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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 4, Number 1, January 2006
Contents
Physiology and Pharmacology of the Vanilloid Receptor Pp.
1-15
A. Messeguer, R. Planells-Cases and A. Ferrer-Montiel
[Abstract]
Emotion, Decision-Making and Substance Dependence:
A Somatic-Marker Model of Addiction Pp. 17-31
A. Verdejo-García, M. Pérez-García
and A. Bechara
[Abstract]
Animal Models for the Development of New Neuropharmacological
Therapeutics in the Status Epilepticus Pp. 33-40
E.D. Martín and M.A. Pozo
[Abstract]
The Action of Prostaglandins on Ion Channels
Pp. 41-59
H. Meves
[Abstract]
Modulation of Midbrain Dopamine Neurotransmission
by Serotonin, a Versatile Interaction Between Neurotransmitters
and Significance for Antipsychotic Drug Action Pp.
59-68
J.E. Olijslagers, T.R. Werkman, A.C. McCreary, C.G. Kruse
and W.J. Wadman
[Abstract]
Mitochondrial Toxins in Basal Ganglia Disorders: From
Animal Models to Therapeutic Strategies Pp. 69-75
P. Bonsi, D. Cuomo, G. Martella, G. Sciamanna, M. Tolu,
P. Calabresi, G. Bernardi and A. Pisani
[Abstract]
Metabotropic Glutamate Receptors in the Trafficking
of Ionotropic Glutamate and GABAA Receptors at
Central Synapses Pp. 77-86
M.-Y. Xiao, B. Gustafsson and Y.-P. Niu
[Abstract]
Cerebral Arachidonate Cascade in Dementia: Alzheimer's
Disease and Vascular Dementia Pp. 87-100
T. Yagami
[Abstract]
Abstracts
[Back to top]
Physiology and Pharmacology of the Vanilloid Receptor
A. Messeguer, R. Planells-Cases and A. Ferrer-Montiel
The identification and cloning of the vanilloid receptor
1 (TRPV1) represented a significant step for the understanding
of the molecular mechanisms underlying the transduction of
noxious chemical and thermal stimuli by peripheral nociceptors.
TRPV1 is a non-selective cation channel gated by noxious heat,
vanilloids and extracellular protons. TRPV1 channel activity
is remarkably potentiated by pro-inflammatory agents, a phenomenon
that is thought to underlie the peripheral sensitisation of
nociceptors that leads to thermal hyperalgesia. Cumulative
evidence is building a strong case for the involvement of
this receptor in the etiology of both peripheral and visceral
inflammatory pain, such as inflammatory bowel disease, bladder
inflammation and cancer pain. The validation of TRPV1 receptor
as a key therapeutic target for pain management has thrust
intensive drug discovery programs aimed at developing orally
active antagonists of the receptor protein. Nonetheless, the
real challenge of these drug discovery platforms is to develop
antagonists that preserve the physiological activity of TRPV1
receptors while correcting over-active channels. This is a
condition to ensure normal pro-prioceptive and nociceptive
responses that represent a safety mechanism to prevent tissue
injury. Recent and exciting advances in the function, dysfunction
and modulation of this receptor will be the focus of this
review.
[Back to top]
Emotion, Decision-Making and Substance Dependence:
A Somatic-Marker Model of Addiction
A. Verdejo-García, M. Pérez-García
and A. Bechara
Similar to patients with orbitofrontal cortex lesions, substance
dependent individuals (SDI) show signs of impairments in decision-making,
characterised by a tendency to choose the immediate reward
at the expense of severe negative future consequences. The
somatic-marker hypothesis proposes that decision-making depends
in many important ways on neural substrates that regulate
homeostasis, emotion and feeling. According to this model,
there should be a link between abnormalities in experiencing
emotions in SDI, and their severe impairments in decision-making
in real-life. Growing evidence from neuroscientific studies
suggests that core aspects of substance addiction may be explained
in terms of abnormal emotional guidance of decision-making.
Behavioural studies have revealed emotional processing and
decision-making deficits in SDI. Combined neuropsychological
and physiological assessment has demonstrated that the poorer
decision-making of SDI is associated with altered reactions
to reward and punishing events. Imaging studies have shown
that impaired decision-making in addiction is associated with
abnormal functioning of a distributed neural network critical
for the processing of emotional information, including the
ventromedial cortex, the amygdala, the striatum, the anterior
cingulate cortex, and the insular/somato-sensory cortices,
as well as non-specific neurotransmitter systems that modulate
activities of neural processes involved in decision-making.
The aim of this paper is to review this growing evidence,
and to examine the extent of which these studies support a
somatic-marker model of addiction.
