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CNS &
Neurological Disorders - Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 5, Number 2, April 2006
Contents
Neuropeptide Systems as Novel Targets for Psychiatric
Disorders
Guest Editor: Guy Griebel
Editorial Pp. 133
Neuropeptides in Psychiatric Diseases: An Overview
with a Particular Focus on Depression and Anxiety Disorders
Pp. 135-145
C. Belzung, I. Yalcin, G. Griebel, A. Surget and S. Leman
[Abstract]
Corticotropin-Releasing Factor Receptor Antagonists
in Affective Disorders and Drug Dependence – An Update
Pp. 147-165
Thomas Steckler and Frank M. Dautzenberg
[Abstract]
The Involvement of the Vasopressin System in Stress-
Related Disorders Pp. 167-179
Rainer Landgraf
[Abstract]
Neuropeptide Y: Role in Emotion and Alcohol Dependence
Pp.181-195
C. Carvajal, Y. Dumont and R. Quirion
[Abstract]
Gastrin-Releasing Peptide Receptor as a Molecular
Target for Psychiatric and Neurological Disorders Pp.
197-204
R. Roesler, J.A.P. Henriques and G. Schwartsmann
[Abstract]
Novel Treatments of Schizophrenia: Targeting the
Neurotensin System Pp. 205-218
B. Kinkead and C.B. Nemeroff
[Abstract]
The Orphanin FQ / Nociceptin Receptor as a Novel
Drug Target in Psychiatric Disorders Pp. 219-224
Rainer K. Reinscheid
[Abstract]
Galanin: A Novel Therapeutic Target for Depression, Anxiety
Disorders and Drug Addiction? Pp. 225-232
A. Holmes and M.R. Picciotto
[Abstract]
Alcoholism and Neuropeptides: An Update Pp. 233-239
M.S. Cowen and A.J. Lawrence
[Abstract]
Abstracts
[Back to top]
Editorial
The health burden of psychiatric disorders is rapidly increasing,
whilst the range of available pharmacotherapies is limited
and suboptimal with regard to efficacy and tolerability. Recent
findings support a major role for neuropeptides in several
of these conditions and thereby identify neuropeptide systems
as potential novel therapeutic targets for the treatment of
psychiatric disorders. In preclinical models, pharmacological
and/or genetic manipulation of corticotropin-releasing factor
(CRF), vasopressin, neuropeptide Y (NPY), galanin, bombesin,
nociceptin and neurotensin alters anxiety-, depression- or
schizophrenia-related responses. Recently, specific and highly
potent small molecule neuropeptide receptor agonists and antagonists
have been developed that can readily cross the blood-brain
barrier. Clinical assessment of several compounds is currently
underway. This issue will provide an overview of recent developments
in this rapidly advancing field.
The introductory paper by Catherine Belzung and colleagues
[1] describes general features of neuropeptides, including
the history of their discovery, their definition, classification,
biosynthesis, transport, release, inactivation, as well as
their interaction with specific neuronal receptors. It focuses
more particularly on the involvement of neuropeptides in depression,
and anxiety disorders.
CRF is undoubtedly the most extensively studied neuropeptide,
notably because of its well-known involvement in the regulation
of the hypothalamo-pituitary-adrenal (HPA) stress axis, whose
dysfunctioning has been directly linked to the development
of stress-related disorders. Thomas Steckler and Frank Dautzenberg
give a comprehensive update on the involvement of CRF and
its receptor subtypes in affective disorders and drug abuse
[2].
Since vasopressin has been shown to be critical for adaptation
of the HPA axis during stress through its ability to potentiate
the stimulatory effect of CRF, it has been hypothesized that
this peptide may provide a good opportunity for pharmacological
treatment of stress-related disorders. The availability of
the first orally active non-nonpeptide V1b receptor
antagonist, SSR149415, opened a new era for examining the
role of vasopressin in stress-related disorders. Rainer Landgraf
in his review [3] elegantly demonstrates that the capability
of vasopressin to respond to both stressful stimuli and mediate
genetic polymorphisms makes the central release of this peptide
a key process for converging behavioral regulation related
to stress disorders.
