the role of habenula

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REVIEW ARTICLE
published: 28 March 2014
doi: 10.3389/fnhum.2014.00174
The role of the habenula in drug addiction
Kenia M. Velasquez, David L. Molfese and Ramiro Salas*
Department of Psychiatry, Baylor College of Medicine, Houston, TX, USA
Edited by:
Masayuki Matsumoto, University of
Tsukuba, Japan
Reviewed by:
Ines Ibañez-Tallon,
Max-Delbrück-Center for Molecular
Medicine, Germany
Thomas Jhou, Medical University of
South Carolina, USA
*Correspondence:
Ramiro Salas, Department of
Psychiatry, Baylor College of
Medicine, One Baylor Plaza, Houston,
TX 77030, USA
e-mail: [email protected]
Interest in the habenula has greatly increased in recent years. The habenula is a small brain
structure located posterior to the thalamus and adjacent to the third ventricle. Despite its
small size, the habenula can be divided into medial habenula (MHb) and lateral habenula
(LHb) nuclei that are anatomically and transcriptionally distinct. The habenula receives
inputs from the limbic system and basal ganglia primarily via the stria medullaris. The
fasciculus retroflexus is the primary habenular output from the habenula to the midbrain
and governs release of glutamate onto gabaergic cells in the rostromedial tegmental
nucleus (RMTg) and onto the interpeduncular nucleus. The resulting GABA released from
RMTg neurons inactivates dopaminergic cells in the ventral tegmental area/substantia nigra
compacta. Through this process, the habenula controls dopamine levels in the striatum.
Thus, the habenula plays a critical role in reward and reward-associated learning. The LHb
also modulates serotonin levels and norepinephrine release, while the MHb modulates
acetylcholine. The habenula is a critical crossroad that influences the brain’s response to
pain, stress, anxiety, sleep, and reward. Dysfunction of the habenula has been linked to
depression, schizophrenia, and the effects of drugs of abuse. This review focuses on the
possible relationships between the habenula and drug abuse.
Keywords: habenula, addiction, dependence, tobacco, nicotine, withdrawal
THE HABENULA – GENERAL OVERVIEW
Historically, the habenula has been neglected in the scientific liter-
ature, yet this small brain structure has increasingly been studied
by neuroscientists and psychologists interested in pain, stress, anx-
iety, sleep, reward, depression, schizophrenia, and drug addiction.
Habenula is Latin for “little rein,” owing to this small structure’s
shape and location near the pineal gland and third ventricle. The
habenula is divided into two anatomically and transcriptionally
distinct structures: the medial habenula (MHb) and lateral habe-
nula (LHb; Klemm, 2004). The LHb plays a critical role in the
brain’s response to reward and thus has been more extensively
studied than the MHb (Matsumoto and Hikosaka, 2007). In addi-
tion, the LHb has been linked to major depression (Sartorius et al.,
2010), while the MHb has been linked to the effects of nicotine
(Salas et al., 2009; Fowler et al., 2011; Frahm et al., 2011).
In terms of white matter connectivity, the stria medullaris is the
primary habenular input and the fasciculus retroflexus is the pri-
mary output. Through the stria medullaris, the habenula receives
inputs from the septum, hippocampus, ventral pallidum, lateral
hypothalamus, globus pallidus, and other basal ganglia structures.
The septum is the main input to the MHb, while the remain-
ing structures project mainly to the LHb (Klemm, 2004). While
the MHb projects to the LHb, no connections from the LHb to
the MHb have been described (Kim and Chang, 2005). Based
on the input received, activity in the habenula is hypothesized to
encode an organism reward state. If the reward state is positive,
Abbreviations: IPN, interpeduncular nucleus; VTA, ventral tegmental area; RMTg,
rostromedial tegmental nucleus; nAChR, nicotinic acetylcholine receptor; GWAS,
genome-wide association study; SNP, single nucleotide polymorphism; fMRI,
functional magnetic resonance imaging; SNc, substantia nigra compacta.
habenular activity is generally diminished. If the reward state is
negative (e.g., during disappointing events) the habenular signal
is enhanced. Information about reward state is then projected via
the fasciculus retroflexus axon bundle to midbrain structures. The
fasciculus retroflexus is divided into two concentric regions. The
outer regionoriginates inthe LHb and projects to the rostromedial
tegmental nucleus (RMTg). The RMTg, sometimes calledthe“tail”
of the ventral tegmental area (VTA), is a small nucleus that con-
tains mainly inhibitory GABAergic cells and ultimately controls
activity in VTA/substantia nigra compacta (SNc), locus coeruleus
and raphe nucleus. The inner region of the fasciculus retroflexus
originates in the MHb and projects to the cholinoceptive interpe-
duncular nucleus (IPN; Herkenham and Nauta, 1977, 1979; Jhou
et al., 2009a; Table 1).