[Back to top]
Animal Models for the Development of New Neuropharmacological
Therapeutics in the Status Epilepticus
E.D. Martín and M.A. Pozo
Status epilepticus (SE) is a major medical
emergency associated with significant morbidity and mortality.
SE is best defined as a continuous, generalized,
convulsive seizure lasting > 5 min, or two or more seizures
during which the patient does not return to baseline consciousness.
The relative efficacy and safety of different drugs in the
treatment of human SE should be determined in a prospective,
randomized, blinded study. However, complementary animal models
of SE are required to answer important questions
concerning the treatment of SE because of the obvious
difficulties of setting up such studies in clinical emergency
conditions. This review offers an overview of the implementation
and characteristics of some of the most prevalent animal models
of SE currently in use. A description is also provide
about how animal models of SE may facilitate the
use of neurobiological techniques to successfully address
critical questions in the drug treatment of SE. In
particular, the experience with recently introduced drugs
such as intravenous valproate will be addressed. Finally,
the importance of some animal models and pharmacological approaches
is explained and we discuss their impact in the development
of therapeutic strategies to improve pharmacological treatment
for SE is discussed.
[Back to top]
The Action of Prostaglandins on Ion Channels
H. Meves
Prostaglandins, in particular PGE2 and prostacyclin
PGI2, have diverse biological effects. Most importantly,
they are involved in inflammation and pain. Prostaglandins
in nano- and micromolar concentrations sensitize nerve cells,
i.e. make them more sensitive to electrical or chemical stimuli.
Sensitization arises from the effect of prostaglandins on
ion channels and occurs both at the peripheral terminal of
nociceptors at the site of tissue injury (peripheral sensitization)
and at the synapses in the spinal cord (central sensitization).
The first step is the binding of prostaglandins to receptors
in the cell membrane, mainly EP and IP receptors. The receptors
couple via G proteins to enzymes such as adenylate
cyclase and phospholipase C (PLC). Activation of adenylate
cyclase leads to increase of cAMP and subsequent activation
of protein kinase A (PKA) or PKA-independent effects of cAMP,
e.g. mediated by Epac (=exchange protein activated by cAMP).
Activation of PLC causes increase of inositol phosphates and
increase of cytosolic calcium. This article summarizes the
effects of PGE2, PGE1, PGI2
and its stable analogues on non-selective cation channels
and sodium, potassium, calcium and chloride channels. It describes
the mechanism responsible for the facilitatory or inhibitory
prostaglandin effects on ion channels. Understanding these
mechanisms is essential for the development of useful new
analgesics.
[Back to top]
Modulation of Midbrain Dopamine Neurotransmission
by Serotonin, a Versatile Interaction Between Neurotransmitters
and Significance for Antipsychotic Drug Action
J.E. Olijslagers, T.R. Werkman, A.C. McCreary, C.G. Kruse
and W.J. Wadman
Schizophrenia has been associated with a dysfunction of
brain dopamine (DA). This, so called, DA hypothesis has been
refined as new insights into the pathophysiology of schizophrenia
have emerged. Currently, dysfunction of prefrontocortical
glutamatergic and GABAergic projections and dysfunction of
serotonin (5-HT) systems are also thought to play a role in
the pathophysiology of schizophrenia. Refinements of the DA
hypothesis have lead to the emergence of new pharmacological
targets for antipsychotic drug development. It was shown that
effective antipsychotic drugs with a low liability for inducing
extra-pyramidal side-effects have affinities for a range of
neurotransmitter receptors in addition to DA receptors, suggesting
that a combination of neurotransmitter receptor affinities
may be favorable for treatment outcome.
This review focuses on the interaction between DA and 5-HT,
as most antipsychotics display affinity for 5-HT receptors.
We will discuss DA/5-HT interactions at the level of receptors
and G protein-coupled potassium channels and consequences
for induction of depolarization blockade with specific attention
to DA neurons in the ventral tegmental area (VTA) and the
substantia nigra zona compacta (SN), neurons implicated in
treatment efficacy and the side-effects of schizophrenia,
respectively. Moreover, it has been reported that electrophysiological
interactions between DA and 5-HT show subtle, but important,
differences between the SN and the VTA which could explain
(in part) the effectiveness and lower propensity to induce
side-effects of the newer atypical antipsychotic drugs. In
that respect the functional implications of DA/5-HT interactions
for schizophrenia will be discussed.
[Back to top]
Mitochondrial Toxins in Basal Ganglia Disorders: From
Animal Models to Therapeutic Strategies
P. Bonsi, D. Cuomo, G. Martella, G. Sciamanna, M. Tolu,
P. Calabresi, G. Bernardi and A. Pisani
Current knowledge of the pathogenesis of basal ganglia disorders,
such as Huntington’s disease (HD) and Parkinson’s
disease (PD) appoints a central role to a dysfunction in mitochondrial
metabolism. The development of animal models, based upon the
use of mitochondrial toxins has been successfully introduced
to reproduce human disease, leading to important acquisitions.
