Chen et al., 1992; Cohen and Greenberg, 2008; Herdegen
and Leah, 1998; Lyons and West, 2011). For instance glutamate and dopamine
can operate synergistically to depolarize neurons and prompt calcium influx and
ERK activation. Neural activity instigates calcium influx through NMDA receptors
and L-type voltage-sensitive calcium channels to activate a variety of calcium-
dependent molecules, including Ras-GRP. The Ras-GRP causes calcium-dependent
activation of the Ras/Raf kinase pathway which phosphorylates and activates ERK
(Agell et al., 2002; Cahill et al., 2014). Phosphorylated ERK then translocates to the
nucleus where it can phosphorylate transcription factors such as Elk-1 and CREB
(via RSK: ribosomal S6 kinase) on the c-Fos promoter (Besnard et al., 2011;
Cahill et al., 2014; Chen et al., 1992; Cohen and Greenberg, 2008; Morgan and
Curran, 1991). Activation of these signaling pathways reflects the intricacies and
cross talk of the signaling pathways that underlie addiction and emphasizes the com-
plex mechanisms involved in the development of addiction. It is therefore clear that a
better understanding of addiction should include knowledge of other neurobiological
systems.

6 REGULATION OF SATIETY
The worldwide concern about the prevalence of obesity and metabolic disorders such
as diabetes has stimulated an interest in the biological mechanisms that regulate sa-
tiety. While satiation and satiety are often interchangeably used, some scientists refer
to the physiological processes and signals that are stimulated during eating as sati-
ation that culminates in satiety at the end of the eating episode. Satiety then lasts until
hunger sets in (Bellisle et al., 2012). Appetite control has been extensively studied
(see review by Wynne et al., 2005). Here follows only a brief summary of the main
hormonal and nerve mechanisms that participate in the control of food intake. Before
and during a meal the hormone ghrelin is secreted from the stomach and reaches the
arcuate nucleus of the hypothalamus where it stimulates the release of neuropeptide Y.
This peptide, in turn, stimulates the release of orexins/hypocretins that are potent en-
hancers of food intake. Orexinergic fibers therefore innervate appetite-enhancing
pathways in the brain. On the other hand, the release of peptide YY3–36 from the
intestines, together with insulin-induced leptin release from fat stores in the body,
inhibits the secretion of neuropeptide Y and the subsequent secretion of orexin.
 7 The hypothalamus: The intersect between addiction and satiety 73

An additional pathway that reduces food intake entails leptin-mediated stimulation of

the secretion of melanocortins from the arcuate nucleus that first inhibit orexin release
and second stimulate the release of corticotropin-releasing hormone (CRF) from the
paraventricular nucleus (PVN) of the hypothalamus. CRF has a suppressing effect on
appetite (Sun et al., 2014; Zs
eli et al., 2016). Hypothalamic areas such as the arcuate
nucleus, PVN nucleus, and lateral hypothalamus (LH) therefore appear to be central to
the regulation of satiety.

7 THE HYPOTHALAMUS: THE INTERSECT BETWEEN

ADDICTION AND SATIETY
There are studies that have implicated the hypothalamus in addictive behavior. In
2001, Sinha defined cocaine dependence as a state characterized by chronic stress
and enhanced activation of the hypothalamic–pituitary–adrenal (HPA) axis, reflect-
ing the interplay between the HPA axis and addiction. In other studies, substantial
damage and disturbed functioning of the hypothalamus were reported following
methamphetamine administration (Carson et al., 2010; King et al., 2010; Sharma
and Kiyatkin, 2009). It was subsequently postulated that such structural and func-
tional changes, in combination with elevated cortisol secretion, may aid in promoting
the constant neuropsychiatric impairments that ensue methamphetamine use (Carson
et al., 2010).
As stated earlier the hypothalamus plays crucial roles in modulating satiety. Pro-
jections from the hypothalamus to areas related to reward (VTA, NAc) suggest a pos-
sible overlap between the neuronal circuitry regulating satiety and drug abuse
(Armario, 2010; Volkow et al., 2013). Additional support for such an interplay be-
tween the pathways that regulate addictive behavior and satiety stems from work
done by researchers interested in the functions of the LH. Evidence suggests that in-
trinsic neuroglial populations of the LH are potentially altered by drugs (such as co-
caine, methamphetamine, heroin, nicotine, and morphine). This may occur via two
mechanisms: (a) the orexin/hypocretin system (Aston-Jones et al., 2010) and/or
(b) the neurotensin pathway (Patterson et al., 2015). A subset of orexin cells in
the LH play a role in reward processing and changes in addictive behaviors
(Aston-Jones et al., 2010). Projections from the LH innervate the VTA and NAc
of the mesolimbic system to moderate the levels of motivation within an individual
(Carson et al., 2010; Dallvechia-Adams et al., 2002). In a recent study by Patterson
et al. (2015), pharmacogenetic stimulation of the LH neurotensin-containing neurons
elicited dopamine-dependent locomotor activity and NAc dopamine efflux. This
finding was associated with an increase in the level of neurotensin in the VTA as
measured by microdialysis-coupled mass spectrometry in mice. These authors fur-
ther showed that the introduction of a neurotensin receptor antagonist into the
VTA abolished the ability of the LH neurotensin cells to promote dopamine release
in the NAc (Patterson et al., 2015).
74 CHAPTER 3 Dysregulation of satiety and inflammatory processes