Because of the role of the habenula in the modulation of
dopamine, serotonin, norepinephrine, and acetylcholine, this
region was the object of detailed study for a number of years
(Herkenham and Nauta, 1977, 1979; Wang and Aghajanian, 1977;
Cuello et al., 1978; Lisoprawski et al., 1980; Herkenham, 1981;
Stern et al., 1981; Hamill et al., 1984). However, due to the small
size of the habenula, the difficulty of doing non-invasive stud-
ies in humans, the lack of a clearly defined functional role (links
to feeding behavior, pain sensitivity, anxiety, parental behavior,
nicotine effects, and other behaviors were all demonstrated), and
the lack of suitable pharmacological agents for habenula research,
interest in the habenula began to taper off until 2007 when Mat-
sumoto and Hikosaka published a seminal report on the habenula
as a region associated with the signaling of negative predic-
tion error events in the brain (Matsumoto and Hikosaka, 2007).
The habenula was then linked to addiction through a series of
rodent experiments and human genome-wide association studies
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Velasquez et al. The habenula and drug addiction
Table 1 | The function and anatomic location of brain structures associated with the habenula.
Structure Anatomic location Function Reference
Medial habenula (MHb) Above the thalamus at its posterior end close to
the midline.
Modulates acetylcholine Klemm (2004)
Lateral habenula (LHb) Above the thalamus at its posterior end close to
the midline, lateral to the MHb.
Associated with negative emotions. Matsumoto and Hikosaka
(2007)
Stria medullaris Located on the medial side of the thalamus; it’s a
bundle of fibers that run along the roof of the third
ventricle to the thalamus and then terminates in
the habenula.
Primary habenular input; projects to the
lateral habenula receives inputs from the
septum, hippocampus, ventral pallidum,
lateral hypothalamus, globus pallidus, and
other basal ganglia structure.
Klemm (2004)
Fasciculus retroflexus Axon bundle divided into two concentric regions.
Outer region originates in the lateral habenula and
projects to the rostoromedial tegmental nucleus
(RMTg). Inner region originates in the MHb and
projects to the cholinergic IPN.
Primary habenular output; reward state is
relayed to the midbrain via the FR.
Klemm (2004), Matsumoto
and Hikosaka (2007)
Interpeduncular nucleus
(IPN)
At the floor of the midbrain. The MHb projects to the IPN. Main
cholinergic center.
Klemm (2004)
Substantia nigra
compacta (SNc)/ventral
tegmental area (VTA)
Collection of neurons located in the midbrain. Where dopaminergic neurons are
located. Receive input from the LHb
through the RMTg.
Matsumoto and Hikosaka
(2007), Jhou et al. (2009a)
Rostromedial tegmental
nucleus (RMTg)
A small nucleus that contains mainly inhibitory
GABAergic cells, formerly called the “tail of the
VTA.”
Receives input from the LHb and projects
to midbrain dopamine neurons (VTA/SNc).
Jhou et al. (2009b)
(GWAS). These studies demonstrated that the nicotinic receptors
expressed in the habenula are not only associated with tobacco
addiction (Amos et al., 2008; Berrettini et al., 2008; Bierut et al.,
2008; Thorgeirsson et al., 2008), but also with alcohol and cocaine
addiction (Grucza et al., 2008; Wang et al., 2009). The dual role of
the habenula in reward and addiction makes the structure an ideal
target for understanding the effects of drugs of abuse on the brain.
To date, most drug abuse-related research on the habenula has
focused on nicotine, although the effects of cocaine, morphine,
and other substances on the habenula have also been researched.
PRECLINICAL WORK ON THE ROLE OF THE MEDIAL
HABENULA ON NICOTINE EFFECTS
The creation of nicotinic acetylcholine receptor (nAChR) sub-
unit mutant mouse lines, both null mice (Picciotto et al., 1998;
Xu et al., 1999a,b; Franceschini et al., 2002; Cui et al., 2003; Salas
et al., 2003a,b, 2004b, 2009; Kedmi et al., 2004; Maskos et al.,
2005) and gain-of-function mice (Broide et al., 2002; Tapper et al.,
2004; Fonck et al., 2005), has allowed for the characterization of
the effects of nicotine on different nAChR subunits (Table 2).
Through this research, the MHb has emerged as a mediator of
nicotine withdrawal symptoms after chronic nicotine treatment.
