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PubMed1998

The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes.

The study of excitatory amino acids (EAAs) has recently resulted in new and fundamental concepts in neuroscience. This progress has led to a growing awareness of the crucial role that brain EAAs systems play in a variety of physiological and pathological processes. The N-methyl-D-aspartate (NMDA) receptor, presently the most well understood subtype of EAAs receptors, has been implicated in crucial physiological processes such as synaptogenesis, learning and memory. Dysfunctions of NMDA receptors seem to play a crucial role in the neurobiology of disorders such as Parkinson's disease, Alzheimer's disease, epilepsy and ischemic stroke. This paper is a review of emerging data indicating that alterations of NMDA receptor function may be pivotal to the pathophysiology of four common psychiatric syndromes: schizophrenia, major depression, posttraumatic stress disorder, and alcoholism. Special emphasis is placed on the current state of development of pharmacological strategies aiming at the modulation of NMDA receptor-mediated neurotransmission in these disorders.

Alcoholism↗

PubMedDate not supplied

Significance of dysfunctional glutamatergic transmission for the development of psychotic symptoms.

It has been postulated that disturbances in glutamatergic transmission may contribute to the pathophysiology of schizophrenia. This view is based on several findings: (1) the noncompetitive NMDA receptor antagonists, phencyclidine and ketamine, induce both positive and negative psychotic symptoms in humans, which closely resemble those observed in schizophrenia; (2) a number of animal studies have shown that neuroleptics that ameliorate symptoms of schizophrenia (e.g. clozapine) also inhibit the effects of NMDA antagonists; (3) postmortem and in vivo studies have revealed alterations in ionotropic glutamate receptors (NMDA, AMPA, KA) and their modulatory sites in schizophrenia; (4) compounds enhancing the function of NMDA receptors potentiate the antipsychotic effects of neuroleptics in schizophrenic patients.

Animals↗

PubMed1977

Botulism: electrophysiological studies.

In a patient with botulism type B, electrophysiological studies showed: (1) a pattern in the repetitive nerve stimulation test resembling that found in the Eaton-Lambert syndrome but without any significant increment at high rates of stimulation or posttetanic exhaustion phenomenon; (2) a prominent response to guanidine hydrochloride; (3) a short mean duration of motor unit potentials that reversed with recovery; (4) a mild, prolonged latency and low amplitude of the H-reflex; (5) mild peripheral nerve dysfunction; and (6) a long-lasting persistence of abnormalities beyond the time of clinical recovery. The literature reports two types of responses in the repetitive nerve stimulation test in botulism: in the severe form one obtains a low-amplitude muscle potential, a decremental response at low rates of stimulation, and an insignificant incremental response at high rates of stimulation; in the mild form a normal amplitude of muscle potential occurs together with a normal response to low rates of stimulation and a significant incremental response at high rates of stimulation.

Botulism↗

PubMed1998

Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression.

Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by increasing noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a consequence of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated addition to the antidepressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four metabolites via demethylation and hydroxylation, followed by glucuronide conjugation. The unconjugated desmethyl metabolite is pharmacologically less active than the parent compound. Mirtazapine lacks auto-induction of hepatic isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and 3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of these enzymes. Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose. Mirtazapine is a unique addition to the antidepressant armamentarium as first-line therapy in patients with major depression and symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia and as a useful alternative in depressed patients who do not adequately respond to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake inhibitors.

Administration, Oral↗

PubMed2001

Sensory nerve somatosensory evoked potentials (SEP) in the evaluation of patients with sciatica: false P1 latency prolongation may be due to admixture of dermatomal SEP.

