Download Alertness and feeding behaviors in ADHD: Does the hypocretin

Medical Hypotheses (2008) 71, 770–775
www.elsevier.com/locate/mehy
Alertness and feeding behaviors in ADHD: Does the
hypocretin/orexin system play a role?
Samuele Cortese
a,b,*
, Eric Konofal
a,c,d
, Michel Lecendreux
a,c
a
APHP, Child and Adolescent Psychopathology Unit, Robert Debré Hospital, Paris VII University,
48 Bd Serurier, 75019 Paris, France
b
Child Neuropsychiatry Unit, G.B. Rossi Hospital, Department of Mother-Child and Biology-Genetics,
Verona University, Verona, Italy
c
APHP, Pediatric Sleep Disorders Center, Robert Debré Hospital, Paris, France
d
APHP, Sleep Disorders Center, Pitié-Salpêtrière Hospital, Paris, France
Received 26 May 2008; accepted 10 June 2008
Summary Increasing evidence has suggested that patients with attention-deficit/hyperactivity disorder (ADHD) may
present with a deficit of alertness and sleep disturbances. Recent studies have also pointed out a previously
underestimated association between ADHD and abnormal eating behaviors, including binge eating. Since sleep/
alertness disturbances and eating disorders may significantly increase the functional impairment of ADHD, gaining
insight into their pathophysiology as well as into their treatment is of relevance to provide a better clinical
management of patients suffering from ADHD. The hypocretin/orexin system comprises two distinct peptides, located
in the hypothalamus, which are involved in several homeostatic functions. In particular, it has been suggested that
hypocretin/orexin neurons located in perifornical and dorsomedial hypothalamic nuclei increase arousal, whereas
those located in the lateral hypothalamus are primarily implicated in reward processing, stimulating feeding and other
reward seeking behaviors. Given the involvement of the hypocretin/orexin system in the control of alertness and
reward seeking (including feeding), we hypothesize that hypocretin/orexin neurons located in perifornical and
dorsomedial hypothalamic areas are hypoactivated, while those located in the lateral hypothalamus are overactivated
in patients with ADHD. If confirmed by further neurophysiological, imaging, and genetics studies, our hypothesis may
help us progress in the understanding of the complex pathophysiology of ADHD. This might set the basis for the study of
novel molecules, acting on the hypocretin/orexin system, aimed at increasing wakefulness and reducing binge eating
and other abnormal reward seeking behaviors in patients with ADHD. We also suggest future studies on the potential
therapeutic role of other molecules which have a complex interplay with the hypocretin/orexin system, such as the
histamine H1 receptor agonists, the histamine H3 receptor antagonists, and the neuropeptide Y receptor antagonists.
All this body of research would provide a tremendous opportunity to improve the quality of life of patients with ADHD
by means of pathophysiologically oriented treatment.
c 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Address: APHP, Child and Adolescent Psychopathology Unit, Robert Debré Hospital, Paris VII University, 48
Bd Serurier, 75019 Paris, France. Tel.: +33 140032263; fax: +33 140032297.
E-mail addresses: [email protected], [email protected] (S. Cortese).
0306-9877/$ - see front matter c 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2008.06.017
Alertness and feeding behaviors in ADHD: Does the hypocretin/orexin system play a role?
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is
one of the most common childhood onset psychiatric disorders, with an estimated worldwide prevalence of about 5% in school-aged children [1].
According to the Diagnostic and Statistical Manual
of Mental Disorders – fourth edition (DSM–IV) [2],
ADHD is characterized by a pattern of pervasive,
impairing, and developmentally inappropriate
symptoms of inattention and/or impulsivity-hyperactivity. Impairing symptoms of ADHD may persist
into adulthood in up to 60% of cases [3].
It is well known that ADHD is often associated
with other disorders, which contribute to the functional impairment of the patient. Commonly reported psychiatric comorbid disorders include
oppositional defiant disorder, conduct disorder,
anxiety disorders, depressive disorders, speech
and learning disorders [4]. On the other hand,
sleep/alertness disturbances and eating disorders
associated with ADHD have been quite overlooked
in research as well as in the clinical practice. However, increasing empirically based evidence has
suggested a significant association between ADHD
and sleep/alertness alterations [5,6], as well as
abnormal feeding behaviors [7].
A better insight into the mechanisms underlying
this association is of relevance for two reasons.
First, it may advance our understanding of the
pathophysiology underlying ADHD. Second, from a
clinical standpoint, it might allow a better and
more comprehensive management of patients with
ADHD. Since sleep/alertness and feeding alterations may significantly increase the functional
impairment of ADHD, this seems noteworthy.