Christina Carjaval and colleagues [4] review recent developments
on the role of NPY in emotion and alcohol dependence and they
examine the potential of the NPY system as a novel therapeutic
strategy in the treatment of anxiety, depression and alcohol-related
disorders.
Although less studied within the CNS field than the previous
peptides, gastrin-releasing peptides and their receptors are
increasingly examined for their involvement in psychiatric
and neurological diseases. Rafael Roesler and his colleagues
[5] review this emerging idea.
Becky Kinkead and Charles Nemeroff [6] discuss the idea that
neurotensin receptor ligands may represent an innovative approach
for the treatment of schizophrenia.
There is now compelling evidence that the orphanin FQ/nociceptin
(OFQ/N) system may represent a valuable target for the development
of drugs treating a variety of psychiatric disorders. Rainer
Reinscheid [7] discusses the recent development of OFQ/N ligands
and their behavioral effects in animal studies.
Our understanding of the role of the galanin system in modulating
emotional behavior and drug withdrawal has progressed in recent
years. Andrew Holmes and Marina Picciotto [8] summarize in
their review current developments and scientific achievements
that have been made to elucidate the functions of galanin
in psychiatric disorders.
In the last review article, Michael Cowen and Andrew Lawrence
[9] discuss the potential of therapeutic strategies targeting
neuropeptide systems implicated in aberrant alcohol-seeking
behaviour.
The search for novel treatment strategies for psychiatric
disorders is driven by the growing medical need to enhance
the response rate, efficacy and side-effect profile of existing
drugs. Given the wealth of animal and human data supporting
the role for neuropeptides in modulating behavioral responses,
targeting these systems remains a highly promising avenue
for the development of novel clinical entities in psychiatric
disorders.
Guy Griebel
Psychopharmacology Department
Sanofi-Aventis
Bagneux
France
E-mail: guy.griebel@sanofi-aventis.com
[Back to top]
Neuropeptides in Psychiatric Diseases: An Overview
with a Particular Focus on Depression and Anxiety Disorders
C. Belzung, I. Yalcin, G. Griebel, A. Surget and S. Leman
This paper aimed at reviewing the involvement of neuropeptides
in various psychiatric diseases, particularly in depression,
and anxiety disorders. General features of neuropeptides are
first described, including the history of their discovery,
their definition, classification, biosynthesis, transport,
release, inactivation, as well as their interaction with specific
neuronal receptors. The differences with classical neurotransmitters
are mentioned, as well as the different patterns of co-transmission.
Finally, different mechanisms, both at the cellular and at
the systemic level, are proposed that may explain the involvement
of these molecules in various psychiatric diseases. Indeed,
at the cellular level, a neuropeptide can be involved in a
psychiatric disease, either because it is co-localized with
a classical neurotransmitter involved in a disease, or because
the neuropeptide-containing neuron projects on a target neuron
involved in the disease. At the systemic level, a neuropeptide
can play a direct role in the expression of a symptom of the
disease. This is illustrated by different exemples.
[Back to top]
Corticotropin-Releasing Factor Receptor Antagonists
in Affective Disorders and Drug Dependence – An Update
Thomas Steckler and Frank M. Dautzenberg
Dysfunctioning of corticotropin-releasing factor (CRF) and
its receptors (CRF1 and CRF2) has been
linked to the development of stress-related disorders, such
as affective disorders and drug abuse. The molecular characterization
of CRF1 and CRF2 receptors and their
splice variants has generated detailed information on their
pharmacology, tissue distribution and physiology. In addition,
the recent development of a small molecule CRF1
antagonist has provided important information on the contribution
of this receptor to the development of stress-related diseases.
Despite the high homology to the CRF1 receptor
and the generation of peptide-based research tools, the physiological
role of the CRF2 receptor is largely unclear. This
is due to different expression patterns in rodents and primates
and the lack of brain-penetrant CRF2-selective
small molecule antagonists. However, the CRF2 receptor
may be important for motivational types of behavior essential
for survival, such as feeding and defense and impacts on cardiovascular
function.
[Back to top]
The Involvement of the Vasopressin System in Stress-
Related Disorders
Rainer Landgraf
The neuropeptide arginine vasopressin (AVP) is released within
distinct brain areas upon appropriate stimulation, including
stressful challenges. Following its predominantly dendritic
release, AVP triggers a variety of receptor-mediated effects
related to behavioral and neuroendocrine regulation. Antagonist
treatment together with other sophisticated loss-of-function
and gain-of-function approaches provide evidence for a multiple
involvement of V1a and V1b receptor subtypes in stress-related
behavior and disorders, including anxiety disorders, comorbid
depression and their neuroendocrine concomitants. Conversely,
in the high versus low anxiety (HAB/LAB) rat model, the phenotype
of extreme trait anxiety is associated with a polymorphism-driven
overexpression of AVP in the hypothalamic paraventricular
nucleus. This overexpression of AVP might be considered a
final common pathway of anxiety-related behavior. The capability
of both responding to stressful stimuli and mediating genetic
polymorphisms makes the central release of AVP a key process
for converging (i.e., environmentally and genetically driven)
behavioral regulation. Polymorphisms in the promoter structures
of the AVP gene and AVP receptor genes, underlying differences
in gene expression, thus contribute to individual variation
in behavior as well as to psychopathology, making genes of
the brain AVP system and their products a promising target
for therapeutic interventions.
[Back to top]
Neuropeptide Y: Role in Emotion and Alcohol Dependence
C. Carvajal, Y. Dumont and R. Quirion
Neuropeptide Y (NPY) is considered to be an important neuromodulator
in the regulation of emotional behavior. For example, NPY
is consistently involved in anxiety-related behaviors and
there is increasing support for a role of this peptide in
mood disorders such as depression. Furthermore, recent evidence
suggests that NPY has a significant role in the neurobiological
response to alcohol, including alcohol consumption, dependence,
and withdrawal. In addition, NPY is beginning to emerge as
an important modulator in the etiology of alcoholism that
is independent from the addictive and reinforcing properties
of the traditional system commonly associated with dopamine
and instead, is strongly associated with innate emotionality.
The recent developments elucidating the role of NPY in emotion
and alcohol dependence are reviewed and the potential of the
NPY system as a novel therapeutic strategy in the treatment
of anxiety, depression and alcohol-related disorders is examined.
[Back to top]
Gastrin-Releasing Peptide Receptor as a Molecular
Target for Psychiatric and Neurological Disorders
R. Roesler, J.A.P. Henriques and G. Schwartsmann
The mammalian bombesin (BB)-like peptide gastrin-releasing
peptide (GRP) stimulates cell proliferation, displays a range
of neuroendocrine activities, and acts as a growth factor
in the pathogenesis of several types of human cancer. Several
lines of evidence have indicated that GRP and its receptor
(GRPR) might also be involved in the neurochemical alterations
associated with psychiatric and neurological disorders. GRP
and GRPR are distributed throughout the mammalian central
nervous system (CNS). Altered levels of BB-like peptides have
been found in the CNS of patients with schizophrenia and Parkinson’s
disease. Dysfunctions in GRPR-induced cellular calcium signaling
have been reported in fibroblasts from patients with Alzheimer’s
disease. A translocation in the GRPR gene has been associated
with autism. Pharmacological and genetic studies in rodents
have shown that GRPRs in brain areas such as the dorsal hippocampus
and amygdala are importantly involved in regulating synaptic
plasticity and aspects of behavior that might be altered in
disorders such as anxiety, schizophrenia, depression, autism
and dementia. Behaviors modulated by the GRPR in rodents include
grooming, food intake, stereotypy, social behavior, and emotionally-motivated
learning and memory. Together, these findings support the
view that the GRPR should be considered a therapeutic target
for a subset of CNS diseases.