Patient-reported stimulus-related radiating sensory symptoms within the territory of the stimulated nerve have been used to verify stimulation in sensory nerve scalp recorded somatosensory evoked potentials (SEP). The main aim of the present study of false positive P1 latency prolongation in lumbosacral sensory nerve SEP was to investigate whether elicitation of such symptoms secures adequate sensory nerve stimulation. Nerve roots were studied on the asymptomatic side in 64 patients with unilateral sciatica. Saphenous (L4), superficial peroneal (L5), and sural (S1) nerve SEP were registered in all patients. Pretibial dermatomal SEP were registered in ten of them. Stimulation was equidistant from the registration electrode in all SEP registrations. The false positive rate was lower in saphenous nerve SEP with than without verified supramaximal stimulation (1/30 vs. 6/22, P = 0.03) in spite of radiating stimulus-related sensory symptoms in both groups. This difference was not caused by subclinical myelographic nerve root compression or general peripheral nerve dysfunction. The P1 latency was longer in the pretibial dermatomal SEP than in the saphenous and superficial peroneal nerve SEP with the same conduction distance (mean difference 4.7 (95% CI = 3.8 to 5.6) and 4.4 ms (95% CI = 3.4 to 5.4), respectively). It is concluded that dermatomal SEP have longer P1 latency than sensory nerve SEP. Verified supramaximal nerve simulation is recommended to avoid false results due to admixture of dermatomal to sensory nerve SEP.

Adult↗

PubMed2004

Astrocyte apoptosis: implications for neuroprotection.

Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.

Animals↗

PubMed1998

Abnormal cone synapses in human cone-rod dystrophy.

OBJECTIVE: Little is known of the cytopathology of photoreceptors in human inherited retinal dystrophies that initially affect the central retina, including the macula. The current study sought to determine the cytologic features of dysfunctional cone and rod photoreceptors, as well as the pattern of degeneration of the cells in representative cases of central retinal dystrophy. STUDY DESIGN: Comparative human tissue study. MATERIALS: Four human donor eyes with the following forms of central retinal dystrophy: cone-rod dystrophy (CRD), central areolar choroidal dystrophy, Bardet-Biedl syndrome, and cone dystrophy-cerebellar ataxia. The cytologic features of retinal photoreceptors in these eyes were compared with those in an eye with retinitis pigmentosa and six normal human eyes. METHODS AND OUTCOME MEASURES: Immunocytochemistry and electron microscopy were used to evaluate the retinal histopathology in the donor eyes. RESULTS: Cone numbers were decreased in the case of CRD, particularly in the central and far peripheral retina, and both cone and rod outer segments were slightly shortened. Occasional degenerate cones had dense cytoplasm and pyknotic nuclei dislocated sclerad to the external-limiting membrane. The most prominent alteration in this retina was marked enlargement and distortion of the cone photoreceptor pedicles, which contained reduced numbers of synaptic vesicles. The retina with central areolar choroidal dystrophy contained a few cones with similarly abnormal synapses. However, comparable cone synapse abnormalities were not observed in the cases of Bardet-Biedl syndrome, cone dystrophy-cerebellar ataxia, retinitis pigmentosa, or in the normal retinas. CONCLUSIONS: The functional consequences of the cone synapse abnormalities in CRD are not known but may correlate with the electroretinographic abnormalities documented in some cases of CRD. To our knowledge, comparable synapse changes have not been noted in either rods or cones in other forms of retinal dystrophy, including retinitis pigmentosa, suggesting that different cytopathologic mechanisms may be involved.

Adult↗

PubMed2005

Grey matter pathology in multiple sclerosis.

The aim of our study is to evaluate the extent and distribution of grey matter demyelinating lesions in multiple sclerosis (MS), addressing also neuronal loss and synaptic loss. Whole coronal sections of 6 MS brains and 6 control brains were selected. Immunohistochemistry was performed for myelin basic protein, neurofilaments, synaptophysin, ubiquitin, and activated caspase-3. Neuronal density and optical density of synaptophysin staining were estimated in cortical lesions and compared with those observed in corresponding areas of normal (i.e. nondemyelinated) cortex in the same section. Demyelinating lesions were observed in the cerebral cortex, in the thalamus, basal ganglia, and in the hippocampus. The percentage of demyelinated cortex was remarkable in 2 cases of secondary progressive MS (48% and 25.5%, respectively). Neuronal density was significantly reduced in cortical lesions (18-23% reduction), if compared with adjacent normal cortex, in the 2 cases showing the higher extent of cortical demyelination; in the same cases, very rare apoptotic neurons expressing caspase-3 were observed in cortical lesions and not in adjacent normal cortex. No significant decrease in optical density of synaptophysin staining was observed in cortical lesions. Grey matter demyelination and neuronal loss could contribute to disability and cognitive dysfunctions in MS.

Adult↗

PubMed1984

A simple, sensitive method for detecting early peripheral nerve dysfunction in the rat following acrylamide treatment.

The "ocular zingerone test" was employed to detect early alterations in peripheral nerve function which were associated with acrylamide intoxication in the rat. Acrylamide treatment resulted in a dose-related prolongation of the behavioral response to ocular zingerone. Significant alterations in the zingerone response occurred prior to detectable alterations in peripheral sensory and motor nerve function. Acrylamide-induced prolongation of the zingerone response appears to be the result of functional alterations in cholinergic neurotransmission in the autonomic nervous system. It is concluded that the "ocular zingerone test" is a simple, sensitive technique with which the degree of acrylamide intoxication may be quantified in the rat.

Acrylamide↗

PubMed2006

Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia.

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) concomitantly with L-DOPA for 2 weeks. A large number of BrdU-positive cells were found in the striatum and its output structures (globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata) in L-DOPA-treated rats that had developed dyskinesia. The vast majority (60-80%) of the newborn cells stained positively for endothelial markers. This endothelial proliferation was associated with an upregulation of immature endothelial markers (nestin) and a downregulation of endothelial barrier antigen on blood vessel walls. In addition, dyskinetic rats exhibited a significant increase in total blood vessel length and a visible extravasation of serum albumin in the two structures in which endothelial proliferation was most pronounced (substantia nigra pars reticulata and entopeduncular nucleus). The present study provides the first evidence of angiogenesis and blood-brain barrier dysfunction in an experimental model of L-DOPA-induced dyskinesia. These microvascular changes are likely to affect the kinetics of L-DOPA entry into the brain, favoring the occurrence of motor complications.

Animals↗

PubMed1984

Inhibition of opiate receptor-mediated signal transmission by rabies virus in persistently infected NG-108-15 mouse neuroblastoma-rat glioma hybrid cells.

Acute and persistent rabies virus infection of mouse neuroblastoma-rat glioma hybrid cells (NG-108-15) results in a loss of the normal inhibiting function of opiates via the opiate receptor on hormone-stimulated adenylate cyclase activity. Previous studies of these persistently infected cells have shown a decrease in the affinity of the opiate receptors for agonists without any change in the number of these receptors. We now demonstrate that persistently infected cells are unable to couple the opiate receptors to the inhibitory regulatory protein Ni of the adenylate cyclase, as measured by the loss of stimulation of the GTPase activity of this protein. However, the unstimulated basal GTPase activities of the regulatory components Ni and Ns are unchanged in the persistently infected cells. These studies also reveal a disorder of the stimulation of the adenylate cyclase by GTP or fluoride via the stimulating regulatory G/F protein (Ns) in persistently infected cells, whereas direct stimulation of the catalytic subunit of the adenylate cyclase by forskolin remains unchanged. Therefore, there are different points of dysfunction caused by the persistent rabies infection in the signal pathway from the opiate receptor to the adenylate cyclase and from the stimulating Ns protein to the enzyme: (i) opiate receptor binding is reduced by a decrease of agonist affinity (previously published data), (ii) the stimulation of GTPase activity of the inhibiting regulatory component Ni of the adenylate cyclase system is inhibited, and (iii) the signal pathway from the stimulating regulatory component of the adenylate cyclase system to the unchanged activity of the catalytic subunit is defective.

Adenylyl Cyclases↗

PubMed1984

Neurochemical psychiatry as a source of hypotheses concerning the role of homeostatic mechanisms in brain function.

Numerous homeostatic mechanisms regulate impulse traffic in the neural pathways of the brain. If, for whatever reason, these mechanisms are unable to maintain neural activity within normal levels, the resulting disruption of the balance of impulse traffic produces brain dysfunction such as mental or neurological disorders. Drug treatment of these disorders involves the use of agents that return impulse traffic to homeostatic levels. Such agents have been found only for certain disorders such as Parkinson's Disease, certain affective disorders and some aspects of schizophrenia. The development of therapeutic interventions for currently untreatable conditions such as Huntington's Chorea or Alzheimer's Disease and the design of drugs for the more efficient treatment of psychiatric disorders, would be greatly facilitated by more detailed knowledge of the specific homeostatic mechanisms controlling brain function.

Brain↗

PubMed1986

Control of sensorimotor function by dopaminergic nigrostriatal neurons: influence on eating and drinking.

The literature on the effects of lesions of the lateral hypothalamic area (LHA) on eating and drinking is reviewed in an effort to understand the function of the neural substrate destroyed. The data suggest that damage to the dopaminergic nigrostriatal neurons that course through the LHA results in a decrease in sensorimotor facilitation; that is, an increase in the threshold for responding to stimuli that elicit orientation, approach and consumption. This increase results in decreased consumption of food and water. Evidence is also reviewed suggesting the possibility that striatal dopaminergic activity may mediate a negative feedback signal related to blood glucose level that influences responsiveness to food, and therefore eating. There is no evidence that the nigrostriatal system mediates a similar signal related to water balance and drinking. A second deficit associated with LHA lesions, caused by damage to the pallidofugal neurons that descend through this area, is a dysfunction of motor control of the head and mouth. This results in an increase in the effort required to consume food and water, also leading to decreased consumption. These two behavioral factors: an increased threshold for responding to the sensory properties of food and water and an increase in the effort required to eat and drink are used to explain the symptoms making up the lateral hypothalamic syndrome without postulating changes in physiological regulatory (set point) mechanisms.

Animals↗

PubMed2002

The neuropathology of primary mood disorder.

The biological mechanisms proposed to underlie primary mood disorder do not usually include a neuropathological component. However, a significant MRI literature attests to structural abnormalities in regions and has encouraged neuropathological investigations from which candidate histological correlates have begun to emerge. In particular, there are several reports of cytoarchitectural alterations in anterior cingulate and prefrontal cortices, characterized by a decrease in the number or density of glia. Reductions in the size and density of some neuronal populations have also been described, accompanied by alterations in indices of synaptic terminals and dendrites. This form of pathology putatively reflects aberrant neurodevelopment or impaired cellular plasticity. A separate pathological process is suggested by the excess of subcortical focal lesions seen on MRI, especially in elderly patients; these probably reflect white matter damage of vascular origin. Both types of pathology have been observed, to a greater or lesser extent, in unipolar as well as bipolar mood disorders. None of the findings appear attributable to treatment with antidepressants, mood stabilizers or electroconvulsive therapy (ECT). However, all findings remain preliminary due to a lack of unequivocal replication and the failure to control fully for other potential confounders and co-morbid conditions. There are also basic questions to be answered concerning the clinical correlates, magnitude, progression and heterogeneity of the pathology. Nevertheless, it must now be considered likely that changes in brain structure, both macroscopic and microscopic, are a feature of primary mood disorder, a fact to be taken into account when interpreting functional imaging, neuropsychological and neurochemical data. The neuropathology is postulated to contribute to the pathophysiology and dysfunction of the neural circuits which regulate mood and its associated cognitions, behaviours and somatic symptoms.

Brain↗

PubMed1999

[The neurobiology of depression].

Neurobiology dominates efforts to understand depression. This psychiatric illness is thought to result from dysfunctions in monoaminergic systems affecting norepinephrine, serotonin and dopamine. Abnormalities are linked to functional deficit of monoamines at several effector sites. Findings include reduced cerebrospinal fluid and urinary concentrations of metabolites, decreased plasma concentrations of precursors, modifications of receptor density and clinical effectiveness of drugs which increase neurotransmission in depressed patients. The original hypothesis of affective disorder envisaged a single transmitter model, but neuroscientific developments highlight the complexity of the central nervous system. Considerable evidence supports the hypothesis of combined alterations of monoaminergic functions and other systems like neuropeptides and neuroendocrine functions.

Adrenergic alpha-Agonists↗

PubMed2001

Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits.