Orexinergic neurons of the hypothalamus project to areas associated with reward,

arousal, and addiction (Wang et al., 2015). Areas expressing orexin receptors include
the NAc, VTA, and the amygdala (Wang et al., 2015). It would therefore be highly
beneficial to evaluate how the LH contributes to the regulation of the VTA and NAc
and which mechanism predominates under what type of conditions. Previous studies
have outlined the effect of different drugs of abuse on orexinergic neurons. Orexin
neurons in the LH which terminate in the VTA caused greater neural activity follow-
ing morphine exposure, in comparison to their orexin-deficient counterparts. Fur-
thermore, it has been postulated that the orexin-1 receptor plays a role in
conditioned cocaine seeking in rats, while exposure to cocaine and alcohol altered
orexin mRNA expression in brain areas linked to addiction (Lawrence et al.,
2006; Zhou et al., 2008).
Ghrelin that has been shown to exert proorexigenic effects through its interaction
with the leptin-responsive circuits of the arcuate nucleus in the hypothalamus has
also been implicated in the modulation of the mesocorticolimbic system, suggesting
a role for ghrelin in reward-seeking behaviors (Jerlhag et al., 2010). Ghrelin has been
shown to bind to the growth hormone secretagogue receptors which are located on
dopaminergic neurons in the VTA. While it has been demonstrated that ghrelin en-
hances rodents to forage for food (Keen-Rhinehart and Bartness, 2005), it also has
the ability to augment cocaine-induced locomotor activity (Davis et al., 2007;
Wellman et al., 2005). Clinical studies have highlighted that individuals experience
hyperghrelinemia following alcohol and methamphetamine abuse (Kim et al., 2005;
Kobeissy et al., 2008). A study by Landgren et al. (2008) has revealed that there is an
association between higher alcohol consumption and a single-nucleotide polymor-
phism in the growth hormone secretagogue receptor 1A. Jerlhag et al. (2010) dem-
onstrated that the administration of a growth hormone secretagogue receptor 1A
antagonist reduces both locomotor stimulation and NAc dopamine release following
administration of either cocaine or amphetamine in mice. Furthermore, a positive
correlation between higher ghrelin levels and behavioral performance exists in an-
imals that had been reintroduced to cocaine-associated cues following a period of
withdrawal (Tessari et al., 2007). There is therefore some evidence that implicate
ghrelin and leptin in drug-seeking behaviors; however, their exact role is yet to be
established. Therefore, taking the current research into context suggests that while
the hypothalamus is not commonly associated with drug dependence, recent evi-
dence suggests that the functioning and role of this brain area have to be considered
in the understanding of addictive behavior.

8 INFLAMMATION AND ADDICTION

Cocaine together with other drugs (alcohol, morphine, and methamphetamine) has
been shown to evoke adaptations of the peripheral immune system and induces var-
ious intracellular changes either directly or indirectly in resident immune cells of the
CNS (Butts and Sternberg, 2008; Moreira et al., 2011; Nennig and Schank, 2017).
 8 Inflammation and addiction 75

Findings such as these suggest a relationship between different drugs of dependence

(such as opioids, psychostimulants, and depressants) and inflammatory processes.

