Begell House Inc.
Critical Reviews™ in Neurobiology
CRN
0892-0915
16
1&2
2004
Neurosciences in the Third Millennium: A Tribute to Mimo Costa
v
10.1615/CritRevNeurobiol.v16.i12.01
Thomas F.
Murray
Department of Pharmacology, School of Medicine, Creighton University, Omaha, NE 68178, USA
Prolog to Special Issue
vi
10.1615/CritRevNeurobiol.v16.i12.02
Norton H.
Neff
A GABAergic Cortical Deficit Dominates Schizophrenia Pathophysiology
1-23
10.1615/CritRevNeurobiol.v16.i12.10
Erminio
Costa
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago IL 60612, USA
J. M.
Davis
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
E.
Dong
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Dennis R.
Grayson
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA
Alessandro
Guidotti
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA
Lucio
Tremolizzo
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA
Marin
Veldic
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA
Several lines of evidence support the role of an epigenetic-induced GABAergic cortical dysfunction in schizophrenia psychopathology, which is probably dependent on an increase in the expression of DNA-methyltransferase-1 occurring selectively in GABAergic neurons. The key enzyme regulating GABA synthesis, termed glutamic acid decarboxylase 67 (GAD67) and the important neurodevelopmental protein called reelin are coexpressed in GABAergic neurons. Upon release, GABA and reelin bind to postsynaptic receptors located in dendrites, somata, or the axon initial segment of pyramidal neurons. Because GAD67 and reelin are downregulated in schizophrenia, it is suggested that schizophrenics may express GABAergic deficit-related alterations of pyramidal neuron function. A reduction of dendritic spines is a finding reported in the prefrontal cortex of schizophrenia patients. Because dendritic spines are innervated by glutamatergic axon terminals, very probably this reduction of dendritic spine expression is translated into a functional deficit of glutamatergic transmission. Plastic modifications of neuronal circuits are probably dependent on GABAergic transmitter tone, and it is likely that GABAergic dysfunction is at the root of synaptic plasticity deficits in schizophrenia. Thus, a possible avenue for the treatment of schizophrenia would be to address this GABAergic functional deficit using positive allosteric modulators of the action of GABA at GABAA receptors. Benzodiazepines (BZ) such as diazepam are effective in treating positive and negative symptoms of schizophrenia, but because they positively modulate GABAA receptors expressing α1 subunits, these BZs cause sedation and tolerance. In contrast, imidazenil, a full allosteric modulator of GABAA receptors expressing α5 subunits may reduce psychotic symptomatology without producing sedation. Hence, imidazenil should be appropriately studied as a prospective candidate for a pharmacological intervention in schizophrenia.
GABA, Reelin, and the Neurodevelopmental Hypothesis of Schizophrenia
25-32
10.1615/CritRevNeurobiol.v16.i12.20
Hector J.
Caruncho
Departments of Cell Biology, University of Santiago de Compostela, Galicia, Spain
Iria G.
Dopeso-Reyes
Departments of Cell Biology, University of Santiago de Compostela, Galicia, Spain
M. Isabel
Loza
Departments Pharmacology, University of Santiago de Compostela, Galicia, Spain
Miguel A.
Rodriguez
Departments of Cell Biology, University of Santiago de Compostela, Galicia, Spain
The GABA—reelin cortical connection (i.e., the expression and secretion of reelin by GABAergic cortical neurons) has been shown to function not only in the adult cortex but also during tangential migration of GABAergic neuroblasts. Therefore, it is of interest to focus on the possibility that a synergic action of these compounds (understood as a topobiological effect, implying place- and time-dependent interactions) may have important implications in regulating developmental processes such as neuronal migration, dendritic sprouting, synaptogenesis, and axon pruning, as well as being involved in regulation of synaptic plasticity trough life. The present review summarizes the actual knowledge in this field and discusses the possible importance that a dysregulation of GABAergic and reelin systems may have as vulnerability factors for the etiology and pathophysiology of schizophrenia.