The prefrontal cortex plays a fundamental role in the working memory functions of the cerebral cortex and is also the site of dysfunction in several neurological and psychiatric disorders, including schizophrenia. Prefrontal neurons are distinguished by their capacity for sustained activity during the time a stimulus is held in memory, and this mnemonic response is considered a substrate for a variety of cognitive functions. The neuronal basis for sustained activity in prefrontal neurons is unknown but is thought to involve recurrent excitation among pyramidal neurons. Recent studies in awake behaving monkeys have demonstrated that the persistent activity in prefrontal neurons is modulated by dopamine. To examine the mechanisms by which dopamine might modulate transmission in local excitatory circuits, we have performed dual whole-cell recordings in connected pyramidal cell pairs with and without dopamine application. We find that dopamine reduces the efficacy of unitary excitatory neurotransmission in layer V pyramidal cells by decreasing its reliability. These effects, which are reproduced by a selective D1 agonist and blocked by a D1 antagonist, are independent of voltage changes and are not attenuated by blockade of sodium and potassium channels in the postsynaptic neurons. We conclude that attenuation of local horizontal excitatory synaptic transmission in layer V pyramidal neurons by dopamine is through D1 actions at a presynaptic site.

Animals↗

PubMed1996

Possibility of 5-HT3 receptor involvement in alcohol dependence: a microdialysis study of nucleus accumbens dopamine and serotonin release in rats with chronic alcohol consumption.

The present study was performed to examine the involvement of serotonin-3 (5-HT3) receptors in the rat nucleus accumbens (ACC) in alcohol dependence. In alcohol-treated rats, perfusion of 40 mM K+ and 100 mM ethanol (EtOH) through the microdialysis probe increased the extracellular levels of ACC dopamine (DA), compared with controls. Perfusion of the serotonin (5-HT) uptake inhibitor sertlarine enhanced the extracellular levels of ACC 5-HT in both groups. Increased 5-HT availability in the synaptic clefts on the ACC further activated ACC DA release in the alcohol-treated rats, in comparison with controls. In the final experiments, perfusion of the 5.0 microM 5-HT3 receptor agonist 2-methyl-5-HT (2-Me-5-HT) through the microdialysis probe enhanced the extracellular levels of ACC DA. Magnitude of 2-Me-5-HT-induced DA release was significantly higher in alcohol-treated rats than in controls. On the other hand, 40 mM K(+)- and 100 mM EtOH-induced extracellular 5-HT release in alcohol-treated rats were markedly inhibited. These results show that (1) chronic alcohol intake increases the sensitivity of 5-HT3 receptors, (2) 5-HT3 receptors regulate DA release in the ACC, (3) the dopaminergic neuronal systems associated with 5-HT3 ionophore in the ACC were upregulated after chronic alcohol exposure, and (4) chronic alcohol intake desensitizes the serotonergic neuronal systems in rat ACC. These findings suggest that neurochemical functions of 5-HT3 receptors in regulating DA release in the ACC after alcohol exposure compensate for the dysfunction of serotonergic activity to restore the original properties in processing alcohol tolerance and that the development of alcohol dependence may be mediated by ACC 5-HT3 receptors.

Alcoholism↗

PubMed2006

Killer proteases and little strokes--how the things that do not kill you make you stronger.

The phenomenon of ischemic preconditioning was initially observed over 20 years ago. The basic tenant is that if stimuli are applied at a subtoxic level, cells upregulate endogenous protective mechanisms to block injury induced by subsequent stress. Since this discovery, many conserved signaling mechanisms that contribute to activation of this potent protective program have been identified in the brain. A clinical correlate of this basic research finding can be found in patients with a history of transient ischemic attack (TIA), who have a decreased morbidity after stroke. In spite of multidisciplinary efforts to design safer, more effective stroke therapies, we have thus far failed to translate our understanding of endogenous protective pathways to treatments for neurodegeneration. This review is designed to provide clinicians and basic scientists with an overview of stress biology after TIA and preconditioning, discuss new therapeutic strategies to target the protein dysfunction that follows ischemic injury, and propose enhanced biochemical profiling to identify individuals at risk of stroke after TIA. We pay particular attention to the unanticipated consequences of overly aggressive intervention after TIA in which we have found that traditional cytotoxic agents such as free radicals and apoptosis associated proteases is essential for neuroprotection and communication in the stressed brain. These data emphasize the importance of understanding the complex interplay between chaperones, apoptotic proteases including caspases, and the proteolytic degradation machinery in adaptation to neurological injury.

Animals↗