The α2, α5, and β4 subunits are involved in withdrawal (Salas
et al., 2003b, 2004b, 2009) while the α3, α5, and β4 subunits
are necessary for nicotine-induced hypolocomotion (or sedation)
and nicotine-induced seizures (Salas et al., 2003a, 2004a). The α5
subunit is involved in nicotine intake: α5 KO mice self-administer
significantly more nicotine than wild type mice, suggesting that
the α5 subunit is necessary for the aversive effects of nicotine
(Fowler et al., 2011). In addition, the activity balance between
the α5 and the β4 subunits in the MHb has been shown to regulate
aversion to nicotine (Frahm et al., 2011). Although, the molec-
ular mechanisms mediating the effect of the MHb on nicotine
withdrawal are not well understood, it was shown that the pace-
maker activity of cholinergic (but not peptidergic) neurons in
the MHb is critical for withdrawal (Gorlich et al., 2013). The
β2 subunit (usually expressed in combination with the α4 sub-
unit) has been widely considered “the addiction subunit” in that
nicotine self-administration in mice is dependent on the pres-
ence of this subunit (Picciotto et al., 1998). However, β2 null mice
exhibit normal nicotine withdrawal symptoms, suggesting that the
effects of nicotine on β2-containing nAChRs are not necessary for
the appearance of withdrawal symptoms in nicotine-treated mice
(Salas et al., 2004b). The α2, α5, and β4 subunits have each been
implicatedinnicotine withdrawal andthese subunits are expressed
in a brain region-specific manner that highlights the MHb. The α5
subunit is expressed in the MHb, IPN, some cortical areas, VTA,
and in area CA1 of the hippocampus. This subunit is an “acces-
sory” subunit that becomes functional when combined with other
α- andβ- subunits (Hsuet al., 2013). Inadditiontobeing expressed
in the habenula, the α3 and β4 subunits are expressed in the pineal
gland and in mitral cells in the olfactory bulb; the α3 subunit
Frontiers in Human Neuroscience www.frontiersin.org March 2014 | Volume 8 | Article 174 | 2
Velasquez et al. The habenula and drug addiction
Table 2 | The function and anatomic location of nicotinic acetylcholine receptors (nAChR) associated with the habenula.
Receptors/subunit Anatomic location Function Reference
Nicotinic
acetylcholine
receptors (nAChR)
Ligand-gated ion channels formed by a
pentameric arrangement of alpha and beta
subunits to create distinct muscle and
neuronal receptors.
Neuronal communication; converts
neurotransmitter binding in to membrane electrical
depolarization; binds the addictive drug nicotine.
Hogg et al. (2003)
α2 IPN, hippocampus. Involved in withdrawal symptoms after chronic
nicotine treatment.
Salas et al. (2009),
Lotfipour et al. (2013)
α3 Pineal gland, mitral cells in the olfactory bulb,
thalamus, MHb.
Necessary for nicotine-induced hypolocomotion
(or sedation) and nicotine-induced seizures.
Necessary for normal development of the
peripheral nervous system.
Xu et al. (1999a)
α4 Hippocampus, cortex, MHb, IPN. Necessary for tolerance, reward and sensitization. Tapper et al. (2004), Salas
et al. (2004a)
α5 Moderately expressed in the MHb. Also
expressed in the IPN, VTA, cerebral cortex and
in area CA1 of the hippocampus.
Involved in withdrawal symptoms after chronic
nicotine treatment.
Fowler et al. (2011),
Frahm et al. (2011), Salas
et al. (2009), Morel et al.
(2013), Bailey et al. (2010)
α6 VTA. Usually expressed with the β3 subunit. Important for addiction, reward and dopaminergic
transmission.
Wang et al. (2013),
Brunzell (2012)
α7 Hippocampus, cortex Forms homopentamers. May be involved in
schizophrenia-related behaviors.
Freedman (2014), Young
and Geyer (2013)
β2 Ubiquitously expressed, usually with the α4
subunit.
Essential for nicotine self-administration in mice. Picciotto et al. (1998)
β3 MHb, VTA. Usually expressed with the α6
subunit.
Important for dopamine release, addiction, and
reward.
Cui et al. (2003)
β4 MHb, pineal gland and mitral cells in the
olfactory bulb.
Implicated in nicotine withdrawal. Salas et al. (2004b)
is also expressed in the thalamus (Wada et al., 1989; Salas et al.,
2003a, 2004a). Further evidence for a link between nicotine with-
drawal and the habenula has been observed following injection
of mecamylamine, a non-specific nAChR blocker, into the MHb
of nicotine-treated mice. Mecamylamine injection precipitates
somatic symptoms of withdrawal such as shakes and scratching,
but only when injected into the MHb or IPN. In addition, β4, α5,
and α2 knockout mice show no nicotine withdrawal effects fol-
lowing mecamylamine injections, suggesting that the MHb/IPN
circuit, with high levels of β4, α5, and α2 subunit expression, is
involved in the expression of behaviors related to nicotine with-
drawal through neural mechanisms linked to these nAChRs (Salas
et al., 2009). Consistent with a role for the α2 subunit in nicotine
withdrawal, a recent study by Lotfipour et al. (2013) showed an
increase in nicotine self-administration and withdrawal behavior
(paw tremors, head shakes, backing, curls, grooming, scratch-
ing, chewing, cage scratching, head nodding, and jumping) in α2
−/− mice. In a separate series of studies, Stanley Glick and his
team examined the drug 18-methoxycoronaridine (18-MC), an
antagonist of β4-containing nAChRs. In rodents, microinjection
of 18-MC into the MHb – but not in several other areas – blocks
the effects of nicotine andcocaine (Glicket al., 2000, 2006; Maison-
neuve and Glick, 2003; Taraschenko et al., 2007). In summary, the
β2 subunit-containing nAChR expressed in the VTA/SNc and in
many other areas is essential for reward-related dopamine release
in the striatum and is important for nicotinic self-administration
in mice (Picciotto et al., 1998; Maskos et al., 2005). However, this
subunit is not necessarily involved in nicotine withdrawal. In con-
trast, β4 subunit-containing nAChRs expressed in the MHb and
α2-containing nAChRs (highly expressed in the IPN) mediate the
symptoms of nicotine withdrawal.