In the present paper, we hypothesize that alterations in the hypocretin/orexin system contribute
to impaired alertness and abnormal feeding behaviors in patients with ADHD.
Background
The hypocretins (also named orexins) were described by two groups in 1998 and comprise two
distinct peptides. Sakurai et al. [8] purified two
peptides from rat brain extracts that activated a
G-protein-coupled receptor. Because intracerebroventricular injection of these peptides in rats
acutely stimulated food consumption, they were
named orexin-A and orexin-B after the Greek word
‘orexis’, meaning appetite. Around the same time,
de Lecea et al. [9] identified a cDNA encoding two
polypeptides in the hypothalamus that they named
hypocretins on the basis of their hypothalamic
771
localization and their proposed sequence similarity
to the secretin family of peptides. It soon became
clear that the peptides isolated by the two groups
were, in principle, identical. Therefore, they are
commonly referred to as the ‘‘hypocretin/orexin
system’’.
Neurons expressing hypocretins/orexins are located exclusively in the lateral and posterior hypothalamus (perifornical areas) [10]. Although small
in number, these neurons have extensive projections throughout central nervous system, including
the cerebral cortex, the limbic system (e.g. the
amygdala and hippocampus), the hypothalamic nuclei (e.g. the arcuate nucleus and the tuberomammillary nucleus), and the brainstem (e.g. the
central gray, locus coeruleus, and raphe nuclei).
Throughout these projections, the hypocretin/
orexin system can affect a variety of physiologic
mechanisms, including sleep/alertness, feeding
behaviors, endocrine, and autonomic functions. In
order to better understand our hypothesis, we detail here some data on the role of the hypocretin/orexin system in the regulation of sleep/
alertness and feeding behavior.
Sleep/alertness
Orexin neurons send their projections to nuclei involved in sleep/wake regulation, including the locus coeruleus, raphe nuclei, tuberomammillary
nucleus, pedunculopontine tegmental nucleus/laterodorsal tegmental nucleus, ventrolateral preoptic nucleus, and basal forebrain (BF) cholinergic
neurons [10]. The hypocretin/orexin system projections to the limbic system may also play a relevant role, since recent evidence suggests the
implication of the limbic system in the generation
of arousal [11]. This highlights the role of emotional factors in the regulation of alertness.
The involvement of the hypocretin/orexin system in the regulation of sleep/wakefulness states
is supported by the deficiency of hypocretin/orexin
neurons in narcolepsy with cataplexy, a debilitating neurological disease characterized by excessive
daytime sleepiness, cataplexy, sleep paralysis, and
sleep onset-associated hallucinations. Several lines
of evidence (reviewed in [10]) have confirmed that
genetic disruption of the hypocretin/orexin system
can cause narcolepsy with cataplexy.
Feeding behaviors
Since the initial demonstration of orexin-induced
hyperphagia in rats, a large body of evidence has
accumulated in support of the involvement of the
772
hypocretin/orexin system in mechanisms of appetite regulation, including motivational aspects of
eating, drive to eat, cephalic phase reflexes, mastication, and insulin secretion [12]. The projections
of the hypocretin/orexin system to the limbic
structures may play a significant role in the regulation of emotional aspects of eating. Several lines of
evidence suggest that hypocretin/orexin induced
hyperphagia is at least partly mediated through
downstream activation of Y1 and Y5 receptors of
neuropeptide Y (NPY), and, vice versa, that NPY-induced hyperphagia may in part be mediated
through activation of orexin mechanisms [13].
Mounting evidence indicates that the hypocretin/
orexin system not only stimulates appetite for
food, but also can stimulate an appetite for other
rewards such as abused drugs [14].
Recently, Harris et al. [14] have proposed a
functional dichotomy for the hypocretin/orexin
neurons, suggesting that hypocretin/orexin neurons located in perifornical and dorsomedial hypothalamic areas are involved in arousal and waking,
whereas those located in the lateral hypothalamus
are primarily involved in reward processing, including feeding behaviors.
Deficit of alertness in ADHD
According to the hypoarousal theory of ADHD, children with ADHD (or at least a subgroup of them)
may actually be sleepier than controls and may
use motor hyperactivity as a strategy to stay awake
and alert, in order to counteract the tendency to
fall asleep [15]. In a seminal study using the multiple sleep latency test (MSLT, an objective procedure used to assess daytime sleepiness)
Lecendreux et al. [16] confirmed that children with
ADHD are sleepier than controls. This result was
subsequently replicated by Golan et al. [17] in a
sample of adolescents with ADHD. In line with
these findings, a more recent study by Miano et
al. [18], using a novel approach (analysis of the
cyclic alternating pattern rates), supported the
hypothesis of the existence of a hypoarousal state
in children with ADHD.
