Search

Background: V-POSSUM and E-PASS scoring systems are usually used to predict morbidity and early mortality in surgical patients. We conducted this study to assess the validity of the V-POSSUM and E-PASS scores in predicting risk of acute kidney injury (AKI) development in patients undergoing elective open abdominal aortic aneurysm (AAA) repair., Methods: We studied a consecutive series of 171 patients with AAA, qualified for elective open infrarenal repair. Patients underwent a thorough examination, and the physiological and surgical stress components of the V-POSSUM and E-PASS scores were calculated. The classification of patients in terms of postoperative AKI was performed in accordance with KDIGO criteria., Results: AKI was recognized in 62 patients. In these patients, we found significantly higher physiological and surgical stress components of V-POSSUM and E-PASS scores in relation to patients without AKI. ROC analysis showed that the E-PASS score with a cutoff point ≥0.796 and the V-POSSUM score (morbidity) with a cutoff point ≥77.2% with sensitivity of 75.8% and 74.2%, respectively, and with specificity of 83.5% for both, identified patients with postoperative AKI., Conclusions: V-POSSUM and E-PASS scores have similar good properties in predicting postoperative AKI in patients undergoing elective open AAA repair., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Hepcidin is a peptide hormone that regulates iron homeostasis. Hepcidin may represent an early, predictive biomarker of acute kidney injury, another model of ischemia-reperfusion injury. Urinary hepcidin-25 has been shown to be elevated in patients who do not develop acute kidney injury. Creatinine is an unreliable indicator during acute changes in kidney; therefore, the aim of the study was to assess whether hepcidin could predict renal outcome in 31 consecutive patients undergoing kidney allograft transplantation. Serum hepcidin was evaluated before and after 1, 3, 6, and 10 days after kidney transplantation, using commercially available kits. Serum creatinine was assessed at the same time., Methods: We found a significant decrease in serum hepcidin, as early as after 1 day after kidney transplantation. Before transplantation, serum hepcidin was related to creatinine. In patients with delayed graft function, there was no decrease in serum hepcidin., Results: Our findings may have important implications for the clinical treatment of patients undergoing kidney transplantation. The "window of opportunity" is narrow in delayed graft function to distinguish between acute rejection and calcineurin inhibitors nephrotoxicity, and time is limited to introduce proper treatment after initiating insult., Conclusions: Hepcidin must be investigated as a potential early marker for delayed graft function, especially in the upcoming setting of early dialysis treatment or anti-rejection therapy and might contribute to early patient risk stratification., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Radiocephalic (RC) fistulae remain the first choice access for hemodialysis. The antecubital fossa is recommended as the next site. However, for some patients a basilic vein can be used to create an arteriovenous (av) fistula. We report a series of patients where the forearm basilic vein served as an alternative conduit for secondary procedures. Over an 8-year period, 30 patients who had a failed RC fistula underwent a basilic vein transposition. The immediate results were satisfactory. All fistulas were successfully cannulated. Cumulative patency was 93% after 1 year, 78% after 2 years, and 55% after 3 years. No ischemic or infectious complications were noted during the study period. The use of the forearm basilic vein to create a native av fistula appears to be a good alternative to procedures in the antecubital fossa or upper arm, thus preserving more proximal veins for future use.

Objectives: Neuropathic pain is commonly encountered in rheumatology practice, often associated with nociceptive mechanisms. It is caused by nervous system lesions, and the usual treatments with analgesics and anti-inflammatory drugs are mostly ineffective. Antiepileptic drugs (AED) have proved effective in relieving neuropathic pain. AED are recently used by rheumatologists since the role of neuropathic pain in rheumatological conditions has only recently been documented. Nevertheless, the tendency seems to be reversed when these drugs are used inappropriately. The CEDR (Cercle d'Etude de la Douleur en Rhumatologie), a specific interest group of the French Society of Rheumatology that focuses on pain in rheumatology, undertook to develop recommendations for the use of AED in Rheumatology., Methods: A list of questions concerning the prescription of AED in painful rheumatic conditions was validated by a working group of 7 experts from the CEDR. The list of questions was used to draw up the recommendations. A literature review was performed using electronic databases (Medline, Embase and Cochrane library between 1980 and 2007) without limitations on the type of publication: case reports, clinical trials, literature review and guidelines about therapeutic management of neuropathic pain. Selected studies were scored for quality. Based on the literature and clinical experience, recommendations were developed using the Delphi method., Results: We identified 29 studies concerning the use of AED in painful rheumatic conditions and 16 studies were considered valid and scored for quality. These few studies, the guidelines published for neuropathic pain treatment and the clinical experience of each expert, were used to develop 11 recommendations for the use of AED in painful rheumatic conditions., Conclusion: These recommendations can be used as guidelines to help prescribers to use AED for the management of pain in rheumatic conditions until further scientific evidence becomes available.

Midbrain dopamine (DA) neurons project to pyramidal cells and interneurons of the prefrontal cortex (PFC). At the microcircuit level, interneurons gate inputs to a network and regulate/pattern its outputs. Whereas several in vitro studies have examined the role of DA on PFC interneurons, few in vivo data are available. In this study, we show that DA influences the timing of interneuron firing. In particular, DA had a reductive influence on interneuron spontaneous firing, which in the context of the excitatory response of interneurons to hippocampal electrical stimulation, lead to a temporal focalization of the interneuron response. This suggests that the reductive influence of DA on interneuron excitability is responsible for filtering out weak excitatory inputs. The increase in the temporal precision of interneuron firing is a mechanism by which DA can modulate the temporal dynamics of feedforward inhibition in PFC circuits and can thereby influence cognitive information processing.

A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by alpha 1b-adrenergic and 5-HT2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated d-amphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

Midbrain dopaminergic (DAergic) neurons play a major regulatory role in in goal-directed behavior and reinforcement learning. DAergic neuron activity, and therefore spatiotemporal properties of dopamine release, precisely encodes reward signals. Neuronal activity is shaped both by external afferences and local interactions (chemical and electrical transmissions). Numerous hints suggest the existence of chemical interactions between DAergic neurons, but direct evidence and characterization are still lacking. Here, we show, using dual patch-clamp recordings in rat brain slices, a widespread bidirectional chemical transmission between DAergic neuron pairs. Hyperpolarizing postsynaptic potentials were partially mediated by D2-like receptors, and entirely resulted from the inhibition of the hyperpolarization-activated depolarizing current (Ih). These results constitute the first evidence in paired recordings of a chemical transmission relying on conductance decrease in mammals. In addition, we show that chemical transmission and electrical synapses frequently coexist within the same neuron pair and dynamically interact to shape DAergic neuron activity.