8.1 THE IMMUNE SYSTEM OF THE BRAIN

The immune response of the body encompasses the interplay between the innate im-
mune system and the adaptive immune system. The innate immune system is con-
sidered as the first line of defense and functions to recognize pathogen-associated
molecular patterns through the involvement of pattern-recognition receptors. The
second line of defense, the adaptive immune system, comprises the activation of
T- and B-lymphocytes with T-cell receptors and B-cell receptors functioning to rec-
ognize a variety of antigens. The CNS was once regarded as an “immune privileged”
body entity. This notion is now disregarded since the CNS was shown to evoke innate
immune responses (Farina et al., 2007). The CNS comprises macroglia and microglia
(Lee et al., 2001). Astrocytes form part of the macroglia in the CNS, along with epen-
dymal cells and oligodendrocytes. Astrocytes fulfill many functions in the brain in-
cluding the maintenance of the integrity of the blood–brain barrier, the quiescence of
microglia, the production of neurotropic factors, and the detoxification of excess ex-
citatory amino acid (Thompson et al., 2001). Microglia, on the other hand, are the
nomadic immune cells of the brain and are active participants in the generation of
innate immune responses (Gehrmann et al., 1995). Microglia are considered to be
the guards within the CNS due to their compilation of Toll-like receptors (TLRs),
their ability to secrete cytokines, initiating an innate immune response. TLRs, a fam-
ily of pattern-recognition receptors, consist of 10 subtypes: namely TLR1-10
(Iwasaki and Medzhitov, 2004). Both microglia and astrocytes express TLR3,
TLR4, TLR5, and TLR9 (Farina et al., 2007; Okun et al., 2009). TLR signaling is as-
sociated with various physiological processes, such as learning, memory, depression,
and mood (Dantzer et al., 2008; Yirmiya and Goshen, 2011). TLRs predominantly use
an MyD88-dependent pathway, which elicits downstream neuroinflammatory signal-
ing cascades, culminating in the activation of transcription factors and consequently
producing inflammatory cytokines and chemokines (Jack et al., 2005; Lehnardt,
2010). Cytokines are small chemical messenger molecules that function to facilitate
intercellular communication and modulate the immune response. However, distur-
bances associated with cytokine expression may result in chronic inflammatory
diseases and neurodegeneration (Keogh and Parker, 2011). Clinical studies have
reported that the pharmacotropic actions of drugs of abuse are also produced and en-
hanced by the central activation of immune signaling in areas and pathways related to
addiction processes (Coller and Hutchinson, 2012).

8.2 DRUGS AFFECTING IMMUNE CELLS

Major histocompatibility complex II (MHC-II), ionized calcium-binding protein
(Iba1), CD11b, CD40, CD80, and CD86 are a few of the indicators of microglial ac-
tivation. In the event of injury or disease, microglia and astrocytes undergo a process
76 CHAPTER 3 Dysregulation of satiety and inflammatory processes

known as activation (Liu et al., 2011). Upon activation, the structure and function of
astrocytes become modified. Subsequent to activation, astrocytes and microglia
release proinflammatory cytokines and enhance protein expression; however,
they decrease the expression of the glutamate transporters (Pekny and Nilsson,
2005; Sofroniew, 2009). Reducing glutamate transporter 1 (GLT-1)/excitatory
amino acid transporter-2 (EAAT2) and GLAST (glutamate and aspartate trans-
porter)/excitatory amino acid transporter-1 (EAAT1) can potentiate excitotoxicity
(Binns et al., 2005; Cata et al., 2006; Pekny and Nilsson, 2005; Sung et al., 2003;
Sweitzer et al., 2001; Tawfik et al., 2008). Interestingly Bowers and Kalivas
(2003) and Kalivas et al. (2003) showed that 3 weeks after acute cocaine adminis-
tration, there are still marked increases in glial fibrillary acidic protein and vimentin
3 expression. These factors usually facilitate neuronal migration, modulate the for-
mation of synapses, regulate synaptic strength, and confer a degree of neuroprotec-
tion. However, in excess, they may be detrimental, resulting in neurodegeneration
(Lawrence et al., 2007).
A number of studies have demonstrated that opioids such as morphine and heroin
affect the immune system either directly through acting on macrophages and lym-
phocytes peripherally or indirectly by eliciting changes in the CNS that may result
in neurotoxicity (Cunha-Oliveira et al., 2010; Fecho et al., 1996; McCarthy et al.,
2001; Nelson et al., 2010; Sacerdote, 2006). Chronic morphine treatment to a rodent
neuropathic model led to substantial increases in proinflammatory cytokine levels
(e.g., IL-1b, TNF-a, IL-6) as well as glial cell overactivation (Raghavendra et al.,
2003), an observation that was supported by reports of significant elevations in cy-
tokine expression in the brain of an animal model of opioid dependence (Chen et al.,
2012). The result of these inflammatory processes associated with chronic exposure
to opioids includes atrophy of the dendrites, abnormal neurogenesis, and neurode-
generation (Eisch et al., 2000; Robinson and Kolb, 1999).
Cocaine is classified as a psychomotor stimulant that affects the physiological,
psychological, and behavioral systems in mammals, following both acute and
chronic use. Multiple physical phases consequently appear indicative of tolerance,
dependence, sensitization, and withdrawal. Ahmed and Koob (2005) demonstrated
that compulsive cocaine abuse was associated with dynamic alterations in gene ex-
pression and structural remodeling in the brain. The increased expression of one such
gene, metalloproteinase-9, was observed in the medial prefrontal cortex and hippo-
campus of rats following a 10 mg/kg dose of cocaine (Brown et al., 2008). In a clin-
ical study, where 10 chronic cocaine abusers and 9 controls were age-, sex-, race-,
and postmortem interval matched, the anterior aspects of the midbrains of the abusers
were significantly more densely populated with activated macrophages and micro-
glia in comparison to the controls (Little et al., 2009). In another study methamphet-
amine abuse was accompanied by glial activation or neuritic growth being reported
(Jernigan et al., 2005. These findings therefore support an association between the
consumption of psychostimulants, immune system responses, and cerebral morpho-
logical changes.
 8 Inflammation and addiction 77