Abnormal eating behaviors in ADHD
According to a recent review of the literature by
our group [7], available evidence suggests that
binge eating or eating disorders with bulimic
behaviors occur at higher than expected rates in
subjects with ADHD.
The mechanisms involved in the so called ‘‘reward deficiency syndrome’’ may play a significant
role to explain the association between ADHD and
Cortese et al.
binge eating. The ‘‘reward deficiency syndrome’’
is characterized by an insufficient dopamine-related natural reward that leads to the use of
‘unnatural’ immediate rewards, such as substance
use, gambling, risk taking and, remarkably, binge
eating [19]. Several lines of evidence suggest that
a subset of patients with ADHD may present with
behaviors consistent with the ‘‘reward deficiency
syndrome’’ [20,21].
The hypothesis
Since the hypocretin/orexin system is involved in
the control of alertness and reward seeking, including feeding, and given that patients with ADHD may
present with a deficit of alertness as well as with
binge eating or other behaviors aimed to provide
unnatural immediate rewards, we speculate that
patients with ADHD (or at least a subgroup of them)
have an alteration in the hypocretin/orexin system. In particular, we hypothesize that hypocretin/orexin neurons located in perifornical and
dorsomedial hypothalamic areas (involved in the
control wakefulness) are hypoactivated, while
those located in the lateral hypothalamus, involved
in reward processing, are overactivated in patients
with ADHD. Since one can suppose that a normal level of alertness is required to adequately control
and regulate eating behaviors, we further speculate that the deficit in alertness contributes to
aggravate the abnormal feeding patterns associated with ADHD.
Interestingly, the hypocretin/orexin system has
been shown to stimulate locomotor behaviors in
animal models [22]. It has been suggested that such
a stimulation is required to support feeding seeking
[22]. Therefore, we speculate that increased motor
activity in ADHD might be a mechanism coupled to
an overstimulation of feeding behaviors due to a
hyperactivation of the hypocretin/orexin system
in the lateral hypothalamus.
To our knowledge, the functioning of the hypocretin/orexin system has never been investigated
in patients with ADHD.
Electrophysiological studies in animal models of
ADHD aimed at quantifying the firing of hypocretin/
orexin neurons in perifornical, dorsomedial, and
lateral hypothalamic areas could provide a first
support to our hypothesis.
Functional neuroimaging studies assessing the
activity of the perifornical, dorsomedial, and lateral hypothalamic of patients with ADHD during
tasks evaluating feeding behaviors and alertness
would be pivotal to confirm our hypothesis.
Dosing the cerebro-spinal fluid levels of hypocretin/orexin in patients with ADHD, as previously
Alertness and feeding behaviors in ADHD: Does the hypocretin/orexin system play a role?
done, for example, in patients with narcolepsy-cataplexy [23] or restless legs syndrome [24], could
provide further strong evidence in favour of our
hypothesis.
Finally, studies of the hypocretin/orexin genes
or their receptors in animals and humans could allow us to discover possible genetic alterations
underlying the putative dysfunctions of the hypocretin/orexin system.
Given the role of the limbic system in the control of alertness and eating behaviors, as previously
pointed out in this paper, we believe that future
research aimed at understanding the role of the
hypocretin/orexin system in ADHD should focus in
particular on the projections of this system to the
limbic structures.
Implications
If confirmed by future studies, our hypothesis could
lead to further refinement in our understanding of
the central mechanisms involved in alertness and
reward seeking behaviors, including abnormal eating behaviors, in patients with ADHD. Since the
molecular underpinnings of these impairing behaviors associated with ADHD are still unclear, research in this field should be encouraged.
Moreover, our hypothesis may also set the basis
for the study of novel molecular targets for the
development of drugs aimed at increasing wakefulness and reducing binge eating and other abnormal
reward seeking behaviors in patients with ADHD.
This would provide a tremendous opportunity to
improve the quality of life of these patients by
means of pathophysiologically oriented treatment.
Interestingly, it has been suggested that the effect of orexin on wakefulness is largely mediated
by activation of the histaminergic system through
hypocretin/orexin receptor 2, while signaling
through hypocretin/orexin receptor 1 is important
for the regulation of abnormal eating behaviors
[22].
Therefore, we speculate that hypocretin/orexin receptor 1 antagonists might have a role in the
treatment of abnormal eating behaviors, while
hypocretin/orexin receptor 2 agonists might be
useful to enhance alertness in patients with
ADHD.
With regard to molecules potentially useful for
abnormal eating behaviors, it has been reported
that the first hypocretin/orexin receptor 1 antagonist (1-(2-methylbenzoxanzol-6-yl)-3-[1,5] naphthyridin-4-yl urea hydrochloride (SB-334867))
inhibits both natural food intake and feeding induced by central administration of hypocretin 1 in
773
rats, accelerates the transition between feeding
and resting, and reduces the occurrence of several
activity-related behaviors. Furthermore, SB334867 has been shown to reduce feeding, body
weight and fat in ob/ob obese mice [25].
As for the treatment of the deficit of alertness,
it has been demonstrated that the replacement of
central hypocretin by either pharmacologic (intracerebroventricular injection of hypocretin-1) or genetic (ectopic expression of hypocretin in the
brain) manipulations allows for the rescue of the
narcolepsy-cataplexy phenotype in animal models
(mice) [25]. Unfortunately, so far, no published
data are available for hypocretin receptor agonists
[25]. Research in this field could lead to important
therapeutic options to promote wakefulness in
ADHD patients, with potential effects on attention
and hyperactivity (as expected according to the
hypoarousal theory of ADHD).
It would also be worthwhile to assess the role of
molecules which act in association with or colocalize with the hypocretin/orexin system. We suggest
here some potential avenues of research.
Recent studies have pointed out that the hypocretin/orexin system and the histaminergic neurons may cooperate in the regulation of sleep/
alertness and feeding [26]. In particular, as for
the regulation of wakefulness, activation of histaminergic neurons by orexins might be important for modulation of the arousal [27]. The
histamine 1 receptor (H1R) play an important
role in the regulation of alertness, because H1R
agonists decrease all phases of sleep, whereas
H1R antagonists increase sleep [26]. With regard
to the control of feeding, it has been reported
that food intake is depressed by activation of
H1R receptors, whereas either treatment with
H1R antagonists or inhibition of histamine synthesis increases feeding [26]. Therefore, we
believe that the role of H1R agonists deserves
special attention in patients with ADHD, because
they might be useful to both increase alertness
and reduce abnormal feeding behaviors. Thus,
the use of just one molecule would allow to
manage at the same time two impairing conditions for ADHD patients.
It is also well-known that the antagonists of the
autoinhibitory histamine 3 receptor (H3R) promote wakefulness [28]. Interestingly, H3R antagonists are under investigation for ADHD itself
[29]. Therefore, these agents may be of special
interest in patients with ADHD, addressing not
only the core symptoms of this disorder, but also
the associated alterations of alertness and feeding behaviors.
774
As previously mentioned, it has been pointed out
that hypocretin/orexin stimulated feeding may
occur at least partly through NPY pathways
[13]. This peptide has scarcely been studied in
ADHD. Since an NPY-Y1 receptor antagonist
(BIBO3340) is now available and it has been
showed that it inhibits food intake, research on
the role of NPY in abnormal eating behaviors
associate with ADHD should be encouraged.
Another potentially interesting line of research
could focus on the role of the cocaine and
amphetamine regulated transcript (CART). It
has been reported that administration of CART
inhibits both normal food intake and orexin-Astimulated food intake in goldfish [30]. Given
the implication of the CART in drug reward,
research on CART and its interactions with the
hypocretin/orexin system in ADHD could provide
a tremendous opportunity for the treatment not
only of abnormal eating behaviors, but also of
other reward seeking behaviors, such as substance abuse disorder, which represents one of
the most impairing comorbidities in adolescents
and adults with ADHD.
Other molecules which deserve further exploration in ADHD are leptin, ghrelin, dynorphin and
galanin, which have a complex interplay with
the hypocretin/orexin system in the control of
feeding and appetite [31]. To our knowledge,
the role of these molecules in the pathophysiology of ADHD has not been addressed.
All this body of research that we propose could
provide further evidence in favour of the complexity of the pathophysiology of ADHD, confirming that
this is a neurobiological disorder which affects several functions, not only the cognitive or the motor
ones. Furthermore, the therapeutic implications of
this research could lead to pharmacological options
which might significantly improve sleep, eating,
and substance abuse disorders of patients with
ADHD, ameliorating their quality of life.
Conflict of interest statement
The authors declare no sources of financement.
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