Neuroanatomical and Pharmacological Evidence for a Functional Interaction Between GABAergic and NPY-Y1 Transmission in the Amygdala of Y1R/LacZ Transgenic Mice
33-42
10.1615/CritRevNeurobiol.v16.i12.30
Carola
Eva
Dipartimento di Anatomia, Farmacologia e Medicina Legale, Sezione di Farmacologia, Universita di Torino, Torino, Italy
Paolo
Mele
Dipartimento di Anatomia, Farmacologia e Medicina Legale, Sezione di Farmacologia, Universita di Torino, Torino, Italy
Alessandra
Oberto
Dipartimento di Anatomia, Farmacologia e Medicina Legale, Sezione di Farmacologia, Universita di Torino, Torino, Italy
Gian Carlo
Panzica
Dipartimento di Anatomia, Farmacologia e Medicina Legale, Sezione di Anatomia, Universita di Torino, Torino, Italy
Maria Giuseppina
Pisu
Dipartimento di Biologia Sperimentale, Sezione di Neuroscienze, Universita di Cagliari, Cagliari, Italy
Mariangela
Serra
Dipartimento di Biologia Sperimentale, Sezione di Neuroscienze, Universita di Cagliari, Cagliari, Italy
Several lines of evidence indicate that GABA and neuropeptide Y (NPY) are functionally coupled and may interact in the regulation of fear- and anxiety-induced behavior. Neuroanatomical studies demonstrated that GABA and NPY coexist in neurons of the amygdaloid complex and that NPY may directly modulate the activity of GABAergic neurons by stimulating Y1 receptors. By using a transgenic mouse model harboring a construct comprising the murine Y1 receptor gene promoter fused to a lacZ reporter gene (Y1R/LacZ mice), we showed that long-term treatment with positive (diazepam or abecarnil) or negative (FG7142) modulators of GABAA receptor function induced a marked increase or decrease, respectively, in Y1 receptor gene expression in the amygdala. Furthermore, we demonstrated that a sustained increase in the brain concentrations of neuroactive steroids, induced by pharmacological treatment or by physiological conditions such as pregnancy, increases Y1 receptor gene expression in the amygdala of Y1R/LacZ transgenic mice, an effect similar to that induced by diazepam or abecarnil. These data provide evidence of a functional interaction between GABAergic and NPY-Y1 mediated transmission and suggest that neuroactive steroids may play an important role in the regulation of the NPY transmission. Finally, our data support a role of Y1 receptors in the behavioral and neuroendocrine responses to stress that, however, appears to be independent on the activation of the GABAergic system.
The BDNF Gene: Exemplifying Complexity in Ca2+-Dependent Gene Expression
43-50
10.1615/CritRevNeurobiol.v16.i12.40
Britt
Mellstrom
Dpto. Biologia Moleculary Celular, Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Begona
Torres
Dpto. Biologia Moleculary Celular, Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Wolfgang A.
Link
Dpto. Biologia Moleculary Celular, Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Jose R.
Naranjo
Dpto. Biologia Moleculary Celular, Centro Nacional de Biotecnologia, CSIC, Madrid, Spain
Over the last 20 years, great effort has been made to decipher the molecular mechanisms used by cells to transform a cytosolic Ca2+ signal into specific, finely-controlled changes in gene expression. Several previous reviews addressed the variety of regulatory mechanisms that participate in Ca2+-dependent gene expression in neurons (Carafoli et al., 2001; Mellström and Naranjo 2001; West et al., 2001). Nevertheless, recent discoveries have revealed new players and new interactions that tune this process. In this review, we will use the four promoters that regulate the expression of the brain-derived neurotrophic factor (BDNF) gene as a magnificent scenario in which these mechanisms intermingle to show the complexity of Ca2+-dependent gene expression.