In addition to stimulants, alcohol-related brain damage has also been linked to an

involvement of the immune system. Animal experiments have shown that chronic
administration of depressants, such as alcohol, induces inflammatory mediators that
are harmful to the brain (Alfonso-Loeches et al., 2010; Vall
es et al., 2004). It has
been proposed that activation of TLR4-associated signaling pathways in glial cells,
causing the release of cytokines, gliosis, and myelin reduction, is the mechanism by
which alcohol may mediate its deleterious effects (Alfonso-Loeches et al., 2012,
2010; Blanco and Guerri, 2007; Fernandez-Lizarbe et al., 2009).
In short, the effects of drugs of abuse on the immune cells of the brain can be
summarized into three steps. First, all drugs of abuse act on glial cells to generate
the production and release of proinflammatory cytokines. Second, these cytokines
induce the activation of quiescent astrocytes and microglia which in turn enhances
the inflammatory response. And finally, the signaling pathways that are initiated by
these cytokines and/or activated immune cells result in damaging morphological
changes in the architecture of the brain.

8.3 IMMUNE CELLS AFFECTING DOPAMINE TRANSMISSION

Drugs of abuse exert changes in molecular signals to increase dopamine, the neuro-
transmitter related to inducing feelings of pleasure, in the brain. It is common knowl-
edge that dopamine forms an integral part of the brain’s reward pathway and changes
in dopamine levels influence multiple downstream postsynaptic events involving
glutamate neurotransmission. Glutamate within the extra synaptic space is gated
by glutamate transporters on adjacent glial cells (Minelli et al., 2001). Glial cells
and presynaptic and postsynaptic neurons form a tripartite architecture which pre-
vents glutamate spillover and maintains localized glutamate homeostasis via a glu-
tamate/cystine exchange system (Perea et al., 2009; Rusakov et al., 2011). Astrocytes
take up cystine in exchange for glutamate that is subsequently released in the extra-
cellular space. The function of this free glutamate is to activate inhibitory glutamate
receptors to decrease the synaptic release of glutamate (Moran et al., 2005). Drug
abuse limits the capability of these metabotropic receptors to effectively regulate
glutamate release in the synapse (Kalivas and Kalivas, 2016). This occurs due to
drug-induced downregulation of GluR 2/3 on the presynaptic neuron, with simulta-
neous downregulation of GLT-1 on the adjacent glial cells (Gass et al., 2011;
Peterson et al., 2000). The dense distribution of glutamate transporters on adjacent
glial cells results in a greater spillover in the synaptic cleft due to GLT-1 downre-
gulation (Lehre and Danbolt, 1998). Glutamate spillover in the extra synaptic space
stimulates the upregulation of GluR5 and the N-methyl-D-aspartate receptors
(NMDARs) (Gipson et al., 2013; Kalivas and Kalivas, 2016).
The glial cells subsequently initiate inflammatory reactions, which lead to
further neuronal excitation. This elicits a surging amount of dopamine to be pro-
pelled throughout the brain. The glutamate spillover disrupts the glutamate–cystine
exchanger system, resulting in glutamate excitotoxicity (Baker et al., 2003;
78 CHAPTER 3 Dysregulation of satiety and inflammatory processes

