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Current Neuropharmacology
ISSN: 1570-159X
Current Neuropharmacology
Volume 4, Number 2, April 2006
Contents
Serotonin as a Modulator of Glutamate- and GABA Mediated Neurotransmission:
Implications in Physiological Functions and in Pathology Pp.
101-114
L. Ciranna
[Abstract]
On the Origin of Cortical Dopamine: Is it a Co-Transmitter
in Noradrenergic Neurons? Pp. 115-125
P. Devoto and G. Flore
[Abstract]
Heterotrimeric G Proteins: Insights into the Neurobiology
of Mood Disorders Pp. 127-138
J. González-Maeso and J.J. Meana
[Abstract]
Neuronal Cell Death in Alzheimer’s Disease and
a Neuroprotective Factor, Humanin Pp. 139-147
T. Niikura, H. Tajima and Y. Kita
[Abstract]
The Role of β-Amyloid
Protein in Synaptic Function: Implications for Alzheimer’s
Disease Therapy Pp. 149-163
F. Peña, A.I. Gutiérrez-Lerma,
R. Quiroz-Baez and C. Arias
[Abstract]
Peripheral Neuropathy Induced by Paclitaxel: Recent
Insights and Future Perspectives Pp. 165-172
C.D. Scripture, W.D. Figg and A. Sparreboom
[Abstract]
Abstracts
[Back to top]
Serotonin as a Modulator of Glutamate- and GABA Mediated
Neurotransmission: Implications in Physiological Functions
and in Pathology
L. Ciranna
The neurotransmitter serotonin (5-HT), widely distributed
in the central nervous system (CNS), is involved in a large
variety of physiological functions. In several brain regions
5-HT is diffusely released by volume transmission and behaves
as a neuromodulator rather than as a “classical”
neurotransmitter. In some cases 5-HT is co-localized in the
same nerve terminal with other neurotransmitters and reciprocal
interactions take place. This review will focus on the modulatory
action of 5-HT on the effects of glutamate and γ-amino-butyric
acid (GABA), which are the principal neurotransmitters mediating
respectively excitatory and inhibitory signals in the CNS.
Examples of interaction at pre- and/or post-synaptic levels
will be illustrated, as well as the receptors involved and
their mechanisms of action. Finally, the physiological meaning
of neuromodulatory effects of 5-HT will be briefly discussed
with respect to pathologies deriving from malfunctioning of
serotonin system.
[Back to top]
On the Origin of Cortical Dopamine: Is it a Co-Transmitter
in Noradrenergic Neurons?
P. Devoto and G. Flore
Dopamine (DA) and noradrenaline (NA) in the prefrontal cortex
(PFC) modulate superior cognitive functions, and are involved
in the aetiology of depressive and psychotic symptoms. Moreover,
microdialysis studies in rats have shown how pharmacological
treatments that induce modifications of extracellular NA in
the medial PFC (mPFC), also produce parallel changes in extracellular
DA.
To explain the coupling of NA and DA changes, this article
reviews the evidence supporting the hypothesis that extracellular
DA in the cerebral cortex originates not only from dopaminergic
terminals but also from noradrenergic ones, where it acts
both as precursor for NA and as a co-transmitter.
Accordingly, extracellular DA concentration in the occipital,
parietal and cerebellar cortex was found to be much higher
than expected in view of the scarce dopaminergic innervation
in these areas.
Systemic administration or intra-cortical perfusion of α2-adrenoceptor
agonists and antagonists, consistent with their action on
noradrenergic neuronal activity, produced concomitant changes
not only in extracellular NA but also in DA in the mPFC, occipital
and parietal cortex.
Chemical modulation of the locus coeruleus by locally applied
carbachol, kainate, NMDA or clonidine modified both NA and
DA in the mPFC.
Electrical stimulation of the locus coeruleus led to an increased
efflux of both NA and DA in mPFC, parietal and occipital cortex,
while in the striatum, NA efflux alone was enhanced.
Atypical antipsychotics, such as clozapine and olanzapine,
or antidepressants, including mirtazapine and mianserine,
have been found to increase both NA and DA throughout the
cerebral cortex, likely through blockade of α2-adrenoceptors.
On the other hand, drugs selectively acting on dopaminergic
transmission produced modest changes in extracellular DA in
mPFC, and had no effect on the occipital or parietal cortex.
Acute administration of morphine did not increase DA levels
in the PFC (where NA is diminished), in contrast with augmented
dopaminergic neuronal activity; moreover, during morphine
withdrawal both DA and NA levels increased, in spite of a
diminished dopaminergic activity, both increases being antagonised
by clonidine but not quinpirole administration.
Extensive 6-hydroxy dopamine lesion of the ventral tegmental
area (VTA) decreases below 95% of control both intra- and
extracellular DA and DOPAC in the nucleus accumbens, but only
partially or not significantly in the mPFC and parietal cortex.
The above evidence points to a common origin for NA and DA
in the cerebral cortex and suggests the possible utility of
noradrenergic system modulation as a target for drugs with
potential clinical efficacy on cognitive functions.
[Back to top]
Heterotrimeric G Proteins: Insights into the Neurobiology
of Mood Disorders
J. González-Maeso and J.J. Meana
Mood disorders such as major depression and bipolar disorder
are common, severe, chronic and often life-threatening illnesses.
Suicide is estimated to be the cause of death in up to approximately
10-15% of individuals with mood disorders. Alterations in
the signal transduction through G protein-coupled receptor
(GPCR) pathways have been reported in the etiopathology of
mood disorders and the suicidal behavior. In this regard,
the implication of certain GPCR subtypes such as α2A-adrenoceptor
has been repeatedly described using different approaches.
However, several discrepancies have been recently reported
in density and functional status of the heterotrimeric G proteins
both in major depression and bipolar disorder. A compilation
of the most relevant research topics about the implication
of heterotrimeric G proteins in the etiology of mood disorders
(i.e., animal models of mood disorders, studies in
peripheral tissue of depressive patients, and studies in postmortem
human brain of suicide victims with mood disorders) will provide
a broad perspective of this potential therapeutic target field.
Proposed causes of the discrepancies reported at the level
of G proteins in postmortem human brain of suicide
victims will be discussed.
[Back to top]
Neuronal Cell Death in Alzheimer’s Disease and
a Neuroprotective Factor, Humanin
T. Niikura, H. Tajima and Y. Kita
Brain atrophy caused by neuronal loss is a prominent pathological
feature of Alzheimer’s disease (AD). Amyloid β
(Aβ),
the major component of senile plaques, is considered to play
a central role in neuronal cell death. In addition to removal
of the toxic Aβ,
direct suppression of neuronal loss is an essential part of
AD treatment; however, no such neuroprotective therapies have
been developed. Excess amount of Aβ
evokes multiple cytotoxic mechanisms, involving increase of
the intracellular Ca2+ level, oxidative
stress, and receptor-mediated activation of cell-death cascades.
Such diversity in cytotoxic mechanisms induced by Aβ
clearly indicates a complex nature of the AD-related neuronal
cell death. We have identified a 24-residue peptide, Humanin
(HN), which suppresses in vitro neuronal cell death
caused by all AD-related insults, including Aβ,
so far tested. The anti-AD effect of HN has been further confirmed
in vivo using mice with Aβ-induced
amnesia. Altogether, such potent neuroprotective activity
of HN against AD-relevant cytotoxicity both in vitro
and in vivo suggests the potential clinical applications
of HN in novel AD therapies aimed at controlling neuronal
death.
[Back to top]
The Role of β-Amyloid
Protein in Synaptic Function: Implications for Alzheimer’s
Disease Therapy
F. Peña, A.I. Gutiérrez-Lerma,
R. Quiroz-Baez and C. Arias
Alzheimer’s disease (AD) is a neurodegenerative disorder
characterized by progressive and irreversible loss of memory
and other cognitive functions. Substantial evidence based
on genetic, neuropathological and biochemical data has established
the central role of β-amyloid
protein (βAP)
in this pathology. Although the precise etiology of AD is
not well understood yet, strong evidence for some of the molecular
events that lead to progressive brain dysfunction and neurodegeneration
in AD has been afforded by identification of biochemical pathways
implicated in the generation of βAP,
development of transgenic models exhibiting progressive disease
pathology and by data on the effects of βAP
at the neuronal network level. However, the mechanisms by
which βAP
causes cognitive decline have not been determined, nor is
it clear if the degree of dementia correlates in time with
the degree of neuronal loss. Hence, it is of interest to understand
the biochemical processes involved in the mechanisms of βAP-induced
neurotoxicity and the mechanisms involved in electrophysiological
effects of this protein on different parameters of synaptic
transmission and on neuronal firing properties. In this review
we analyze recent evidence suggesting a complex role of βAP
in the molecular events that lead to progressive loss of function
and eventually to neurodegeneration in AD as well as the therapeutic
implications based on βAP
metabolism inhibition.
[Back to top]
Peripheral Neuropathy Induced by Paclitaxel: Recent
Insights and Future Perspectives
C.D. Scripture, W.D. Figg and A. Sparreboom
Paclitaxel is an antineoplastic agent derived from the bark
of the western yew, Taxus brevifolia, with a broad
spectrum of activity. Because paclitaxel promotes microtubule
assembly, neurotoxicity is one of its side effects. Clinical
use of paclitaxel has led to peripheral neuropathy and this
has been demonstrated to be dependent upon the dose administered,
the duration of the infusion, and the schedule of administration.
Vehicles in the drug formulation, for example Cremophor in
Taxol®,
have been investigated for their potential to induce peripheral
neuropathy. A variety of neuroprotective agents have been
tested in animal and clinical studies to prevent paclitaxel
neurotoxicity. Recently, novel paclitaxel formulations have
been developed to minimize toxicities. This review focuses
on recent advances in the etiology of paclitaxel-mediated
peripheral neurotoxicity, and discusses current and ongoing
strategies for amelioration of this side effect.
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