The striatum, the main input nucleus of basal ganglia, receives a massive innervation from the entire cerebral cortex and is in charge of the detection of behaviorally relevant signals. In turn, via its projections to the output nuclei of basal ganglia, the striatum contributes to the organization of appropriate compartmental responses. Substantia nigra pars compacta dopaminergic neurons project predominantly to the striatum and regulate striatal functions. Implications of dopaminergic receptors on the physiology of striatal neurons are now well documented. By contrast, the effects of acute dopamine depletion on striatal neurons remain poorly explored. Here, the alpha-methyl-para-tyrosine was used to deplete dopamine from rat brain slices. We analyzed the consequences of a alpha-methyl-para-tyrosine treatment on membrane properties of striatal neurons: the medium-sized spiny neurons and the interneurons (GABAergic, cholinergic and NO-synthase). After acute dopamine depletion, medium-sized spiny neurons became more excitable. GABAergic interneurons became less excitable whereas cholinergic cells displayed an increased excitability. NO-synthase-containing interneurons did not show noticeable changes in their excitability. Such membrane properties changes indicate that striatal circuits should undergo major alteration in cortico-basal ganglia information processing.

Information processing within the striatum is regulated by local circuits involving dopamine, cholinergic interneurons and neuropeptides released by recurrent collaterals of striatal output neurons. In the limbic-prefrontal territory of the dorsal striatum, enkephalin inhibits the NMDA-evoked release of acetylcholine directly through micro-opioid receptors (MORs) located on cholinergic interneurons and indirectly through MORs of output neurons of striosomes. In this territory, we investigated the consequence of changes in dopamine transmission, bilateral 6-hydroxydopamine-induced degeneration of striatal dopaminergic innervation or cocaine (acute and chronic) exposure on (i) MOR expression in both cholinergic interneurons and output neurons of striosomes, and (ii) the direct and indirect enkephalin-MOR regulations of the NMDA-evoked release of acetylcholine. Expression of MORs in cholinergic interneurons was preserved after 6-hydroxydopamine and down-regulated after cocaine treatments. Accordingly, the direct enkephalin-MOR control of acetylcholine release was preserved after 6-hydroxydopamine treatment and lost after cocaine exposure. Expression of MORs in output neurons of striosomes was down-regulated in the 6-hydroxydopamine situation and either preserved or up-regulated after acute or chronic cocaine exposure, respectively. Accordingly, the indirect enkephalin-MOR control of acetylcholine release disappeared in the 6-hydroxydopamine situation but surprisingly, despite preservation of MORs in striosomes, disappeared after cocaine treatment. Showing that MORs of striosomes are still functional in this situation, the MOR agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin inhibited the NMDA-evoked release of acetylcholine after cocaine exposure. Therefore, alteration in the regulation of cholinergic transmission by the enkephalin-MOR system might play a major role in the motivational and cognitive disorders associated with dopamine dysfunctions in fronto-cortico-basal ganglia circuits.

The basal ganglia (BG) provide a major integrative system of the forebrain involved in the organization of goal-directed behaviour. Pathological alteration of BG function leads to major motor and cognitive impairments such as observed in Parkinson's disease. Recent advances in BG research stress the role of neural oscillations and synchronization in the normal and pathological function of BG. As demonstrated in several brain structures, these patterns of neural activity can emerge from electrically coupled neuronal networks. This review aims at addressing the presence, functionality and putative role of electrical synapses in BG, with a particular emphasis on the striatum and the substantia nigra pars compacta (SNc), two main BG nuclei in which the existence and functional properties of neuronal coupling are best documented.

Dopaminergic neurons of the substantia nigra pars compacta play a major role in goal-directed behavior and reinforcement learning. The study of their local interactions has revealed that they are connected by electrical synapses. Connexins, the molecular substrate of electrical synapses, constitute a multigenic family of 20 proteins in rodents. The permeability and regulation properties of electrical synapses depend on their connexin composition. Therefore, the knowledge of the molecular composition of electrical synapses is fundamental to the understanding of their specific functions. We have investigated the connexin mRNA expression pattern of dopaminergic neurons by single-cell RT-PCR analysis, during two periods in which dopaminergic neurons are electrically coupled in vitro (P7-P10 and P17-P21). Our results show that dopaminergic neurons express mRNAs of various connexins (Cx26, Cx30, Cx31.1, Cx32, Cx36 and Cx43) in a developmentally regulated manner. Furthermore, we have observed that dopaminergic neurons display different connexin expression patterns, and that multiple connexins can be expressed in a single dopaminergic neuron. These observations underline the importance of electrical coupling in the development of dopaminergic neurons and raise the question of the existence of functionally distinct electrically coupled networks in the substantia nigra pars compacta.

Although nicotine is generally considered as the main compound responsible for addictive properties of tobacco, some experimental data indicate that nicotine does not exhibit all the characteristics of other substances of misuse such as psychostimulants and opiates. For example, nicotine generally fails to induce locomotor response in mice and self-administration of nicotine is difficult to obtain in rats. We have shown recently that a pretreatment with mixed irreversible monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, triggers a locomotor response to nicotine in mice and induces a robust self-administration of nicotine in rats. We show here that when mice were pretreated with enhancers of extracellular levels of noradrenaline, dopamine or serotonin (D-amphetamine, GBR12783 or para-chloro-amphetamine, respectively) and injected with nicotine (1 mg/kg), only those animals pretreated with para-chloro-amphetamine exhibited a specific locomotor response to nicotine. These data indicate a critical role of serotonin in nicotine-induced locomotor activity in mice. This was further confirmed in microdialysis experiments showing that nicotine induces an increase in extracellular serotonin levels in the ventral striatum in mice pretreated with tranylcypromine. This effect of nicotine on extracellular serotonin levels was absent in mice lacking the beta2-subunit of the nicotinic acetylcholine receptor. Our data suggest that mixed irreversible MAOIs contained in tobacco facilitate the effects of nicotine on serotonin release, thus allowing the locomotor and rewarding effects of nicotine.

The brain is particularly vulnerable to ischaemia; however, neurons can become tolerant to ischaemic insult. This tolerance has been shown to involve activation of NMDA receptors, but its mechanisms have not yet been fully elucidated. Using a preconditioning protocol, we show that neurons surviving to a transient NMDA exposure become resistant to the glutamatergic agonist. Using a proteomic approach, we found that alterations of the protein pattern of NMDA-resistant neurons are restricted mainly to the five collapsin response mediator proteins (CRMPs). A sustained increase in calpain activity following NMDA treatment is responsible for the production of cleaved CRMPs. Finally, we provide evidence for the involvement of the cleaved form of WT-CRMP2 in the down-regulation of NR2B. Our data suggests that, beside their role in neuronal morphogenesis, CRMPs may contribute to neuronal plasticity.

In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhances this response. This effect, called behavioral sensitization, persists many months after the last administration, thus mimicking long-term sensitivity to drugs observed in human addicts. We show here that, in naïve animals, noradrenergic and serotonergic systems, besides their behavioral activating effects, inhibit each other by means of the stimulation of alpha1b-adrenergic and 5-HT(2A) receptors and that this mutual inhibition vanishes with repeated injections of d-amphetamine; this uncoupling may be responsible for behavioral sensitization and for an increased reactivity of dopaminergic neurons. First, after repeated d-amphetamine injections, a d-amphetamine challenge induces a dramatic increase in cortical extracellular norepinephrine (NE) levels. This increased cortical NE release still occurs after 1 month of withdrawal but is diminished or blocked if sensitization is performed in the presence of prazosin, SR46349B, or both alpha1-adrenergic and 5-HT(2A) receptor antagonists, respectively. A strong correlation between increases in cortical extracellular NE levels and the expression of behavioral sensitization was found. Second, repeated d-amphetamine injections induce an increased reactivity of serotonergic neurons measured by cortical extracellular serotonin (5-HT) levels after the administration of a 5-HT releaser, p-chloroamphetamine. Third, knockout mice for alpha1b-adrenergic (alpha1b-AR KO) or 5-HT(2A) (5-HT(2A)-R KO) receptor, respectively, exhibit a behavioral and biochemical hyperreactivity to the acute injection of p-chloroamphetamine (alpha1b-AR KO; 5-HT levels) and d-amphetamine (5-HT(2A)-R KO; NE levels). Uncoupling between noradrenergic and serotonergic neurons may occur not only in addiction but also during chronic stressful situations, thus facilitating the onset of mental illness.