Brain-Derived Neurotrophic Factor Activation of TrkB Protects Neurons from HIV-1/gp120-Induced Cell Death
51-58
10.1615/CritRevNeurobiol.v16.i12.50
Italo
Mocchetti
Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
Alessia
Bachis
Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA
Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-Related Dementia (ADC). These patients exhibit cortical and subcortical atrophy. Considerable experimental data indicate that the HIV-1 envelope glycoprotein gp120 may be one of the agents causing neuronal cell death. Gp120 causes neuronal cell death both in vitro and in vivo by activating a caspase-dependent apoptotic pathway, and in particular caspase-3. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to prevent gp120-mediated apoptosis of cerebellar granule cells by inhibiting caspase-3 activation. However, the signal transduction pathway that contributes to the neuroprotective effects of BDNF has not been determined. BDNF binds with high affinity to the tyrosine kinase receptor TrkB and activates different intracellular signaling cascade including the extracellular signal-related kinases (ERK) and the phosphatidylinositol 3-kinase (PI3-K). Pharmacological inhibition of TrkB or ERK1/2, but not PI3-K, greatly reduced the ability of BDNF to block gp120-mediated apoptosis of cerebellar granule cells. These findings suggest that TrkB-mediated activation of ERK1/2 is the main signaling pathway that contributes to neuroprotection against gp120.
Cerebellar Granular Cell Cultures as an In Vitro Model for Antidepressant Drug-Induced Neurogenesis
59-65
10.1615/CritRevNeurobiol.v16.i12.60
M.
Zusso
Department of Pharmacology and Anesthesiology, University of Padova, Italy
P.
Debetto
Department of Pharmacology and Anesthesiology, University of Padova, Italy
D.
Guidolin
Department of Human Anatomy and Physiology, University of Padova, Italy
P.
Giusti
Department of Pharmacology and Anesthesiology, University of Padova, Italy
Both preclinical and clinical evidence suggested that antidepressant drugs upregulate hippocampal cell proliferation and neurogenesis. In addition, direct evidence was recently published that hippocampal de novo cell proliferation is necessary for antidepressant action. Within this frame, we used primary cultures of rat cerebellar granule cells (CGC) as an in vitro model of central nervous system (CNS) to investigate whether a neurogenic response could be elicited also in the cerebellum, upon chronic treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, we assayed the presence of neural precursor cells in CGC, possibly responsive to proliferation and differentiation stimuli. We found that 1 μ;M fluoxetine increased cell proliferation, as assayed by [3H]-thymidine incorporation. CGC immunocytochemical analysis with neural cell-specific markers revealed the presence of granule neurons, glial cells, and a cell component that we named "round cells." Because only round cells displayed proliferation ability, as revealed by 5-bromo-2’-deoxyuridine (BrdU) labeling, they were further characterized. For this purpose, round cells were isolated and expanded by culturing in a serum-free medium, containing basic fibroblast growth factor (bFGF), before immunocytochemical analysis. We found that round cells were not immunoreactive for glial, neuronal, and oligodendrocyte markers, whereas they were immunoreactive for several immature neuronal markers. Accordingly, round cells could be induced to differentiate into astrocytes, neurons, and oligodendrocytes, either by withdrawing the mitogen bFGF or by exposing them to fluoxetine. These findings suggest that round cells in CGC possess the features and potentials of neural precursors, able to differentiate in mature neural cells upon a pharmacological simulum.