GENOME WIDE ASSOCIATION STUDIES IN HUMANS
Drug addiction has been linked to both environmental and genetic
variables. Several studies have shown that susceptibility to drug
addiction has a strong genetic component (Tsuang et al., 1998;
Karkowski et al., 2000; Kendler et al., 2000). To discern the relative
effects of genes and environment, a series of familial studies exam-
ined inheritance, twins, and adoption (Hall et al., 2013). These
studies suggest a 30–50% genetic component to drug addiction.
Many genetic studies were based on a priori hypotheses about spe-
cific gene targets in each population. While those early studies
Frontiers in Human Neuroscience www.frontiersin.org March 2014 | Volume 8 | Article 174 | 3
Velasquez et al. The habenula and drug addiction
were met with several successes, bias introduced by testing only
a limited number of genes was inevitable. The development of
new tools for examining genetic relationships across the entire
genome GWAS opened a new era in genetic studies. In GWAS, a
large number of genetic variants [typically hundreds of thousands
or even millions of single nucleotide polymorphisms (SNPs)] are
tested for association with a specific trait, such as smoking suscep-
tibility, alcoholism, or drug addiction. Large samples (usually in
the thousands) of control and affected populations are compared
using rigorous corrections for multiple comparisons. Increased
expression of specific gene variants within the affected population
can thus be associated with the disease or condition being studied.
It is important to note that these are association studies and not
studies of causality (Amos, 2007).
Genome-wide association study studies of tobacco addiction
have produced highly consistent results across laboratories with
variants in the α3, α5, and β4 nAChRs gene cluster associated
with several measures of tobacco use and addiction (Amos et al.,
2008; Berrettini et al., 2008; Bierut et al., 2008; Thorgeirsson et al.,
2008). In particular, a significant link between the rs16969968 α5
SNP and smoking addiction was identified, and a meta-analysis
yielded a significance of p < 10
−71
(Bierut, 2011). Brain expres-
sion of the α3, α5, and β4 nAChRs is highly restricted; the MHb
is the only region that co-expresses the mRNA for all three of
these subunits at either very high (α3 and β4) or moderate (α5)
levels. The IPN, the main output from the MHb, is a primary
site of α5 and β4 nAChR subunit expression. Thus, GWAS data
suggests that the habenula and associated regions expressing the
α5 and β4 nAChR subunits may play a role in tobacco addiction.
Interestingly, the same SNPs that are associated with the risk of
tobacco use are also associated with cocaine abuse (Grucza et al.,
2008) and alcohol abuse (Wang et al., 2009). This suggests that the
mechanism of addiction for different drugs of abuse shares over-
lapping genetic factors and anatomical brain regions. Given the
role of the habenula in modulating reward and disappointment, it
is not surprising that genes controlling habenular activity are also
associated with drugs of abuse (Quick et al., 1999).
THE LATERAL HABENULA AND THE NEGATIVE PREDICTION
ERROR
Drugs of abuse increase dopamine levels in the striatum. Since
dopamine levels have been related to reward, it is believed that
drug-induced increases in dopamine are important for the abuse
potential of drugs (Di Chiara and Imperato, 1988). Activity of
dopaminergic cells in the VTA/SNc is of critical importance for
reward signaling and in addictive behaviors. Indeed, early work in
primates showed that dopaminergic cells in the VTA/SNc are acti-
vated by oral delivery of sweet juice (Montague et al., 1996; Schultz
et al., 1997). However, more recent experiments have shown that
the role of dopamine in reward is more complex than simple
stimulus-response. Monkeys that learn to associate juice reward
with a predictive cue, such as a flash of light, shift the spike of
dopaminergic activity to the cue. Following cue-juice association,
the juice no longer induces dopaminergic activity, yet withhold-
ing of the expected juice reward causes dopamine levels to drop.