Cerebral ischaemia is associated with brain damage and inhibition of neuronal protein synthesis. A deficit in neuronal metabolism and altered excitatory amino acid release may both contribute to those phenomena. In the present study, we demonstrate that both NMDA and metabolic impairment by 2-deoxyglucose or inhibitors of mitochondrial respiration inhibit protein synthesis in cortical neurons through the phosphorylation of eukaryotic elongation factor (eEF-2), without any change in phosphorylation of initiation factor eIF-2alpha. eEF-2 kinase may be activated both by Ca(2+)-independent AMP kinase or by an increase in cytosolic Ca2+. Although NMDA decreases ATP levels in neurons, only the effects of 2-deoxyglucose on protein synthesis and phosphorylation of elongation factor eEF-2 were reversed by Na(+) pyruvate. Protein synthesis inhibition by 2-deoxyglucose was not as a result of a secondary release of glutamate from cortical neurons as it was not prevented by the NMDA receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine hydrogen maleate (MK 801), nor to an increase in cytosolic-free Ca2+. Conversely, 2-deoxyglucose likely activates eEF-2 kinase through a process involving phosphorylation by AMP kinase. In conclusion, we provide evidence that protein synthesis can be inhibited by NMDA and metabolic deprivation by two distinct mechanisms involving, respectively, Ca(2+)-dependent and Ca(2+)-independent eEF-2 phosphorylation.

Brain macrophages are known to exert dual and opposing functions on neuronal survival, which can be either beneficial or detrimental. The rationale of our study is that this duality could arise from an exclusive secretion of either pro- or anti-inflammatory cytokine by distinct cell subsets, cytokines that could respectively mediate neurotoxic or neurotrophic effects. Innate immune response was induced in macrophage cultures prepared from embryonic-day-16 to postnatal-day-8 mouse brains. By immunofluorescent detection of intracellular cytokines, we have assessed the occurrence of TNFalpha or IL10 synthesis at single cell level and observed distinct secretory patterns that include cells producing exclusively TNFalpha or IL10, cells producing both cytokines and non-producer cells. These secretory patterns are differentially regulated by MAP-kinase inhibitors. Altogether, these results demonstrate that synthesis of either a pro- or an anti-inflammatory cytokine can segregate distinct brain macrophages and suggests a functional cell-subset-specialisation.

Corticostriatal projections originate from the entire cerebral cortex and provide the major source of glutamatergic inputs to the basal ganglia. Despite the importance of corticostriatal connections in sensorimotor learning and cognitive functions, plasticity forms at these synapses remain strongly debated. Using a corticostriatal slice preserving the connections between the somatosensory cortex and the target striatal cells, we report the induction of both non-Hebbian and Hebbian forms of long-term potentiation (LTP) and long-term depression (LTD) on striatal output neurons (SONs). LTP and LTD can be induced selectively by different stimulation patterns (high-frequency trains vs low-frequency pulses) and were evoked with similar efficiency in non-Hebbian and Hebbian modes. Combination of LTP-LTD and LTD-LTP sequences revealed that bidirectional plasticity occurs at the same SONs and provides efficient homeostatic mechanisms leading to a resetting of corticostriatal synapses avoiding synaptic saturation. The effect of temporal relationship between cortical stimulation and SON activity was assessed using spike-timing-dependent plasticity (STDP) protocols. An LTP was observed when an action potential was triggered in the striatal neuron before the cortical stimulus, and, conversely, an LTD was induced when the striatal neuron discharge was triggered after the cortical stimulation. Such STDP was reversed when compared with those described so far in other mammalian brain structures. This mechanism may be essential for the role of the striatum in learning of motor sequences in which sensory and motor events are associated in a precise time sequence.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) remarkably alleviates motor disorders in parkinsonian patients. The mechanisms by which STN HFS exerts its beneficial effects were investigated in anesthetized rats, using a model of acute interruption of dopaminergic transmission. Combined systemic injections of SCH-23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine] and raclopride, antagonists of the D1 and D2 classes of dopaminergic receptors, respectively, were performed, and the parameters of STN HFS that reversed the neuroleptic-induced catalepsy were determined in freely moving animals. The effects of neuroleptics and the impact of STN HFS applied at parameters alleviating neuroleptic-induced catalepsy were analyzed in the substantia nigra pars reticulata (SNR), a major basal ganglia output structure, by recording the neuronal firing pattern and the responses evoked by cortical stimulation. Neuroleptic injection altered the tonic and regular mode of discharge of SNR neurons, most of them becoming irregular with bursts of spikes and pauses. The inhibitory component of the cortically evoked response, which is attributable to the activation of the direct striatonigral circuit, was decreased, whereas the late excitatory response resulting from the indirect striato-pallido-subthalamo-nigral circuit was reinforced. During STN HFS, the spontaneous firing of SNR cells was either increased or decreased with a global enhancement of the firing rate in the overall population of SNR cells recorded. However, in all of the cases, SNR firing pattern was regularized, and the bias between the trans-striatal and trans-subthalamic circuits was reversed. By these effects, STN HFS restores the functional properties of the circuits by which basal ganglia contribute to motor activity.

Striatal cholinergic interneurons play a crucial role in the control of movement as well as in motivational and learning aspects of behaviour. Neuropeptides regulate striatal cholinergic transmission and particularly activation of mu opioid receptor (MOR) inhibits acetylcholine (ACh) release in the dorsal striatum. In the present study we investigated whether this cholinergic transmission could be modulated by an enkephalin/MOR direct process. We show that mRNA and protein of MORs are expressed by cholinergic interneurons in the limbic/prefrontal territory but not by those in the sensorimotor territory of the dorsal striatum. These MORs are functional because potassium-evoked release of ACh from striatal synaptosomes was dose-dependently reduced by a selective MOR agonist, this effect being suppressed by a MOR antagonist. The MOR regulation of cholinergic interneurons presented a diurnal variation. (i) The percentage of cholinergic interneurons containing MORs that was 32% at the beginning of the light period (morning) increased to 80% in the afternoon. (ii) The MOR-mediated inhibition of synaptosomal ACh release was higher in the afternoon than in the morning. (iii) While preproenkephalin mRNA levels remained stable, enkephalin tissue content was the lowest (-32%) in the afternoon when the spontaneous (+35%) and the N-methyl-d-aspartate-evoked (+140%) releases of enkephalin (from microsuperfused slices) were the highest. Therefore, by acting on MORs present on cholinergic interneurons, endogenously released enkephalin reduces ACh release. This direct enkephalin/MOR regulation of cholinergic transmission that operates only in the limbic/prefrontal territory of the dorsal striatum might contribute to information processing in fronto-cortico-basal ganglia circuits.

Albumin, a blood protein absent from the adult brain in physiological situations, can be brought into contact with brain cells during development or, in adult, following breakdown of the blood-brain barrier occurring as a result of local inflammation. In the present study, we show that ovalbumin and albumin induce the release of monocyte chemotactic protein 1 (MCP-1/CCL2) from rat embryonic mixed brain cells. A short-term exposure to ovalbumin during the cell dissociation procedure is sufficient to generate MCP-1 mRNA. A comparable effect is observed when the cells are incubated for 4 hr with ovalbumin or rat albumin, while MCP-1 messengers are barely detectable following bovine albumin exposure. The amount of MCP-1 protein measured in 4 hr-supernatants of albumin-treated cells followed the same albumin-inducing pattern as that of MCP-1 mRNA, while all albumins tested induced MCP-1 protein after a 17 hr-incubation period. The albumin-induced MCP-1 production is significantly inhibited in calphostin C-treated cells, suggesting the implication of a protein kinase C-dependent signaling pathway. This MCP-1-inducing activity is maintained after a lipid extraction procedure but abolished by proteinase K or trypsin treatments of albumin. The MCP-1 secretion following albumin contact with nervous cells could thus interfere, by chemotactic gradient formation, with the brain infiltration program of blood-derived cells during development or brain injury., ((c) 2005 Wiley-Liss, Inc.)

CRMP1, CRMP2, and CRMP5 have been identified as cytosolic proteins relaying semaphorin 3A signalling, one of the molecular cues conducting axon and dendrite growth and guidance. They are highly expressed during brain ontogenesis, but, because of their lower levels in the adult, their distribution in the mature brain is poorly documented. By using specific antibodies, we investigated the cellular distribution of these CRMPs in different adult brain structures and in neural cell cultures with a special focus on the splice variants CRMP2A and CRMP2B. In brain sections of adult mouse, CRMP1, CRMP2B, and CRMP5 were located predominantly in dendrites of specific neuronal populations, such as cortical pyramidal neurons, hippocampal CA1 pyramidal cells, or Purkinje cerebellar cells. On the contrary, CRMP2A was specifically associated with axons of the corpus callosum, bundles of the striatum, and mossy fibers of the hippocampus. In cultures of cortical neurons, CRMP1, CRMP2A, CRMP2B, and CRMP5 were equally distributed throughout cell bodies, axons, or dendrites of neurons, whereas CRMP2A and CRMP5 were completely absent from Purkinje cerebellar cells in 12-day-old animals. By comparison, oligodendrocytes exclusively express CRMP2B and CRMP5 in cell bodies and processes both in situ in the adult brain and in primary cultures. Overall, our results demonstrate specific subcellular localizations of CRMP1, CRMP2A, CRMP2B, and CRMP5 depending on cell types, neuronal compartment, and developmental stage. This study suggests that, beyond their signalling function in axon outgrowth and guidance, CRMPs also play a role in mature neurons both in axons and in dendrites., ((c) 2005 Wiley-Liss, Inc.)

Spatiotemporal properties of dopamine release play a major role both in striatal and nigral physiology because dopamine is released from nerve terminals and dendrites of nigrostriatal dopaminergic (DA) neurons. Pioneering work revealed gap junctional communication (assessed by dye-coupling experiments) between DA cells in the substantia nigra pars compacta (SNc). However, direct evidence of functional electrical synapses between DA neurons is still lacking. In this study, gap junctional communication between DA neurons was investigated in rat brain slices. Tracer coupling was observed in postnatal day 5 (P5) to P10 and P15-P25 rats. Dual whole-cell patch-clamp recordings revealed that 96% of DA neurons were coupled by electrical synapses in P7-P10 rats, and 20% were coupled in P17-P21 rats. These electrical synapses were mainly symmetrical and displayed strong low-pass filtering properties. When spontaneous firing activity was monitored, no significant synchronization was observed. Nevertheless, an efficient modulation of the spontaneous firing frequency of the postsynaptic cell occurred during injection of hyperpolarizing and depolarizing currents in the coupled presynaptic cell. Together, these observations demonstrate the existence of a fast communication between SNc DA neurons through electrical synapses.

The aim of the study was to assess the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in neointima of polyester vascular grafts. Anastomotic areas were examined at 1, 4 and 12 months after prosthesis implantation in dogs, as well as in human vascular grafts. Immunohistochemistry was performed for uPA and uPAR. Graft neointima in dogs was positively stained for uPA with increased intensity at 4 and 12 months, whereas uPAR expression appeared at 4 and its intensity was increased at 12 months. Intensive uPA and positive uPAR labeling was shown in human grafts. The results demonstrated that in the early period of the healing process of polyester vascular grafts only uPA is present in the neointima in the region of the graft to adjacent artery anastomosis, whereas in healed grafts in dogs and humans uPAR is found as well., (Copyright (c) 2005 S. Karger AG, Basel.)

The aim of the study was to evaluate dynamic changes in the expression of fibrinolytic system components in neointima forming in polyester vascular grafts. The study was carried out on 18 mongrel dogs divided into three groups, that underwent replacement of abdominal aorta with a polyester double velour prosthesis. Grafts were removed at 1, 4 and 12 months. The specimens were fixed according to AMeX method. Immunohistochemical labeling for von Willebrand factor (vWf), tissue plasminogen activator (t-PA), urokinase (u-PA), its receptor (u-PAR), plasminogen activator inhibitor type 1 (PAI-1) and D-dimer (DD) was performed. Increasing intensity of vWf expression on the graft luminal surface was found in successive periods of the study. A light positive t-PA and u-PA staining was shown in neointima at 1 month and its intensity was significantly increased at 4 and 12 months. Expression of u-PAR appeared at 4 months. A light positive PAI-1 and DD staining was demonstrated in neointima in all periods of the study. The results demonstrated increasing expression of fibrinolysis activators in neointima of polyester vascular grafts. Intensive expression of plasminogen activators, when compared to their inhibitor may reduce thrombotic properties of graft neointima particularly in the late period after prosthesis implantation.

Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.

D-amphetamine is known to induce an increase in dopamine release in subcortical structures, thus inducing locomotor hyperactivity in rodents. Previous data have indicated that only 15% of the D-amphetamine-induced release of dopamine in the nucleus accumbens is related to locomotor activity and that this 'functional' dopamine release is controlled by alpha1b-adrenergic receptors located in the prefrontal cortex. We show here that SR46349B (0.5 mg/kg, 30 min before D-amphetamine), a specific serotonin2A (5-HT(2A)) antagonist, can completely block 0.75 mg/kg D-amphetamine-induced locomotor activity without decreasing D-amphetamine-induced extracellular dopamine levels in the nucleus accumbens. Using the same experimental paradigm as before, i.e. a systemic injection of D-amphetamine accompanied by a continuous local perfusion of 3 microM D-amphetamine, we find that SR46349B (0.5 mg/kg) blocks completely the systemic (0.75 mg/kg) D-amphetamine-induced functional dopamine release in the nucleus accumbens. Finally, the bilateral injection of SR46349B (500 pmol/side) into the ventral tegmental area blocked both the D-amphetamine-induced locomotor activity and functional dopamine release in the nucleus accumbens, whereas bilateral injection of SR46349B into the medial prefrontal cortex was ineffective. We propose that 5-HT(2A) and alpha1b-adrenergic receptors control a common neural pathway responsible for the release of dopamine in the nucleus accumbens by psychostimulants.

Basal ganglia are interconnected subcortical nuclei, connected to the thalamus and all cortical areas involved in sensory motor control, limbic functions and cognition. The striatal output neurones (SONs), the major striatal population, are believed to act as detectors and integrators of distributed patterns of cerebral cortex inputs. Despite the key role of SONs in cortico-striatal information processing, little is known about their local interactions. Here, we report the existence and characterization of electrical and GABAergic transmission between SONs in rat brain slices. Tracer coupling (biocytin) incidence was high during the first two postnatal weeks and then decreased (postnatal days (P) 5-25, 60%; P25-30, 29%; n= 61). Electrical coupling was observed between 27% of SON pairs (coupling coefficient: 3.1 +/- 0.3%, n= 89 at P15) and as shown by single-cell RT-PCR, several connexin (Cx) mRNAs were found to be expressed (Cx31.1, Cx32, Cx36 and Cx47). GABAergic synaptic transmission (abolished by bicuculline, a GABA(A) receptor antagonist) observed in 19% of SON pairs (n= 62) was reliable (mean failure rate of 6 +/- 3%), precise (variation coefficient of latency, 0.06), strong (IPSC amplitudes of 38 +/- 12 pA) and unidirectional. Interestingly, electrical and chemical transmission were mutually exclusive. These results suggest that preferential networks of electrically and chemically connected SONs, might be involved in the channelling of cortico-basal ganglia information processing.

The hippocampus and prefrontal cortex (PFC), two structures implicated in learning and memory processes, are linked by a direct hippocampo-prefrontal pathway. It has been shown that PFC pyramidal cells receive monosynaptic excitatory inputs from the hippocampus and, in this study, we sought to determine the influence of the hippocampus on PFC interneurons in anesthetized rats. Extracellular recordings were coupled to juxtacellular injections of neurobiotin or biotinylated dextran amine to morphologically differentiate interneurons from pyramidal cells. In all cases, the action potentials of labeled interneurons were of shorter duration (< 0.70 ms) than those of identified pyramidal cells (> 0.70 ms). Single pulse stimulation of the hippocampal CA1/subiculum region induced an excitatory response in 70% of recorded interneurons in the prelimbic and medial-orbital areas of the PFC. In contrast to the one to two action potentials generated by pyramidal cells, an important group of interneurons fired a burst of action potentials in response to hippocampal stimulation. A large proportion of these excitatory responses was probably monosynaptic as their latency is consistent with the conduction time of the hippocampo-prefrontal pathway. In addition, when both a pyramidal cell and an interneuron were simultaneously recorded and both responded to stimulation, the interneuron consistently fired before the pyramidal cell. In conclusion, the hippocampus exerts a direct excitatory influence on PFC interneurons and is thus capable of feedforward inhibition of pyramidal cells. Hippocampal output is spatially and temporally focalized via this inhibitory process and consequently could facilitate the synchronization of a specific subset of PFC neurons with hippocampal activity.

Several aspects of our 25 year adventure in the field of tachykinins will be successively described. They concern: substance P (SP) synthesis and release in the basal ganglia, the identification and pharmacological characterization of central tachykinin NK(1), NK(2) and NK(3) binding sites and their topographical distribution, the description of some new biological tests for corresponding receptors, the identification of tachykinin NK(1) receptor subtypes or conformers sensitive to all endogenous tachykinins (substance P, neurokinin A (NKA), neurokinin B (NKB), neuropeptide gamma (NP gamma) and neuropeptide K (NPK)) and finally, the functional involvement of these receptors and their subtypes in tachykinin-induced regulations of dopamine and acetylcholine release in the striatum.

Gap junctional communication (GJC) is a typical feature of astrocytes proposed to contribute to the role played by these glial cells in brain physiology and pathology. In acutely isolated hippocampal slices from rat (P11-P19), intercellular diffusion of biocytin through gap junction channels was shown to occur between hundreds of cells immuno-positive for astrocytic markers studied in the CA1/CA2 region. Single-cell RT-PCR demonstrated astrocytic mRNA expression of several connexin (Cx) subtypes, the molecular constituent of gap junction channels, whereas immunoblotting confirmed that Cx43 and Cx30 are the main gap junction proteins in hippocampal astrocytes. In the brain, astrocytes represent a major target for endothelins (Ets), a vasoactive family of peptides. Our results demonstrate that Ets decrease the expression of phosphorylated Cx43 forms and are potent inhibitors of GJC. The Et-induced effects were investigated using specific Et receptor agonists and antagonists, including Bosentan (Tracleer trade mark ), an EtA/B receptor antagonist, and using hippocampal slices and cultures from EtB-receptor-deficient rats. Interestingly, the pharmacological profile of Ets effects did not follow the classical profile established in cardiovascular systems. The present study therefore identifies Ets as potent endogenous inhibitory regulators of astrocyte networks. As such, the action of these peptides on astrocyte GJC might be involved in the contribution of astrocytes to neuroprotective processes and have a therapeutic potential in neuropathological situations.

Cultured astrocytes are highly coupled by gap junction channels mainly constituted by connexin 43. We have previously shown that gap junctional communication (GJC) represents a functional property of astrocytes that is a target for their interaction with other brain cell types, including neurons and brain macrophages. In pathological situations, neurons as well as brain macrophages produce superoxide ions leading to the formation of hydrogen peroxide (H2O2) that can be cytotoxic. We report here that 10-min exposure to 100 microM H2O2 increases GJC in astrocytes. Moreover, 30-min exposure to 100 microM H2O2 induces, 24 h later, an astrocyte cell death by both apoptosis and necrosis. This H2O2-induced astrocyte cell death is not affected when gap junctions are inhibited by several uncoupling agents, including 18alpha-glycyrrhetinic acid, halothane, heptanol, and endothelin-1, indicating that the proportion of cell death is not related to the level of GJC. The effect of H2O2 on gap junction channels does not result from the production of free radicals but is rather linked to modification of the redox equilibrium in astrocytes. Indeed, an oxidative agent reproduces the H2O2-evoked response while reducing agents prevent the effect of H2O2. Finally, when astrocytes are cocultured with brain macrophages, the effects of H2O2 on both GJC and toxicity are not observed, revealing a new protective role of brain macrophages during oxidative stress., (Copyright 2003 Wiley-Liss, Inc.)

Using an in vitro microsuperfusion procedure, the release of newly synthesized [(3)H]-acetylcholine (ACh), evoked by N-methyl-D-aspartate (NMDA) receptor stimulation, was investigated in striosome-enriched areas and matrix of the rat striatum. The role of micro-opioid receptors, activated by endogenously released enkephalin, on the NMDA-evoked release of ACh was studied using the selective micro-opioid receptor antagonist, beta-funaltrexamine. Experiments were performed 2 (morning) or 8 (afternoon) h after light onset, in either the presence or absence (alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis) of dopaminergic transmission. As expected, based on the presence of micro-opioid receptors in striosomes, beta-funaltrexamine (0.1 nM, 10 nM and 1 microM) enhanced the NMDA (1 mM+10 microM D-serine)-evoked release of ACh in striosome-enriched areas but not in the matrix. Interestingly, these responses were significantly more pronounced in afternoon than in morning experiments. In the presence of alpha-methyl-p-tyrosine, the NMDA-evoked release of ACh was increased with similar amplitude in morning and afternoon experiments. However, in this condition (without dopamine transmission), the facilitatory effects of beta-funaltrexamine on the NMDA-evoked release of ACh were suppressed totally in the morning and only partially in the afternoon. The selective micro-opiate agonist, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (1 microM, coapplied with NMDA), was without effect on the NMDA-evoked release of ACh but abolished both dopamine-dependent (morning) and dopamine-independent (afternoon) responses of beta-funaltrexamine (10 nM and 1 microM).Therefore, in the limbic territory of the striatum enriched in striosomes, the micro-opioid-inhibitory regulation of ACh release follows diurnal rhythms. While dopamine is required for this regulation in the morning and the afternoon, an additional dopamine-independent process is present only in the afternoon.

Nucleotides are signaling molecules involved in variety of interactions between neurons, between glial cells as well as between neurons and glial cells. In addition, ATP and other nucleotides are massively released following brain insults, including inflammation, and may thereby be involved in mechanisms of cerebral injury. Recent concepts have shown that in astrocytes intercellular communication through gap junctions may play an important role in neuroprotection. Therefore, we have studied the effects of nucleotides on gap junction communication in astrocytes. Based on measurement of intercellular dye coupling and recording of junctional currents, the present study shows that ATP (10-100 microM) induces a rapid and a concentration-dependent inhibition of gap junction communication in cultured cortical astrocytes from newborn mice. Effects of agonists and antagonists of purinergic receptors indicate that the inhibition of gap junctional communication by ATP mainly involves the stimulation of metabotropic purinergic 1 (P2Y(1)) receptors. Pretreatment with the pro-inflammatory cytokine interleukin-1beta (10 ng/ml, 24 h), which has no effect by itself on gap junctional communication, increases the inhibitory effect of ATP and astrocytes become sensitive to uridine 5'-triphosphate (UTP). As indicated by the enhanced expression of P2Y(2) receptor mRNA, P2Y(2) receptors are responsible for the increased responses evoked by ATP and UTP in interleukin-1beta-treated cells. In addition, the effect of endothelin-1, a well-known inhibitor of gap junctional communication in astrocytes was also exacerbated following interleukin-1beta treatment. We conclude that ATP decreases intercellular communication through gap junctions in astrocytes and that the increased sensitivity of gap junction channels to nucleotides and endothelin-1 is a characteristic feature of astrocytes exposed to pro-inflammatory treatments.

Recent experiments have shown that mice lacking the alpha1b-adrenergic receptor (alpha1b-AR KO) are less responsive to the locomotor hyperactivity induced by psychostimulants, such as D-amphetamine or cocaine, than their wild-type littermates (WT). These findings suggested that psychostimulants induce locomotor hyperactivity not only because they increase dopamine (DA) transmission, but also because they release norepinephrine (NE). To test whether NE release could increase DA-mediated locomotor hyperactivity, rats were treated with GBR 12783 (10 mg/kg), a specific inhibitor of the DA transporter, and NE release was enhanced with dexefaroxan (0.63-10 mg/kg), a potent and specific antagonist at alpha2-adrenergic receptors. Dexefaroxan increased the GBR 12783-mediated locomotor response by almost 8-fold. The role of alpha1b-ARs in this effect was then verified in alpha1b-AR KO mice: whereas dexefaroxan (1 mg/kg) doubled locomotor hyperactivity induced by GBR 12783 (14 mg/kg) in WT mice, it decreased it by 43% in alpha1b-AR KO mice. Finally, to test whether this latter inhibition was related to the occupation of alpha2-adrenergic autoreceptors or of alpha2-ARs not located on noradrenergic neurons, effects of dexefaroxan on locomotor hyperactivity induced by D-amphetamine (0.75 mg/kg) were monitored in rats depleted in ascending noradrenergic neurons. In these animals dexefaroxan inhibited by 25-70% D-amphetamine-induced locomotor hyperactivity. These data indicate not only that the stimulation of alpha1b-ARs increases DA-mediated locomotor response, but also suggest a significant implication of postsynaptic alpha2-ARs. Involvement of these adrenergic receptor mechanisms may be exploited in the therapy of Parkinson's disease., (Copyright 2003 Wiley-Liss, Inc.)

The subthalamic nucleus (STN), a major component of the basal ganglia, exerts an excitatory influence on the output structures of this system i.e., the substantia nigra pars reticulata (SNR) and the internal segment of the globus pallidus. High-frequency stimulation of the STN is a method currently used to treat parkinsonian symptoms. The aim of the present study was to analyze the effects of STN high-frequency stimulation on the activity of SNR neurons and to investigate its impact on the transfer of information between the cerebral cortex and the SNR. During STN high-frequency stimulation, the activity of SNR cells was decreased at low-intensity stimulation, whereas it was increased at a higher intensity. The decrease in the discharge of SNR cells likely results from the activation of a GABAergic transmission in the SNR because this effect was blocked by local application of bicuculline. The increased activity likely results from the activation of the glutamatergic subthalamonigral projection because the latency of the evoked excitations was consistent with the conduction time of the subthalamonigral neurons. Finally, during STN high-frequency stimulation, the transmission of cortical information along the direct trans-striatal pathway was preserved, whereas the functionality of the trans-subthalamic pathways was partly preserved or completely blocked depending on the stimulation intensity. The present data indicate that STN high-frequency stimulation influences the activity of SNR cells through activation of their excitatory and inhibitory synaptic afferent pathways as well as antidromic activation of the projection neurons.

Using an in vitro microsuperfusion procedure, the NMDA-evoked release of [3H]ACh was studied after suppression of dopamine (DA) transmission (alpha-methyl-p-tyrosine) in striatal compartments of the rat. The effects of tachykinin neurokinin 1 (NK1) receptor antagonists and the ability of appropriate agonists to counteract the antagonist responses were investigated to determine whether tachykinin NK1 classic, septide-sensitive and/or new NK1-sensitive receptors mediate these regulations. The NK1 antagonists, SR140333, SSR240600, GR205171 but not GR82334 and RP67580 (0.1 and 1 microM) markedly reduced the NMDA (1 mm + D-serine 10 microM)-evoked release of [3H]ACh only in the matrix. These responses unchanged by coapplication with NMDA of NK2 or NK3 agonists, [Lys5,MeLeu9,Nle10]NKA(4-10) or senktide, respectively, were completely counteracted by the selective NK1 agonist, [Pro9]substance P but also by neurokinin A and neuropeptide K (1 nM each). According to the rank order of potency of agonists for counteracting the antagonist responses ([Pro9]substance P, 0.013 nM > neurokinin A, 0.15 nM >> substance P(6-11) 7.7 nM = septide 8.7 nM), the new NK1-sensitive receptors mediate the facilitation by endogenous tachykinins of the NMDA-evoked release of ACh in the matrix, after suppression of DA transmission. Solely the NK1 antagonists having a high affinity for these receptors could be used as indirect anti-cholinergic agents.

Drugs of abuse, such as D-amphetamine or nicotine, are generally considered as acting through an increased release of dopamine in a subcortical structure, the nucleus accumbens, thus inducing locomotor hyperactivity in rats. Following repeated treatments, the same drugs induce a progressive increase in locomotor response called behavioral sensitization. This process has been suggested to play a role in the acquisition and maintenance of addictive behaviors. Here we show that whereas behavioral sensitization to D-amphetamine (0.5 and 0.75 mg/kg) stays constant following three consecutive periods of withdrawal (15, 30 and 30 days), the same experimental conditions completely abolish behavioral sensitization to 0.3 and 0.5 mg/kg nicotine. Indeed, following these periods of withdrawal, locomotor responses to nicotine are identical to those obtained at the first nicotine injection or after repeated saline injections. However, when a monoamine oxidases inhibitor (MAOI), tranylcypromine (3 mg/kg) or pargyline (30 mg/kg), is co-injected with nicotine, behavioral sensitization is maintained despite submission of the animals to the same withdrawal experimental design. Since tobacco smoke is known to contain many compounds including MAOIs, our data suggest that addictive properties of tobacco may not be limited to nicotine. We propose that MAOIs potentiate effects of nicotine on monoamines release.

The surface of synthetic vascular grafts is thrombogenic, which implies a risk for their occlusion. The aim of the study was to evaluate expression of coagulation components in the polyester vascular grafts neointima. The study was carried out on 18 dogs, which underwent replacement of the abdominal aorta with a polyester prosthesis. Grafts were removed after 1, 4 and 12 months. Immunohistochemical labeling for von Willebrand factor, tissue factor, factor XII, tissue factor pathway inhibitor, thrombomodulin, protein C, protein S and prothrombin activation fragment F1 + 2 was performed. Increasing intensity of von Willebrand factor expression was found in successive periods of the study. Factor XII was shown in the whole neointima after 1 month, whereas in the following periods its presence was limited to the luminal surface. Tissue factor expression was demonstrated after 1 month and its intensity increased in later periods. Tissue factor pathway inhibitor and thrombomodulin expression was demonstrated after 4 and 12 months. Protein C and protein S were present in all observation periods, as well as prothrombin activation fragment F1 + 2. Results indicate a high thrombotic potential of the graft neointima early after prosthesis implantation, whereas in the late postoperative follow-up increasing expression of coagulation inhibitors reduces thrombotic properties of the graft neointima.

The hippocampus and prefrontal cortex are two structures implicated in learning and memory and are related through a direct excitatory pathway. The characteristics of the synaptic influence of the hippocampus on pyramidal cells of the prefrontal cortex were determined using intracellular recordings in anesthetized rats. Single-pulse stimulation of the hippocampus induced an early EPSP of fixed latency in most of the recorded pyramidal cells (n = 106/116) thereby demonstrating a monosynaptic connection between hippocampal neurons and pyramidal cells of the prefrontal cortex. Furthermore, the EPSP was followed by a prolonged IPSP and suggests a simultaneous engagement of pyramidal and non-pyramidal neurons that may ultimately constrain the spread of excitation in response to hippocampal input. Paired-pulse stimulation induced short-term modifications in the synaptic responses and this short-term plasticity may contribute to the temporal filtering of information. Finally, tetanic stimulation of the hippocampus produced long-term potentiation of the monosynaptic EPSP with a concomitant potentiation of the IPSP, indicating that the hippocampo-prefrontal network can participate in the formation and consolidation of memories. In conclusion, the characteristics of the synaptic transmission in the hippocampo-prefrontal cortex pathway further supports the existence of a cooperative relationship between two structures known to be involved in higher cognitive processes.

We present the case of a 50 years old male revealed by a recurrent pericardial effusion. The diagnosis of malignancy was confirmed by direct biopsy. The treatment consisted in surgical excision and chemotherapy. The patient was asymptomatic 17 months after surgery.

The substantia nigra pars reticulata (SNR), a major output station of basal ganglia, receives information from the cerebral cortex through three main pathways, i.e. a direct inhibitory trans-striatal pathway, an indirect excitatory trans-striatal pathway that involves the pallidum and the subthalamus and a direct excitatory trans-subthalamic pathway. In order to determine how cortical information flow originating from functionally distinct cortical areas and processed through the trans-striatal and trans-subthalamic pathways is integrated within the SNR, the responses induced by electrical stimulation of prefrontal, motor and auditory cortex in SNR cells were analyzed in anesthetized rats. Further confirming that direct striato-nigral pathways related to these functionally distinct cortical areas are organized in parallel channels, stimulation of the prefrontal, motor and auditory cortex induced an inhibitory response on distinct subpopulations of SNR cells. Within a given channel, the direct trans-striatal and the trans-subthalamic pathways converge on a large number of nigral cells. In addition, the present study reveals that nigral cells receiving an inhibitory input from a given cortical area through the direct trans-striatal pathway can also receive an excitatory input from a functionally distinct cortical area through the trans-subthalamic pathways. Such a convergence mainly occurred between the direct striato-nigral pathway issued from the auditory cortex and the trans-subthalamic pathways issued from the motor cortex. These data reveal the existence of a converging influence of trans-subthalamic and direct striato-nigral pathways not only within but also across channels. Within a given cortico-basal ganglia channel, the trans-subthalamic pathways likely contribute to the temporal shaping of the striato-nigral inhibition and thus of the disinhibition of the related nigral target nuclei in the thalamus and mesencephalon. Across channels, the specific interactions between trans-subthalamic and direct striato-nigral pathways could contribute to prevent inhibition of subpopulations of nigral cells implicated in competing functions.

The autoradiographic distribution of tachykinin NK(2) binding sites was determined in the adult rat brain using [(125)I]neurokinin A in the presence of either senktide (NK(3) agonist) and [Pro(9)]substance P (NK(1) agonist) or senktide and SR 140333 (NK(1) antagonist). Indeed, this radioligand labels two subtypes of NK(1) binding sites (which present a high affinity not only for SP but also for neurokinin A, neuropeptide K and neuropeptide gamma) as well as NK(3) binding sites. The distribution of NK(2) binding sites was also compared with those of NK(1) and NK(3) binding sites, these sites being labeled with [(125)I]Bolton and Hunter substance P and [(125)I]Bolton and Hunter eledoisin, respectively. In agreement with our results obtained with membranes from various brain structures, NK(2)-sensitive [(125)I]neurokinin A labeling was mainly observed in few structures including the dorsal and ventral hippocampus, the septum, the thalamus and the prefrontal cortex. The density of NK(2) binding sites was weak when compared with those of NK(1) and NK(3) binding sites. Marked differences were observed in the distributions of NK(1), NK(2) and NK(3) binding sites. These results are discussed taking into consideration differences or similarities between the distributions of NK(2)-sensitive [(125)I]neurokinin A binding sites and of their endogenous ligands (neurokinin A, neuropeptide K and neuropeptide gamma) but also local NK(2) agonist responses blocked by NK(2) antagonists. Insights on the roles of endogenous tachykinins in several brain functions are also discussed on the basis of the respective distributions of different neurokinin binding sites.

The main neuronal population of the striatum is composed of the medium spiny neurones (MSNs). In fact several sub-populations of MSNs can be distinguished according to the striatal compartment (striosomes and matrix) to which they belong, their afferents and their sites of projection, their biochemical markers and their morphologies. However, these cells are generally described as an electrophysiological homogeneous population. Using brain slices from the rat and whole cell patch clamp recordings, we show that at P(15) 28% of the MSNs display a spike frequency adaptation. While the mean frequency adaptation ratio for non-adapting cells was 1.07+/-0.01 it reached 2.66+/-0.09 in adapting MSNs and the incidence of this frequency adaptation phenotype appeared to be stable during post-natal development. Single-cell RT-PCR analysis of mRNAs for mu opioid receptors, enkephalin and substance P precursors suggested that adapting MSNs are present in both striatal compartments as well as in the direct and indirect pathways of the matrix. Adapting neurones were also distinguished from non-adapting cells by a lower membrane time constant, a higher AP threshold, a reduced delay to the first spike and a higher initial firing rate. Micro-domains differing by their magnitude of adaptation could be distinguished within the spike frequency adaptation process.A subgroup of MSNs exists, showing a marked spike frequency adaptation together with other distinct properties, such as shorter delay to first spike and membrane time constant, and higher initial frequency and action potential threshold. In conclusion, when strong cortical inputs are delivered in coincidence, adapting MSNs could not only transmit faster the first AP but also exert a sort of cutoff of the transmission due to their spike frequency adaptation process.

It was found recently that locomotor and rewarding effects of psychostimulants and opiates were dramatically decreased or suppressed in mice lacking alpha1b-adrenergic receptors [alpha1b-adrenergic receptor knock-outs (alpha1bAR-KOs)] (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3 and 6 mg/kg d-amphetamine in alpha1bAR-KO mice [-84 and -74%, respectively, when compared with wild-type (WT) mice] are correlated with an absence of d-amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus accumbens of alpha1bAR-KO mice. Moreover, basal extracellular DA levels in the nucleus accumbens are lower in alpha1bAR-KO than in WT littermates (-28%; p < 0.001). In rats however, prazosin, an alpha1-adrenergic antagonist, decreases d-amphetamine-induced locomotor hyperactivity without affecting extracellular DA levels in the nucleus accumbens, a finding related to the presence of an important nonfunctional release of DA (Darracq et al., 1998). We show here that local d-amphetamine releases nonfunctional DA with the same affinity but a more than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats. Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA into nonfunctional DA release. Our data confirm the presence of a powerful coupling between noradrenergic and dopaminergic neurons through the stimulation of alpha1b-adrenergic receptors and indicate that nonfunctional DA release is critical in the interpretation of changes in extracellular DA levels. These results suggest that alpha1b-adrenergic receptors may be important therapeutic pharmacological targets not only in addiction but also in psychosis because most neuroleptics possess anti-alpha1-adrenergic properties.

Zinc released from a subpopulation of glutamatergic synapses, mainly localized in the cerebral cortex and the hippocampus, facilitates or reduces glutamatergic transmission by acting on neuronal AMPA and NMDA receptors, respectively. However, neurons are not the only targets of zinc. In the present study, we provide evidence that zinc inhibits protein synthesis in cultured astrocytes from the cerebral cortex of embryonic mice. This inhibition, which reached 85% in the presence of 100 micro m zinc, was partially and slowly reversible and resulted from the successive inhibition of the elongation and the initiation steps of the protein translation process. This was assessed by measuring the phosphorylation level of the elongation factor eEF-2 and of the alpha subunit of the initiation factor eIF-2. Due to the rapid turnover of connexin-43 that forms junction channels in cultured astrocytes, the zinc-induced decrease of protein synthesis led to a partial disappearance of connexin-43, which was associated with an inhibition of the cellular coupling in the astrocytic syncitium. In conclusion, zinc not only inhibits protein synthesis in neurons, as previously demonstrated, but also in astrocytes. The resulting decrease in the intercellular communication between astrocytes should alter the function of surrounding neurons as well as their survival.

In the present study, GABA was shown to induce a necrotic neuronal death in cultured striatal neurones from mouse embryos. This effect did not depend on the activation of GABA(A), GABA(B) or GABA(C) receptors as it was neither antagonized by bicuculline, saclofen or picrotoxin, respectively, nor reproduced by the GABA receptor agonists, muscimol and baclofen. Excluding the participation of glutamate, GABA neurotoxicity persisted in the presence of either the antagonists of ionotropic and metabotropic glutamate receptors or glutamate pyruvate transaminase, which induces an immediate catabolism of glutamate. A GABA transport-associated process is involved in GABA neurotoxicity as nipecotic acid and NO 711, two inhibitors of the high-affinity neuronal GABA transporters (GAT-1, in particular), completely prevented the neurotoxic effect of GABA. The activation of a subset of G proteins is also implicated in the GABA transport-mediated neuronal death as GABA neurotoxicity was completely suppressed when striatal neurones were pre-treated with pertussis toxin. Further demonstrating the specificity of this neurotoxic process, GABA-induced neurotoxicity was not observed in cortical neurones which, in contrast to striatal neurones, are largely represented by glutamatergic neurones. In conclusion, our study suggests that glutamate is not the sole neurotransmitter that can be responsible for brain damage and that GABA neurotoxicity involves both GABA transport and G protein transduction pathways.

Objectives: to evaluate the content of lipid peroxidation products (expressed by the concentration of thiobarbituric acid-reactive substances; TBARS), the content of myeloperoxidase (MPO), and the localisation of xanthine oxidase (XO) in varicose veins (vv), varicose veins with superficial thrombophlebitis and unchanged saphenous veins., Methods: varicose saphenous veins, varicose veins with superficial thrombophlebitis and normal saphenous veins obtained during varicose vein surgery on 36 patients as well as healthy saphenous veins from cadaver organ donors (control). Homogenates were prepared in which TBARS concentration and MPO content were determined. Immunohistochemical staining to detect XO was also performed., Results: the highest concentration of TBARS occurred in vv with superficial thrombophlebitis, the lowest in donor vein. The highest content of MPO was observed in vv and slightly lower - in varicose veins with thrombophlebitis. A positive reaction for XO was seen in vv wall endothelium. Specimens of vv with thrombophlebitis revealed strong, intense staining in endothelium as well as in vasa vasorum., Conclusions: varicose veins, especially those complicated with superficial thrombophlebitis revealed increased free radical generation. Its sources might be neutrophils, and in vv complicated with superficial thrombophlebitis-xanthine oxidase., (Copyright 2002 Elsevier Science Ltd.)