Neurosteroidogenesis: Relevance to Neurosteroid Actions in Brain and Modulation by Psychotropic Drugs
67-74
10.1615/CritRevNeurobiol.v16.i12.70
Maria Luisa
Barbaccia
Department of Neuroscience, Section of Pharmacology, University of Rome "Tor Vergata" Schoool of Medicine, Via Montpellier, 1, 00133-Rome, Italy
Neurosteroids—i.e., steroid produced in brain ex novo or through metabolism of precursors—affect neuronal and brain functions through genomic and nongenomic mechanisms, depending on their molecular structure. Among neurosteroids, 3α-hydroxylated, 5α-reduced metabolites of progesterone (3α-hydroxy,5α-pregnan-20one/3α,5α-THP) and deoxycorticosterone (3α,21-dihydroxy,5α-pregnan-20one/3α,5α-THDOC) are positive allosteric modulators of γ-aminobutyric acid (GABA) action at GABAA receptors. In rodents, a reduction of their endogenous brain concentrations rapidly lowers the potency of GABA in eliciting GABAA receptor-mediated inhibitory postsynaptic currents. This effect is related to anxiety-like behavior, increased aggression, and a reduced sensitivity to the loss of righting reflex induced by GABAA receptor agonist or positive modulators. Conversely, enhancement of 3α,5α-THP or 3α,5α-THDOC brain content results in anxiolysis, sedation/hypnosis, anticonvulsant, and anesthetic action. Different classes of psychotropic drugs—i.e., antidepressants, selected atypical antipsychotics, ethanol, γ-hydroxybutyric acid—increase neurosteroid concentrations in brain, and these increases may be relevant to their pharmacological actions. Drug-induced increases of neurosteroids in rodent brain are often associated with elevation of their plasma content, such that alterations of plasma steroid concentrations are assumed to reflect parallel changes in brain. Nevertheless, brain neurosteroid concentrations are uneven across various regions, and the dose-dependence of their response to a pharmacological challenge shows brain-regional differences as well. These observations are consistent with the present knowledge on the distribution of steroidogenic enzymes in brain—they show not only a brain region, but also a cell-specific expression that may spatially and temporally determine the local concentrations of specific neurosteroids, either produced ex novo or through metabolism of steroid precursors that reach the brain through blood.
Brain Neurosteroids in Gender-Related Aggression Induced by Social Isolation
75-82
10.1615/CritRevNeurobiol.v16.i12.80
Graziano
Pinna
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Roberto Carlos
Agis-Balboa
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Mohemed-Salim
Doueiri
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Alessandro
Guidotti
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA
Erminio
Costa
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor St., Chicago IL 60612, USA
Genetic, environmental, or hormonal factors and their interactions have been implicated in the expression of gender-related aggressive behavior in humans. Several independent lines of evidence support the role of hormonal and environmental factors in the aggressive behavior of experimental animals. Social isolation (SI) for 2−4 weeks in male but not in female mice results in the expression of aggression to a same-sex intruder. Long-term treatment (3 weeks) with anabolic steroids during SI in female mice induces aggressive behavior toward a male intruder of a severity similar to that observed in socially isolated (SI) male mice. The induced aggression in male and female mice is associated with a decrease of brain allopreg-nanolone (Allo). In SI male mice, aggression can be prevented by treatment with L-methionine (MET), which has also been shown to decrease reelin and GAD67 mRNA expression and maintain normal brain Allo content. The histone deacetylase inhibitor valproic acid can reverse this process, suggesting that histone tail acetylation may reverse the action of MET.
We conclude that during social isolation, aggression can be controlled either by preventing Allo downregulation (e.g., by treatment with MET) or by direct administration of Allo or of agents (e.g., fluoxetine) that upregulate brain Allo content in SI mice.
Neuroprotective and Neurotrophic Actions of the Mood Stabilizer Lithium: Can It Be Used to Treat Neurodegenerative Diseases?
83-90
10.1615/CritRevNeurobiol.v16.i12.90
De-Maw
Chuang
Molecular Neurobiology Section, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA
The mood stabilizing drug lithium has emerged as a robust neuroprotective agent in preventing apoptosis of neurons. Long-term treatment with lithium effectively protects primary cultures of rat brain neurons from glutamate-induced, NMDA receptor-mediated excitotoxicity. This neuroprotection is accompanied by an inhibition of NMDA-receptor—mediated calcium influx, upregulation of anti-apoptotic Bcl-2, downregulation of pro-apoptotic p53 and Bax, and activation of cell survival factors. Lithium treatment antagonizes glutamate-induced activation of c-Jun-N-terminal kinase (JNK), p38 kinase, and AP-1 binding, which has a major role in cytotoxicity, and suppresses glutamate-induced loss of phosphorylated cAMP responsive element binding protein (CREB). Lithium also induces the expression of brain-derived neurotrophic factor (BDNF) and subsequent activation TrkB, the receptor for BDNF, in cortical neurons. The activation of BDNF/TrkB signaling is essential for the neuroprotective effects of this drug. In addition, lithium stimulates the proliferation of neuroblasts in primary cultures of CNS neurons.