This suggests that dopamine may actually signal reward predic-
tion, rather than reward itself, and a negative prediction error or
“disappointment” following lack of reward (Montague et al., 1996;
Schultz et al., 1997). The decrease in dopaminergic activity is anal-
ogous to a negative prediction error and has been hypothesized to
play a role in learning from mistakes. Only recently has the neural
signal responsible for this drop in dopamine release been localized
to the LHb (Matsumoto and Hikosaka, 2007). In their seminal
2007 work, Matsumoto and Hikosaka trained monkeys to perform
lateral saccadic eye movements. A saccade to one side predicted
juice delivery while saccades to the other side did not predict juice
reward. By altering the probability of juice reward, Matsumoto
and Hikosaka were able to create conditions of both unexpected
rewardandof rewarddisappointment whenthe juice was expected,
but not delivered. They demonstrated that activity of neurons
in the LHb increased following negative prediction error events
(lack of expected reward) and decreased following unexpected
juice reward. It follows that the habenula is activated by nega-
tive events. This activation decreases downstream dopaminergic
activity through GABAergic inhibition of brain structures receiv-
ing habenular inputs and results in negative affect (Matsumoto
and Hikosaka, 2007). In humans, the decreased reward experi-
enced by chronic drug users may result from increased habenular
activity and the resulting inhibition of dopamine in the VTA/SNc.
HABENULAR CONTROL OF DOPAMINE, SEROTONIN, AND
NOREPINEPHRINE
Neural signals from the LHb ultimately affect the VTA/SNc, the
raphe nucleus, and the locus coeruleus (both directly and indi-
rectly through the RMTg; Klemm, 2004; Balcita-Pedicino et al.,
2011). The VTA/SNc is the most studied downstream habenu-
lar target, although both the raphe nucleus and locus coeruleus
also receive strong signals from the LHb (Hikosaka et al., 2008).
Given the role these structures play in the regulation of dopamine,
serotonin, and norepinephrine, the LHb likely modulates neuro-
transmitter release in those three systems. Thus, it is not entirely
surprising that habenular activity has been linked to several seem-
ingly unrelated behaviors and disease conditions. For example,
the habenula has been linked to stress-enhanced acoustic startle,
probably via effects on the locus coeruleus (Heldt and Ressler,
2006). The LHb has been linked to maternal feeding and sex-
ual behaviors (Klemm, 2004). The LHb has also been linked to
major depressive disorder (MDD) in both preclinical and clin-
ical research. In mice, learned helplessness (an animal model
for studying depression-like symptoms) results in potentiation of
LHb outputs, suggesting an increase in negative neural signal-
ing (Li et al., 2011). Using cytochrome oxidase histochemistry, a
metabolic marker, both the MHb and the LHb have been impli-
cated in learned helplessness and depressive behavior in rats reared
to exhibit these traits (Shumake et al., 2004). In humans, the
severity of depression symptoms in patients correlated with the
level of coupling between the habenula and the raphe nucleus:
The stronger the link between these brain structures, the more
severe the depression symptoms after a tryptophane-free diet
was given to depression patients in remission to acutely precip-
itate depression symptoms (Morris et al., 1999). The link between
habenular activity and MDD was further demonstrated in a
treatment-resistant MDD patient who responded to deep brain
stimulation of the LHb when other treatments for depression were
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Velasquez et al. The habenula and drug addiction
shown to be ineffective (Sartorius et al., 2010). Taken together,
these findings suggest that MDD may result from a combina-
tion of habenular hyperactivity that disrupts dopaminergic and
serotonergic signaling following negative or disappointing events
along with decreased dopaminergic activity following positive
events.
THE ROLE OF THE HABENULA IN COCAINE DEPENDENCE
Using cocaine reinstatement protocols it was demonstrated that
high reinstatement rats and mice show higher c-fos activity than
low reinstatement animals (Brown et al., 2010; James et al., 2011).
While cocaine is initially rewarding, cocaine aversion usually
develops about 15 min after injection (Ettenberg et al., 1999). Sig-
nals from the LHb inhibit dopaminergic neurons reducing the
dopaminergic reward signal which can account for the aversive
effects of cocaine (Jhou et al., 2013).
A study by Maroteaux and Mameli (2012) showed the synap-
tic plasticity of LHb neurons in mice, when exposed to cocaine.
They demonstrated that exposure to cocaine selectively potenti-
ates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor (AMPAR)-mediated transmission in LHb neurons pro-
jecting to the RMTg but not to the VTA. They stereotaxically
injected green and red fluorobeads in the VTA and RMTg and
then examined if cocaine affected excitatory synaptic transmission
on the LHb neurons. These mice were injected with cocaine and
saline for two consecutive days. They found that cocaine exposure
strengthens AMPAR-mediated synaptic transmission but only in
LHb to RMTg neurons. Their data suggests that the composition
of the synaptic AMPARs in LHb to RMTg neurons was not sig-
nificantly changed by the cocaine. A residual current at positive
potentials was detected, suggesting that excitatory synapses onto
LHb neurons likely contain GluA2-lacking and GluA2-containing
AMPARs. Insum, they offer evidence for a synaptic potentiationin
the LHb that could represent an important mechanism involved
in the formation of drug-associated memories (Maroteaux and
Mameli, 2012).