Kau et al., 2008; Knackstedt et al., 2009; Madayag et al., 2007). It has been shown
that blocking the exchanger system reduces extracellular glutamate levels in drug-
naı̈ve rats but not in rats exposed to cocaine (Baker et al., 2003). Physical interaction
between the subunits of the NMDAR with D2 forms a heteromer. These heteromers
have unlocked new avenues for addiction research as they may possess diverse phar-
macological and functional properties which differ from their constituent receptors
(Baragli et al., 2007; Ferrada et al., 2008, 2009; Gin
es et al., 2000; Hillion et al.,
2002; Lee et al., 2004; Marcellino et al., 2008a,b; Scarselli et al., 2001; Torvinen
et al., 2005). Liu et al. (2006) demonstrated that the physical association of the
two receptors was increased following acute cocaine administration in vivo. Previous
studies have demonstrated that interruption of the D2-NR2B (NMDA receptor 2B)
heteromeric complex significantly reduces locomotor activity and stereotypy in a co-
caine model of addiction (Liu et al., 2006; Perreault et al., 2014). This highlights the
possible role for the D2-NR2B heteromeric complex in the development of
addictive-like behaviors. The upregulation of NMDARs facilitates the entry of cal-
cium into the postsynaptic neuron. Excess calcium leads to the potentiation of reac-
tive oxygen species and the activation of the apoptotic pathway. Alterations in
cysteine levels also modulate oxidative balance (Dean et al., 2011; Himi et al.,
2003; Janáky et al., 2008). This is consistent with evidence from previous studies
which demonstrated cell loss to result from excessive drug use, e.g., the reduction
in the dopamine neurons of the VTA following chronic morphine use (Chu et al.,
2008; Sklair-Tavron et al., 1996).

8.4 DRUGS AFFECTING CYTOKINE RELEASE

To validate that human brain cells were capable of activating members of the innate
immune system, Lee et al. (2009) isolated microglia and astrocytes from 20-week-
old human fetal cerebral cortex and investigated the expression of receptors for
proinflammatory cytokines. Although the cells were exposed to only 100 mM cocaine
for a brief period of 24 h, the microglia and astrocytes exhibited increased expression
of interleukin-1b (IL-1b) and tumor necrosis factor (TNF) receptors along with di-
minished expression of the glutamate receptors, respectively. The researchers
employed the use of focused limited cDNA arrays and confirmed their findings using
quantitative real-time PCR (Lee et al., 2009).
Proinflammatory cytokines have been reported to be upregulated following co-
caine exposure; however, significant reductions in TNF-a, chemokine ligand-2/
monocyte chemoattractant protein 1, and stromal cell-derived factor 1 were observed
in the plasma of outpatients attending a rehabilitation facility (Fox et al., 2012). On
the other hand, increased levels of TNF-a and decreased levels of IL-1ra were ob-
served in a group of cocaine users following exposure to cued imagery. Interestingly
an upregulation of TNF-a has also been observed during early withdrawal period in
people who has been taking cocaine. These clinical studies were supported by pre-
clinical experiments where mice treated with cocaine revealed comparable TNF-a
 8 Inflammation and addiction 79

results (Kubera et al., 2008; Wang et al., 1994) as well as enhanced responses in IL-4
and IL-10 production (Gardner et al., 2004; Kubera et al., 2008).
A number of studies have demonstrated morphine-evoked proinflammatory re-
sponses similar to cocaine. For instance, single or chronic administration of mor-
phine to experimental models of addiction significantly increased the secretion of
TNF-a (Pacifici et al., 2000; Peng et al., 2000; Zubelewicz et al., 2000). These ob-
servations have been supported by in vitro studies reporting the stimulation of the
secretion of TNF-a after 18 h of morphine exposure (Kapasi et al., 2000). This result
further suggested that proinflammatory cytokine release may occur within a rela-
tively short time following drug exposure. Besides TNF-a, augmented IL-6 produc-
tion has been documented in patients receiving morphine for postoperative pain
management (Beilin et al., 2003). Elevated IL-6 levels were also noted in a
morphine-treated rat model of addiction (Zubelewicz et al., 1998). Evidence indicat-
ing drug-mediated stimulation of proinflammatory cytokine release is therefore
considerable.