Lithium also shows neuroprotective effects in rodent models of diseases. In a rat model of stroke, post-insult treatment with lithium or valproate, another mood stabilizer, at therapeutic doses markedly reduces brain infarction and neurological deficits. This neuroprotection is associated with suppression of caspase-3 activation and induction of chaperone proteins such as heat shock protein 70. In a rat model of Huntington's disease (HD) in which an excitotoxin is unilaterally infused into the striatum, both long- and short-term pretreatment with lithium reduces DNA damage, caspase-3 activation, and loss of striatal neurons. This neuroprotection is associated with upregulation of Bcl-2. Lithium also induces cell proliferation near the injury site with a concomitant loss of proliferating cells in the subventricular zone. Some of these proliferating cells display neuronal or astroglial phenotypes. These results corroborate our findings obtained in primary neuronal cultures. The neuroprotective and neurotrophic actions of lithium have profound clinical implications. In addition to its present use in bipolar patients, lithium could be used to treat acute brain injuries such as stroke and chronic progressive neurodegenerative diseases.
Protecting the Brain: The Search for a Clinically Effective Neuroprotective Drug for Stroke
91-98
10.1615/CritRevNeurobiol.v16.i12.100
A. Richard
Green
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, UK
The idea that it should be possible to develop a neuroprotective drug that protects the brain from some of the consequences of an acute ischaemic stroke has been in existence for some time and has developed from our increasing knowledge of the biochemical consequences of an acute ischaemic episode. A variety of drugs have been developed to interfere with these biochemical changes. However, while many of these compounds have been shown to be efficacious in animal models of stroke, none has succeeded in clinical trials and reached the market in the Western world. Partly as a result of these failures, guidelines have been published and further extended that detail criteria that should be met before a novel compound is progressed to clinical investigation. These guidelines are reviewed herein, and the author suggests the probability that none of the compounds that have previously failed clinically would have fulfilled the current selection criteria for advancement to clinical trial. It is proposed that NXY-059 (Cerovive®) is the first neuroprotective agent to reach the clinical trial phase that meets all the suggested guidelines for neuroprotective drug development, and the preclinical profile of this compound is reviewed.
Adenosine A2A Receptor Antagonism and Neuroprotection: Mechanisms, Lights, and Shadows
99-106
10.1615/CritRevNeurobiol.v16.i12.110
Patrizia
Popoli
Department of Drug Research and Evaluation, Istituto Superiore di Sanita, Roma, Italy
Luisa
Minghetti
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanita, Roma, Italy
Maria Teresa
Tebano
Department of Drug Research and Evaluation, Istituto Superiore di Sanita, Roma, Italy
Annita
Pintor
Department of Drug Research and Evaluation, Istituto Superiore di Sanita, Roma, Italy
Maria Rosaria
Domenici
Department of Drug Research and Evaluation, Istituto Superiore di Sanita, Roma, Italy
Marino
Massotti
Department of Drug Research and Evaluation, Istituto Superiore di Sanita, Roma, Italy
Adenosine A2A receptor antagonists are regarded as potential neuroprotective drugs, although the mechanisms underlying their effects remain to be elucidated. In this review, quinolinic acid (QA)-induced striatal toxicity was used as a tool to investigate the mechanisms of the neuroprotective effects of A2A receptor antagonists. After having examined the effects of selective A2A receptor antagonists toward different mechanisms of QA toxicity, we conclude that (1) the effect elicited by A2A receptor blockade on QA-induced glutamate outflow may be one of the mechanisms of the neuroprotective activity of A2A receptor antagonists; (2) A2A receptor antagonists have a potentially worsening influence on QA-dependent NMDA receptor activation; and (3) the ability of A2A receptor antagonists to prevent QA-induced lipid peroxidation does not correlate with the neuroprotective effects.
These results suggest that A2A receptor antagonists may have either potentially beneficial or detrimental influence in models of neurodegeneration that are mainly due to increased glutamate levels or enhanced sensitivity of NMDA receptors, respectively.