THE ROLE OF THE HABENULA IN MORPHINE DEPENDENCE
The habenula has also been implicated in morphine addic-
tion, although the exact relationship between habenular activity
and morphine is inconsistent across studies. Chronic morphine
administration (escalating doses of 20, 40, 60, 80, 100, and
100 mg/kg three times per day) leads to a reduction in acetyl-
cholinesterase (AChE) activity in the MHb (Neugebauer et al.,
2013). During morphine withdrawal, AChE activity in MHb
returns to baseline, suggesting a homeostatic balance. However,
a second study using higher doses of morphine (450 mg/kg)
administered for a longer period of time (15 days), showed
increasedAChEactivity inthe habenula (Mohanakumar andSood,
1983).
Unlike cocaine, which increases Fos protein expression in the
habenula (Brown et al., 2010; James et al., 2011), chronic mor-
phine exposure reduces c-fos activity in the MHb (Neugebauer
et al., 2013). Morphine withdrawal has also been shown to increase
glucose metabolism in a number of limbic and thalamic regions,
including the MHb (Kimes et al., 1990). Again suggestive of a
homeostatic balancing mechanism, morphine withdrawal elevates
Fos protein levels in the LHb. Somewhat surprisingly, similar pat-
terns of c-fos positive cell activation have been reported in animals
seeking sucrose following abstinence (Madsen et al., 2012).
THE FASCICULUS RETROFLEXUS DEGENERATES FOLLOWING
TREATMENT WITH DRUGS OF ABUSE
The rodent fasciculus retroflexus has been shown to degenerate
following chronic exposure to stimulants such as D-amphetamine,
methamphetamine, MDMA, cocaine, and nicotine. The fasciculus
retroflexus nerve bundle connects the habenula to its main targets,
the IPN and RMTg. Interestingly, nicotine treatment prompts
cell death and axonal degeneration in the central region of the
fasciculus (axons coming from the MHb) while other drugs of
abuse prompted neurodegeneration in the external region (axons
coming from the LHb; Ellison, 2002; Ciani et al., 2005). A recent
study of fasciculus retroflexus integrity in rats showed neurode-
generation of the habenular efferent following increased cocaine
self-administration, indicating a reduction in LHb to midbrain
connectivity (Lax et al., 2013). Overall, the fasciculus retroflexus
appears to be a “weak link” in the brain’s reward circuitry, one
that is particularly susceptible to drugs of abuse (Ellison, 2002).
The cause of fasciculus retroflexus degeneration remains unclear,
however, multiple drugs of abuse may affect this pathway in that
the habenula is activated during cocaine, morphine, and nicotine
drug seeking behavior and during drug re-instatement following
abstinence (Brown et al., 2010; James et al., 2011).
18-MC, AN ANTAGONIST OF β4-CONTAINING nAChR,
DECREASES SEVERAL EFFECTS OF ABUSED DRUGS
Ibogaine, an extract from the African shrub Tabermanthe iboga,
is a hallucinatory alkaloid used in African spiritual ceremonies.
In the 1960s, ibogaine was used to treat several forms of addic-
tion through apparent effects on the cholinergic and glutamatergic
neurotransmitter systems. In rodents, ibogaine was shown to
reduce self-administration of cocaine (Cappendijk and Dzoljic,
1993), alcohol (Rezvani et al., 1995), and morphine (Glick et al.,
1991). However, because of the severe side-effects associated with
ibogaine (e.g., headaches, nausea, hallucinations), the alkaloid
has been banned in the USA and other countries. Ibogaine drug
derivatives, such as 18-MC, however, have been created in an
attempt to develop medications to treat drug addiction. The
18-MC compound has been shown to effectively block cravings
and withdrawal and to decrease self-administration of morphine,
cocaine, and nicotine in laboratory animals (Glick et al., 2000).
The drug does not affect water consumption, unlike the natu-
rally occurring Ibogaine. Furthermore, the effectiveness of 18-MC
increases with repeated treatments and reduces the overall inten-
sity of morphine withdrawal symptoms in rats (Glick et al., 2000).
The mechanism of action for 18-MC and the site of action remain
unclear. While direct injection of 18-MC into the locus coeruleus
reduces symptoms of morphine withdrawal, direct injection into
the MHb has mixed effects. Low doses of 18-MC in the habe-
nula reduce teeth chattering and weight loss while higher doses
increase teeth chattering and reduce burying behaviors during
morphine withdrawal (Panchal et al., 2005). 18-MC also blocks
the acquisition of conditioned place preference (CPP) for cocaine,
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Velasquez et al. The habenula and drug addiction
but enhances the reinstatement of cocaine-seeking behavior fol-
lowing extinction (McCallum and Glick, 2009). 18-MC does not
affect glutamate receptors, but retains antagonistic activity toward
the highly expressed β4-containing nAChRs in the MHb and IPN
(Glick et al., 2006). Additionally, 18-MC affects dopaminergic
activity, which is regulated by the LHb. Consequently, targeting
of β4-containing nAChRs in the MHb could prove therapeutic
to the treatment of nicotine, cocaine, morphine, alcohol, and
methamphetamine addiction.
VARENICLINE AFFECTS DEPENDENCE ON DRUGS OF ABUSE
Varenicline is a partial agonist of nAChRs and is approved by the
FDA for use in tobacco quitting therapies (Coe et al., 2005). The
effects of varenicline on tobacco addiction are well studied, but it
is becoming evident that varenicline may also be effective in the
treatment of other drugs of abuse. Varenicline effectively weakens
cocaine reinstatement in small doses, but increases cocaine rein-
statement in higher doses even as it decreases self-administration
(Guillem and Peoples, 2010). In rodent studies of varenicline and
alcohol abuse, the drug reduced ethanol seeking behavior at the
same doses previously shown to reduce nicotine-seeking behavior,
but did not alter sucrose-seeking behavior in self-administration
experiments. In mice, voluntary ethanol consumption was also
decreased, but not water consumption (Steensland et al., 2007).
These results suggest that varenicline may be an effective treat-
ment not only for tobacco but also for other drugs of abuse
(Crunelle et al., 2010). Although most of the literature points to
α4β2-containing nAChR as the relevant target the α3β4 subunit
receptor has also been implicated in addiction and the β4 subunit
was recently linked to varenicline’s reduction of ethanol consump-
tion (Chatterjee et al., 2011). Mihalak et al. (2006) have shown that
varenicline is a partial agonist of both α4β2 and α3β4 nAChRs.
Thus, it is likely that at least some of the effects of varenicline on
drug abuse are mediated by the habenula where these receptors
are expressed at high concentration.
THE MEDIAL AND THE LATERAL HABENULA
The role of the MHb indrug addictionand abuse has beendemon-
strated through rodent studies of nicotinic receptors as well as
suggestedby GWAS studies inhumans. Arole for the LHbinaddic-
tion is suggested by negative prediction error studies (Matsumoto
and Hikosaka, 2007; Salas et al., 2010), deep brain stimulation in
rodents (Lax et al., 2013), and drug-induced fasciculus retroflexus
degeneration in rodents (Ellison, 1992, 2002). While it is possi-
ble that the MHb and the LHb regulate distinct mechanisms of
drug dependence and abuse, we believe that this is not necessarily
the case. McCallum et al. (2012) recently showed that blockade
of β4 subunit-containing nAChRs in the MHb directly affects
mesolimbic dopamine. Microinjections of 18-MC or AuIB (both
preferential β4 antagonists) into the MHb prevented nicotine-
induced increases in nucleus accumbens (NAcc) dopamine. Thus,
there must be a connection between the MHb and NAcc dopamine
levels (McCallum et al., 2012). The MHb may regulate dopamine
in striatal regions through several mechanisms, although two can-
didate pathways appear most likely. First, the IPN is the primary
target of the MHb and projects directly to dopaminergic areas,
making it possible that activity in the MHb influences dopamine
levels in the striatum independent of LHb activity (Groenewegen
et al., 1986; Klemm, 2004). Second, direct connections from the
MHb to the LHb have also been reported, but not in the oppo-
site direction, making it possible that one of the functions of the
MHb is to provide additional input to the LHb (Kim and Chang,
2005). The mechanisms by which these structures may modulate
dopamine availability in the striatum are unknown at this time.
ELECTRICAL STIMULATION IN THE LATERAL HABENULA
REDUCES COCAINE-SEEKING BEHAVIOR
Deep brain stimulation is an effective treatment for several neuro-
logical diseases and conditions, including Parkinson’s disease and
depression (Mayberg, 2009; Callesen et al., 2013). In rodent stud-
ies, electrical stimulation of the LHb reduced cocaine cravings,
self-administration, and reinstatement while improving extinc-
tion. Damage to the LHb increased cocaine-seeking behavior,
suggesting that this behavior may result from a weakening of
cocaine-induced glutamatergic inputs to the VTA(Friedman et al.,
2010). Since cocaine treatment causes degeneration of the fascicu-
lus retroflexus (Ellison, 1992), it is important to knowthe status of
the fasciculus retroflexus in human cocaine users before attempt-
ing to use deep brain stimulation as a possible therapy for cocaine
abuse.
INSIGHT FROMHUMAN fMRI STUDIES
Most of what we know about the habenula comes from rodent
and monkey models. In humans, study of the habenula has been
hampered by its small size. In the first functional magnetic res-
onance imaging (fMRI) report focusing on the habenula, the
authors asked human participants to guess which of two visual
stimuli would reach a target first. The task difficulty was modu-
lated so that all participants would commit a similar number of
errors and receive the same degree of positive and negative feed-
back. Negative feedback activated the habenula (Ullsperger and
von Cramon, 2003). Using a similar strategy, Shepard et al. (2006)
reported that schizophrenic patients lack habenular activation fol-
lowing negative feedback. Of the limited number of human fMRI
studies focusing on the habenula, only one specifically addressed
reward. In that study, a juice reward paradigm previously used in
monkey studies of the habenula was employed. Juice was used as
a reward and delay of expected juice was used as a disappointing
stimulus. As in the monkey studies, the human habenula is acti-
vated following non-delivery of expected juice reward (Salas et al.,
2010). Arelated study by Ide and Li (2011) used fMRI connectivity
analysis to study humans performing a stop signal task in which
subjects hadtorapidly followthe instructionof “go”or“stop.”Each
“stop” event could be successful (the prompt called for a “stop”) or
failed (the prompt indicated “go” when the participant stopped).
The investigators looked for regions with larger psychophysiolog-
ical interaction with the habenula during stop-error than during
stop-success trials and identified task-specific activation of the
VTA/SNc, internal segment of globus pallidus, bilateral amygdala,
and insula. Using Granger causality and mediation analyses they
showed a directional link between habenula and VTA/SNc fMRI
activation. These results suggest that habenular activity results in
a decrease in VTA/SNc activity (Ide and Li, 2011). Finally, there
are two reports linking the habenula to human MDD. In a PET
Frontiers in Human Neuroscience www.frontiersin.org March 2014 | Volume 8 | Article 174 | 6
Velasquez et al. The habenula and drug addiction
study, Morris et al. (1999) observed increased coupling between
habenula/raphe nucleuses following tryptophan depletion in for-
mer MDD patients exhibiting signs of remission. This increase
in habenular/raphe coupling correlated with the re-appearance of
depression symptoms (Morris et al., 1999). Anatomically, Savitz
et al. (2011) presented evidence for a reduction in habenular vol-
ume in non-medicated, depressed bipolar disorder patients and
female MDD patients.
CONCLUSION
Much of the work linking the habenula to drug addiction is based
on studies of nicotine and nicotinic receptors in the MHb. Addi-
tional studies have linked the habenula to morphine and cocaine
addiction and withdrawal. Importantly, deep brain stimulation of
the habenula has been shown to decrease cocaine-seeking behav-
ior in rodents, which may open the door to possible therapies
against cocaine abuse. A caveat to this approach is that cocaine
and other drugs of abuse are known to cause degeneration of
the fasciculus retroflexus, the primary habenular output, poten-
tially reducing the effectiveness of deep brain stimulation as a
treatment for drug abuse. Similarly, nicotine causes degener-
ation of the internal component of the fasciculus retroflexus,
which connects the MHb to the IPN. As a result of this “weak
link” between the habenula and downstream structures, the
IPN and the RMTg may be more effective primary targets for
anti-addiction drugs. Additional research is required to better
understand the role of the MHb and the LHb in drug addic-
tion and to illuminate the relationship between the habenula
and downstream structures in the face of addiction. Promising
technological advances, such as the use of 7T MRI scanners,
may soon allow researchers to differentiate the roles of the MHb
and the LHb in humans with drug addiction, depression, and
other disorders (Strotmann et al., 2013). The habenula is a wor-
thy target for study in that it has been shown to play a role
in addiction, depression, and negative feedback and negative
prediction error events (likely two manifestations of the same
phenomenon). The habenula also acts as a major regulator of
several neurotransmitter systems, including dopamine, serotonin,
norepinephrine, and acetylcholine. These neurotransmitters alter
neural activity throughout the brain and thus have the potential
to influence a wide-range of both normal and abnormal human
behaviors.
ACKNOWLEDGMENTS
NIDA (026539, 09167); McNair Medical Institute, The Brain and
Behavior Foundation.
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Conflict of Interest Statement: The authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 25 October 2013; accepted: 09 March 2014; published online: 28 March 2014.
Citation: Velasquez KM, Molfese DL and Salas R (2014) The role of the habenula in
drug addiction. Front. Hum. Neurosci. 8:174. doi: 10.3389/fnhum.2014.00174
This article was submitted to the journal Frontiers in Human Neuroscience.
Copyright © 2014 Velasquez, Molfese and Salas. This is an open-access article dis-
tributed under the terms of the Creative Commons Attribution License (CC BY). The
use, distribution or reproduction in other forums is permitted, provided the original
author(s) or licensor are creditedandthat the original publicationinthis journal is cited,
in accordance with accepted academic practice. No use, distribution or reproduction is
permitted which does not comply with these terms.
Frontiers in Human Neuroscience www.frontiersin.org March 2014 | Volume 8 | Article 174 | 10

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