[Back to top]
Novel Treatments of Schizophrenia: Targeting the Neurotensin
System
B. Kinkead and C.B. Nemeroff
Evidence implicating neural circuits that utilize the neuropeptide
transmitter neurotensin (NT) in the pathophysiology of schizophrenia
and in the mechanism of action of antipsychotic drugs has
previously been reviewed. The majority of evidence, taken
together, supports the development of NT receptor agonists
as novel antipsychotic drugs. This review comprehensively
describes the NT receptor subtypes, discusses the development
of NT receptor agonists and the behavioral effects of currently
available NT receptor agonists. The compilation of data suggests
that NT receptor agonists may represent a novel class of antipsychotic
drugs for the treatment of schizophrenia.
[Back to top]
The Orphanin FQ / Nociceptin Receptor as a Novel Drug
Target in Psychiatric Disorders
Rainer K. Reinscheid
Almost 10 years after the discovery of Orphanin FQ / Nociceptin
(OFQ/N) a large number of synthetic small molecule agonists
and antagonists have been developed and tested in various
physiological assays. Together with the academic work on the
physiological functions of OFQ/N, we now have compelling evidence
that this neuropeptide system might represent a valuable target
for the development of drugs treating a variety of psychiatric
disorders. Most prominently, the anti-stress and anxiolytic
effects of OFQ/N agonists have been investigated although
clinical trials have not yet been launched. Other possible
applications of OFQ/N agonists and antagonists include treatment
of depression, anorexia and rewarding aspects of drug addiction.
This paper will summarize current developments and highlight
the scientific achievements that have been made to elucidate
the functions of OFQ/N with respect to psychiatric disorders.
[Back to top]
Galanin: A Novel Therapeutic Target for Depression, Anxiety
Disorders and Drug Addiction?
A. Holmes and M.R. Picciotto
Galanin is a neuropeptide synthesized in many neuronal types
including brainstem norepinephrine-producing cells of the
locus coeruleus and the serotonin-producing neurons of the
dorsal raphe nucleus. Galanin inhibits the firing of rodent
norepinephrine, serotonin and dopamine neurons and reduces
release of these neurotransmitters in forebrain target regions.
The distribution of galanin and its receptors and its actions
on monoamine signaling has fostered interest in this neuropeptide
in the field of behavioral pharmacology and the potential
role of galanin in the pathophysiology of neurological diseases
such as Alzheimer’s disease, epilepsy, stroke, and in
psychiatric disorders such as anxiety, depression, and drug
addiction, particularly withdrawal. In rodent models, expression
of galanin in brain is altered by various stressors, while
administration of galanin can modulate anxiety-like responses
to stress. Emerging evidence further supports a role for galanin
in the mediation of depression-related behaviors in rodents.
Recently, galanin agonists have been shown to decrease behavioral
signs of opiate withdrawal, which are thought to result from
hyperactivation of brain stress pathways. Studies using genetically
modified mice suggest that galanin normally plays a protective
role against opiate reinforcement and withdrawal. The present
article reviews current evidence on a potential role for galanin
in modulating stress-related neural pathways and behaviors,
and speculates on the therapeutic potential of targeting this
galanin system for emotional disorders and opiate addiction.
[Back to top]
Alcoholism and Neuropeptides: An Update
M.S. Cowen and A.J. Lawrence
As with other addictions, human alcoholism is characterised
as a chronically relapsing condition. Consequently, the “holy
grail” from a therapeutic viewpoint is the development
of clinically effective, safe drugs that promote high compliance
rates and prevent relapse. Here we discuss the potential of
therapeutics targeting neuropeptide systems implicated in
aberrant alcohol-seeking behaviour. Clearly, much of the data
so far available comes from pre-clinical studies; however,
one of the first effective therapeutic strategies for alcoholism
(still in use today) was the use of non-selective opioid receptor
antagonists, such as naltrexone (Revia ™). In addition
to opioid receptors, other neuropeptide receptors including
those for corticotrophin releasing factor (CRF), neuropeptide
Y and nociceptin may represent valid therapeutic targets to
regulate alcohol consumption and the affective consequences
of alcohol withdrawal.
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