Transactivation of Cell Death Signals by Glutamate Transmission in Dopaminergic Neurons
107-119
10.1615/CritRevNeurobiol.v16.i12.120
Gabriel A.
de Erausquin
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA
The intrinsic susceptibility of dopaminergic neurons underlies the pathophysiology of Parkinson's disease and is possibly related to developmental injury in schizophrenia. However, the molecular substrates for this susceptibility are not well understood. We review the evidence of selective susceptibility of dopaminergic neurons to excessive glutamate receptor stimulation and discuss the molecular pathways that differentiate between physiological and pathological signaling leading to this particular form of neuronal death. In vitro as well as in vivo, activation of GluRAMPA causes concentration-dependent, severe pruning of neurites and selective death of dopaminergic neurons. In primary cultures of mesencephalon, this form of injury is mediated through release of calcium from intracellular stores (CICR), leading to loss of calcium homeostasis, oxidative stress, and activation of the transcription factor NFκB and the cell death protein p53. Post-translational modification of p53 may be an important target for neuroprotection in Parkinson's disease and perhaps in prevention of other neuropsychiatric disorders.
Dopamine Reuptake by Norepinephrine Neurons: Exception or Rule?
121-128
10.1615/CritRevNeurobiol.v16.i12.130
Ezio
Carboni
Department of Toxicology and Centre of Excellence on Neurobiology of Addiction, University of Cagliari, Cagliari, Italy
Alessandra
Silvagni
Department of Toxicology and Centre of Excellence on Neurobiology of Addiction, University of Cagliari, Cagliari, Italy
Dopamine reuptake by norepinephrine terminals can occur in brain areas such as the prefrontal cortex, the nucleus accumbens shell, and the bed nucleus of stria terminalis that are innervated, although unevenly, by both dopamine and norepinephrine neurons. Therefore the antidepressants that bind selectively the norepinephrine transporter might produce their therapeutic effect by raising the extracellular concentration of dopamine besides that of norepinephrine. Moreover, cocaine can be reinforcing even in knock-out mice for the dopamine transporter because it might raise synaptic dopamine in the nucleus accumbens shell by preventing its uptake by the norepinephrine transporter, an effect that could take place even in wild animals. Recently, it has also been suggested that dopamine can be co-released with norepinephrine by norepinephrine neurons, although it is not clear whether this feature might be related to a previous nonspecific uptake of dopamine by the norepinephrine transporter. In this review we discuss the potential role of the nonspecific uptake of dopamine by norepinephrine transporter in the mechanism of action of drugs of abuse, antipsychotics, and antidepressants.
AMPA Receptor Blockade Potentiates the Stimulatory Effect of L-DOPA on Dopamine Release in Dopamine-Deficient Corticostriatal Slice Preparation
129-139
10.1615/CritRevNeurobiol.v16.i12.140
Zsolt
Juranyi
Division of Preclinical Research, EGIS Pharmaceuticals Ltd., Budapest, Hungary
Nora
Sziray
Division of Preclinical Research, EGIS Pharmaceuticals Ltd., Budapest, Hungary
Bernadett
Marko
Division of Preclinical Research, EGIS Pharmaceuticals Ltd., Budapest, Hungary
Gyorgy
Levay
Division of Preclinical Research, EGIS Pharmaceuticals Ltd., Budapest, Hungary
Laszlo G.
Harsing, Jr.