8.5 CYTOKINES MEDIATING DRUG-ASSOCIATED MOLECULAR

EFFECTS
Glia modulates postsynaptic glutamatergic signaling, and in some instances, this oc-
curs via TNF-a increasing postsynaptic glutamate receptor levels (Beattie et al.,
2002). Following an insult, activated microglia become producers of TNF-a. Follow-
ing the release of TNF-a, there is a temporary reduction in NMDAR/a-amino-
3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) ratio. During
withdrawal, the microglia gradually deactivates, leading to a normalization in the
levels of NMDAR/AMPAR (Lewitus et al., 2016). This suggests that TNF-a likely
plays an adaptive role in the NAc by controlling glutamatergic neurotransmission
(Lewitus et al., 2016; Stellwagen and Malenka, 2006). Glia produce neurotrophic
factors and cytokines which also contribute and alter neuroplasticity of neurons
(Allen and Barres, 2005).
Cytokines, for example, TNF-a, exert their effects by activating intracellular sig-
naling pathways such as the nuclear factor kappa B (NF-kB) and the mitogen-
activated protein (MAP) kinase pathways (Lee et al., 2013; Sabio and Davis,
2014). Cocaine and ethanol exposure is known to increase NF-kB activity, respec-
tively (Ang et al., 2001; Mayfield et al., 2013; Qin et al., 2008; Russo et al., 2009) that
may promote oxidative stress (López-Pedrajas et al., 2015) and neuron cell death
(Lee et al., 2013). Similarly, activation of ERK, a member of the MAP kinase family,
has been strongly implicated in the abuse of drugs including cocaine, amphetamine,
methamphetamine, marijuana, nicotine, and alcohol (Sun et al., 2016). ERK is pro-
posed to modulate neuroadaptive changes that are associated with the reward prop-
erties of drugs, their psychomotor activity, as well as processes that are responsible
for drug-seeking behaviors (Fig. 2).
80 CHAPTER 3 Dysregulation of satiety and inflammatory processes

FIG. 2
The process of glial activation following cocaine exposure.
Modified from Crews, F.T., Zou, J., Qin, L., 2011. Induction of innate immune genes in brain create the
neurobiology of addiction. Brain Behav. Immun. 25, S4–S12.

9 CONCLUSION
Substance use disorder is complex and it is therefore not surprising that scientists
worldwide continue to grapple with understanding its pathophysiology. The central
role of the mesocorticolimbic system in the development of addictive behavior is
undisputed. However, it has now become clear that other homeostasis-regulating
systems also contribute to the complexities of addiction. In this regard, the control
of satiety has received much attention with a special emphasis on the orexinergic
projections from the hypothalamus to midbrain areas involved in reward and drug
seeking (Aston-Jones et al., 2010), and in turn, dopamine regulating orexin release
from the LH (Bubser et al., 2005).
In parallel a multitude of studies support the notion that inflammatory processes
form an integral part of the mechanisms precipitating drug addiction. The involve-
ment of the immune system has developed to such an extent that immunotherapy is
being considered in the management of addiction (Fox et al., 2012). The advantages
of using antiinflammatory cytokines as pharmacotherapies are that they are well tol-
erated and safe across multiple clinical populations (Fox et al., 2012). Recombinant
IL-10 injections have been effective treatments for inflammatory bowel disease and
psoriasis (Yamagata and Ichinose, 2006), and its efficacy is being evaluated in mul-
tiple sclerosis phase II clinical trials. Clinical studies incorporating patients with var-
ied drug exposure times and relapse rates are imperative to determine which
treatment strategy would be most pertinent to them. Innovative approaches that tar-
get the progression of inflammation in the context of drug addiction may therefore be
a useful strategy to assist those who have to fight the battle against drug addiction.
 References 81

Competing interests: The authors declare that they have no competing interests.
Authors’ contribution: R.H., O.A., and W.D., were involved in reviewing ab-
stracts for this study. All the authors were involved with reviewing the literature, in-
tegrating their information appropriately, and additionally, each provided their
intellectual input. All authors read and approved the final manuscript.

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