Most notably, experimental evidence supports the existence,
within basal ganglia, of a peculiar regional vulnerability
to distinct mitochondrial toxins. MPTP and rotenone, both
selective inhibitors of mitochondrial complex I have been
extensively used to mimic PD. Accordingly, in human PD, a
specific dysfunction of complex I activity was found in vulnerable
dopaminergic neurons of the substantia nigra. Conversely,
in HD a selective impairment of mitochondrial succinate dehydrogenase,
key enzyme in complex II activity was found in medium spiny
neurons of the caudate-putamen. The relevance of such finding
is further demonstrated by the evidence that toxins able to
primarily target mitochondrial complex II, such as malonic
acid and 3-nitropropionic acid (3-NP), strikingly reproduce
the main phenotypic and pathological features of HD.
Despite the advances obtained from these experimental models,
a deeper understanding of the molecular and cellular mechanisms
underlying such neuronal vulnerability is lacking.
The present review provides a brief survey of currently utilized
animal models of mitochondrial intoxication, in attempt to
address the cellular mechanisms triggered by energy metabolism
failure and to identify potential therapeutic targets.
[Back to top]
Metabotropic Glutamate Receptors in the Trafficking
of Ionotropic Glutamate and GABAA Receptors at
Central Synapses
M.-Y. Xiao, B. Gustafsson and Y.-P. Niu
The trafficking of ionotropic glutamate (AMPA, NMDA and
kainate) and GABAA receptors in and out of, or
laterally along, the postsynaptic membrane has recently emerged
as an important mechanism in the regulation of synaptic function,
both under physiological and pathological conditions, such
as information processing, learning and memory formation,
neuronal development, and neurodegenerative diseases. Non-ionotropic
glutamate receptors, primarily group I metabotropic glutamate
receptors (mGluRs), co-exist with the postsynaptic ionotropic
glutamate and GABAA receptors. The ability of mGluRs
to regulate postsynaptic phosphorylation and Ca2+
concentration, as well as their interactions with postsynaptic
scaffolding/signaling proteins, makes them well suited to
influence the trafficking of ionotropic glutamate and GABAA
receptors. Recent studies have provided insights into how
mGluRs may impose such an influence at central synapses, and
thus how they may affect synaptic signaling and the maintenance
of long-term synaptic plasticity. In this review we will discuss
some of the recent progress in this area: i) long-term synaptic
plasticity and the involvement of mGluRs; ii) ionotropic glutamate
receptor trafficking and long-term synaptic plasticity; iii)
the involvement of postsynaptic group I mGluRs in regulating
ionotropic glutamate receptor trafficking; iv) involvement
of postsynaptic group I mGluRs in regulating GABAA
receptor trafficking; v) and the trafficking of postsynaptic
group I mGluRs themselves.
[Back to top]
Cerebral Arachidonate Cascade in Dementia: Alzheimer's
Disease and Vascular Dementia
T. Yagami
Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin
(PG) synthase are enzymes involved in arachidonate cascade.
PLA2 liberates arachidonic acid (AA) from cell membrane lipids.
COX oxidizes AA to PGG2 followed by an endoperoxidase reaction
that converts PGG2 into PGH2. PGs are generated from astrocytes,
microglial cells and neurons in the central nervous system,
and are altered in the brain of demented patients. Dementia
is principally diagnosed into Alzheimer's disease (AD) and
vascular dementia (VaD). In older patients, the brain lesions
associated with each pathological process often occur together.
Regional brain microvascular abnormalities appear before cognitive
decline and neurodegeneration. The coexistence of AD and VaD
pathology is often termed mixed dementia. AD and VaD brain
lesions interact in important ways to decline cognition, suggesting
common pathways of the two neurological diseases. Arachidonate
cascade is one of the converged intracellular signal transductions
between AD and VaD. PLA2 from mammalian sources are classified
as secreted (sPLA2), Ca2+-dependent, cytosolic (cPLA2) and
Ca2+-independent cytosolic PLA2 (iPLA2). PLA2 activity can
be regulated by calcium, by phosphorylation, and by agonists
binding to G-protein-coupled receptors. cPLA2 is upregulalted
in AD, but iPLA2 is downregulated. On the other hand, sPLA2
is increased in animal models for VaD. COX-2 is induced and
PGD2 are elevated in both AD and VaD. This review presents
evidences for central roles of PLA2s, COXs and PGs in the
dementia.
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