Division of Preclinical Research, EGIS Pharmaceuticals Ltd., Budapest, Hungary
The release of [3H]dopamine was measured in rat corticostriatal slice preparations that contained the striatum and the adjacent prefrontal cortex to maintained glutamatergic corticostriatal afferentation. These slices were prepared from either nontreated or 6-hydroxydopamine—pretreated rats. The slices were loaded with [3H]dopamine, submerged in a two-compartment bath so that the cortical region was contained in one compartment, the corpus callosum was passed through a silicone greased slot, and the striatal region was contained in the other compartment. The cortical and the striatal parts were superfused with Krebs-bicarbonate buffer independently. The release of [3H]dopamine was determined from the striatal part at rest and in response to electrical stimulation of the cortical area. Electrical stimulation of the cortical part increased the release of [3H]dopamine from the striatal part of the slices, and this release was found to be higher after lesion of the nigrostriatal dopaminergic pathway with 6-hydroxydopamine. Cortically evoked [3H]dopamine release was even higher in the presence of the dopamine precursor L-DOPA after 6-hydroxdopamine lesion. Perfusion of GYKI-53405, a noncompetitive AMPA receptor antagonist, in combination with L-DOPA further increased both basal and stimulation-evoked [3H]dopamine release, whereas GYKI-53405 by itself did not influence basal [3H]dopamine outflow from striatum. These findings indicate that, in parkinsonian striatum, the stimulatory effect of L-DOPA on dopamine release is potentiated by AMPA receptor blockade, and the antiparkinsonian effect of GYKI-53405 may be due to its L-DOPA sparing effect.
Peripheral Markers of Glutamatergic Dysfunction in Neurological Diseases: Focus on Ex Vivo Tools
141-146
10.1615/CritRevNeurobiol.v16.i12.150
Lucio
Tremolizzo
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago Illinois, USA
Simone
Beretta
Department of Neurology, S. Gerardo Hospital and Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy
Carlo
Ferrarese
Department of Neurology, S. Gerardo Hospital and Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy
Since the proposal that excessive glutamatergic stimulation could be responsible for neuronal suffering and death, excitotoxicity and glutamate uptake deficits have been repeatedly confirmed to play a key role in the pathogenesis of different neurological diseases. Therefore, it is conceivable that assessing the glutamatergic system function directly in patients could be extremely useful for early diagnosis, prognostic evaluation, and optimization of the therapy. A possibility is offered by assessing glutamate levels in biological fluid, such as plasma and CSF, where increased levels of this amino acid have been reported in patients affected by stroke, amyotrophic lateral sclerosis (ALS), and AIDS dementia complex. However, the metabolic role of this amino acid acts as a confounding factor, and the possibility of directly assessing glutamatergic functional parameters, such as amino acid reuptake, would probably mirror closely the actual excitotoxic damage operative in each patient. Here we will describe our findings obtained in peripheral ex vivo cells, such as platelets and fibroblasts, both displaying a functional glutamate reuptake system. Consistent with a systemic-impairment assumption, glutamate uptake was shown to be reduced in peripheral cells of Alzheimer's disease, Down syndrome, Parkinson's disease, ALS, and stroke patients. Different systemic factors might be responsible for this phenomenon, including genetic predisposition, oxidative stress, and inflammatory response, raising new, exciting questions about the relevance of their possible interactions for the pathogenesis of neurological disorders.
Cannabinoids and Reward: Interactions with the Opioid System
147-158
10.1615/CritRevNeurobiol.v16.i12.160
Liana
Fattore
Institute of Neuroscience, National Research Council CNR, Section of Cagliari; and Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
Gregorio
Cossu
Department of Neuroscience and Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
Maria S.
Spano
Department of Neuroscience and Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
Serena
Deiana
Department of Neuroscience and Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
Paola
Fadda
Department of Neuroscience and 3 Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
Maria
Scherma
Department of Neuroscience and Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
Walter
Fratta
Institute of Neuroscience, National Research Council CNR, Section of Cagliari; and Department of Neuroscience and Centre of Excellence "Neurobiology of Dependence," Cittadella Universitaria di Monserrato, University of Cagliari, Italy
There is currently substantial evidence that Cannabis sativa derivates act on brain reward in a way very similar to other drugs of abuse and exert numerous pharmacological effects through their interaction with various neurotransmitters and neuromodulators. Among them, the endogenous opioids seem to play an important role in modulating the addictive properties of cannabinoids. Given the plethora of research activity on such a topic, this brief review is necessarily focused on cannabinoid/opioid interaction in reward-related events and restricted to the recent literature. Recent findings from our and other laboratories concerning cannabinoid reinforcing effects as revealed by behavioral animal models of addiction are here summarized. Evidence is then provided demonstrating a functional cross-talk between the cannabinoid and opioid systems in the mutual modulation of the addictive behavior; accordingly, very recent data from transgenic mice lacking either the cannabinoid CB1 or opioid receptors are also presented. Finally, the role of the endogenous cannabinoid system in relapse to opioids is investigated by means of extinction/reinstatement animal models following a period, even prolonged, of drug abstinence. Altogether, the reviewed studies provided a better understanding of the neurobiological mechanisms involved in cannabinoid actions and revealed a bidirectional interaction between the endogenous cannabinoid and opioid systems in reward that extends to central mechanisms underlying relapsing phenomena. Challenges for the future involve elucidation of the neuroanatomical substrates of cannabinoids action, even in light of the therapeutic potential of these compounds.
Cannabinoid/Opioid Crosstalk in the Central Nervous System
159-172
10.1615/CritRevNeurobiol.v16.i12.170
Javier
Corchero
Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain
Jorge
Manzanares
Servicio de Psiquiatria, Hospital Universitario 12 de Octubre, Madrid, Spain
Jose A.
Fuentes
Departamento de Farmacologia, Facultad de Farmacia and Unidad de Cartografia Cerebral, Instituto Plurisciplinar, Universidad Complutense de Madrid, Madrid, Spain
Promising therapeutic uses and a great variety of pharmacological effects are the leading forces that focus actual cannabinoid research. Cannabinoid and opioid systems share neuroanatomical, neurochemical, and paharmacological features. This fact supports the notion that actions induced by each one of these types of drugs involved an interaction between the endogenous opioid and endocannabinoid neuronal systems. Over the last decade our group and others have investigated cannabinoid/opioid crosstalk in the central nervous system by studying the mechanisms underlying pharmacological and biochemical interactions between the two systems in experimental paradigms of antinociception, drug reinforcement, and anxiety. The goal of this review is to revise the latest work done on this subject, with special emphasis on the research done with genetically modified animals. Whereas clinical progress is going ahead slowly, basic research in this area is progressing rapidly. Clinical applications derived from the cannabinoid/opioid crosstalk and based tightly on medical evidence are yet to come, but it is hoped that knowledge of this central messenger interaction will help to develop new alternatives for the treatment of some pathological states.
Spatio-Temporal Regulation of Neurotransmitter Release by PKC; Studies in Adrenal Chromaffin Cells
173-179
10.1615/CritRevNeurobiol.v16.i12.180
Konosuke
Kumakura
Life Science Institute, Sophia University, Tokyo, Japan
Nobuyiki
Sasakawa
Life Science Institute, Sophia University, Tokyo, Japan
Norie
Murayama
Life Science Institute, Sophia University, Tokyo, Japan
Mica
Ohara-Imaizumi
Life Science Institute, Sophia University; and Department of Biochemistry, Kyorin University School of Medicine, Tokyo, Japan
Activation of protein kinase C (PKC) seems to promote vesicle recruitment to the release-ready state prior to Ca2+-triggered fusion in chromaffin cells. To understand spatio-temporal regulation of vesicle recruitment by PKC, we studied the effects of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on the vesicle movements in living chromaffin cells by imaging with a fluorescence microscope-cooled CCD system. About 60~80% of the chromaffin vesicles showed a rapid movement, about 20% showed a moderate movement, and the rest showed slow/no movement in resting and post-stimulation. The vesicles with slow/no movement increased to 40% upon a depolarizing stimulation, and TPA increased this population to about 70%. TPA treatment, in addition, increased the number of visible chromaffin vesicles beneath the plasma membrane, suggesting that the potentiation of vesicle recruitment by PKC involves a substantial increase in the subplasmalemmal distribution of vesicles.
5-Lipoxygenase as a Putative Link Between Cardiovascular and Psychiatric Disorders
181-186
10.1615/CritRevNeurobiol.v16.i12.190
Radmila
Manev
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
Hari
Manev
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA
There is evidence of an association between depression and anxiety and cardio— cerebro—vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio—cerebro—vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio—cerebro—vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids