Influence of corticostriatal δ-opioid receptors on abnormal involuntary movements induced by L-DOPA in hemiparkinsonian rats

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease induces in time numerous side effects, such as abnormal involuntary movements called L-DOPA-induced dyskinesias (LIDs). An involvement of glutamate transmission, dopamine transmission and opioid transmission in striatal output pathways has been hypothesized for the induction of LIDs. Interestingly, our previous experiments indicated that some striatal δ-opioid receptors are located on terminals of glutamatergic corticostriatal neurons and that stimulation of these receptors modulates the release of glutamate and dopamine. The present study was performed to test the involvement of δ-opioid receptors, and more precisely of those located on corticostriatal neurons, in abnormal involuntary movements induced by L-DOPA in hemiparkinsonian rats. The effects of a selective agonist, [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE) and a selective antagonist (naltrindole) of δ-opioid receptors on LIDs were investigated in animals submitted or not to a corticostriatal deafferentation. Our results indicate that DPDPE and naltrindole respectively enhanced and reduced LIDs in animals in which the ipsilateral cortex was preserved intact. However, the lesion of the ipsilateral cortex prevented the stimulant effect of DPDPE on LIDs. The [(3)H]-DPDPE binding to striatal membranes prepared from the whole striatum was also studied. A significant increase in density of δ-opioid receptors was found in the striatum of dyskinetic animals as compared to non-dyskinetic animals but this difference was abolished by the corticostriatal deafferentation. These results indicate that δ-opioid transmission modulates the expression of LIDs in rodents and suggest that the δ-opioid receptors involved in this effect are located on terminals of corticostriatal neurons.     

Water intake induced in rats by serotonin and 5-hydroxytryptophan: Different mechanisms?

The present studies were designed to investigate further the mechanism by which water intake is induced in rats by peripheral administration of either serotonin (5HT) or its precursor 5-hydroxytryptophan (5HTP). Consistent with previous studies that have implicated mediation by the renal renin-angiotensin system (RAS), we now report that bilateral nephrectomy completely abolishes the drinking response to various doses of 5HT. In contrast, nephrectomy had little effect on the drinking induced by 5HTP. Thus, 5HTP may induce drinking by mechanisms other than its peripheral conversion to 5HT and subsequent activation of the RAS. The drinking responses to both 5HT and 5HTP were blocked by peripheral administration of the 5HT receptor antagonist, metergoline, but the drug was at least ten-fold more potent against 5HTP than 5HT. Intracerebroventricular (ICV) administration of metergoline also prevented the drinking response to peripherally-administered 5HTP. The drinking responses to both 5HT and 5HTP were enhanced by peripheral administration of low doses of an angiotensin I converting enzyme inhibitor, captopril. Collectively, these findings support previous conclusions that 5HT-induced intake of water is mediated exclusively by the renal RAS. However, 5HTP-induced drinking may additionally involve a renin-independent, serotonin-mediated mechanism, possibly in the brain.     

What is the role of muscle receptors in proprioception?

The role of muscle afferents is discussed in terms of their contribution to kinesthesia, the senses of position and movement of the limbs. It is argued that muscle spindles are not well suited as position sensors, on several grounds. Yet we know from muscle vibration experiments that they do contribute to kinesthesia. A number of recent experiments have shown that positional information is of particular significance to the central nervous system. In other experiments it has been demonstrated that a disturbance to kinesthesia follows fatigue from exercise. Fatigue of elbow flexor muscles led subjects to make significant positional errors in a forearm matching task. The size of the errors correlated with the fall in force from fatigue. These data suggest that we derive a positional cue from the effort required to hold a limb against the force of gravity. A challenge for the future will be to reveal how the centrally derived sense of effort and peripherally derived afferent information interact to give us our kinesthetic sense.     

Do different reperfusion methods affect the outcomes of stroke induced by MCAO in adult rats?

There are two patterns of ischemia/reperfusion (I/R) models used in rat middle cerebral artery occlusion (MCAO) I/R models, which differ in the use of unilateral or bilateral carotid artery reperfusion. The primary difference between the two patterns of I/R models is the complexity of the surgery procedure. However, researchers in this field have no idea whether there are any differences in outcomes of these two methods. In this study, we investigated the effects of the two methods on neurological deficits, infarct volume, blood–brain barrier (BBB) integrity and brain derived neurotrophic factor (BDNF) expression. Through evaluating the current way of bilateral common carotid artery reperfusion, we tried to find whether it could be replaced by an easier way. We found that there were no statistical significant differences between the different methods in infarct volume, neurological deficits, BBB integrity, and the level of BDNF (P > 0.05). These data demonstrated that different methods did not affect the neurological deficits, infarct volume, BBB integrity, and the BDNF protein level, which provides reference when we use an experimental stroke. These results suggest that the two methods have similar capability for inducing cerebral I/R injury and can be interchanged.     

δ-opioid receptor function in the dorsal striatum plays a role in high levels of ethanol consumption in rats

Binge-like patterns of excessive drinking during young adulthood increase the propensity for alcohol use disorders (AUDs) later in adult life; however, the mechanisms that drive this are not completely understood. Previous studies showed that the δ-opioid peptide receptor (DOP-R) is dynamically regulated by exposure to ethanol and that the DOP-R plays a role in ethanol-mediated behaviors. The aim of this study was to determine the role of the DOP-R in high ethanol consumption from young adulthood through to late adulthood by measuring DOP-R-mediated [(35)S]GTPγS binding in brain membranes and DOP-R-mediated analgesia using a rat model of high ethanol consumption in Long Evans rats. We show that DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia changes during development, being highest during early adulthood and reduced in late adulthood. Intermittent access to ethanol but not continuous ethanol or water from young adulthood leads to an increase in DOP-R activity in the dorsal striatum and DOP-R-mediated analgesia into late adulthood. Multiple microinfusions of naltrindole into the dorsal striatum or multiple systemic administration of naltrindole reduces ethanol consumption, and following termination of treatment, DOP-R activity in the dorsal striatum is attenuated. These findings suggest that DOP-R activity in the dorsal striatum plays a role in high levels of ethanol consumption and suggest that targeting the DOP-R is an alternative strategy for the treatment of AUDs.     

Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-β

The toxicity of amyloid-beta（Aβ） is strongly associated with Alzheimer’s disease（AD）,which has a high incidence in the elderly worldwide.Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors（NMDARs） plays a key role in Aβ-induced neurotoxicity.However,the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity,gene regulation,neuronal death,and Aβ production.This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ.On one hand,Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis,leading to either neurotoxicity or neuroprotection.On the other hand,Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover,subsequently causing neurotoxicity.In addition,selective enhancement of synaptic activity by low doses of NMDA,or reduction of extrasynaptic activity by memantine,a non-competitive NMDAR antagonist,halts Aβ-induced neurotoxicity.Therefore,future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.     

Simvastatin attenuates hypomyelination induced by hypoxia–ischemia in neonatal rats

Abstract

Objectives: Simvastatin, the most widely used cholesterol-lowering drug, has been reported to protect the adult brain from ischemia. Nevertheless, little is known about its action on developing brain after stroke. Although a few reports have found recently that simvastatin displays anti-inflammation and anti-apoptosis properties and improves the cognitive and morphological consequences in the neonatal rats after hypoxia–ischemia (HI) damage, to our best knowledge, there has been no study of the effect of it on myelin formation after neonatal brain damage. Therefore, we investigated whether simvastatin could promote the myelination of oligodendrocytes in the neonatal rats after HI and explored the possible role of microglial responses in this process.

Methods: Postnatal day 7 Sprague–Dawley rats were subjected to HI. White matter integrity and myelination were evaluated by the densitometry of myelin basic protein (MBP) immunostaining. OX-42 immunoreactivity and nissl staining were used for identifying microglial responses and the structure changes of white matter and adjacent gray matter after HI. Simvastatin was administrated prophylactically to rats.

Results: HI induced serious hypomyelination especially in external and internal capsules 3 and 7 days after HI, accompanying with microglial activation remarkably. Simvastatin treatment greatly increased the densities of MBP immunostaining, inhibited microglial activation and reduced the numbers of pyknotic cells and neuronal loss.

Discussion: The present study shows that simvastatin treatment in neonatal rats attenuates HI-induced developing oligodendrocytes injury and hypomyelination. Its anti-inflammatory properties via suppression of microglial activation are likely to contribute to this action. It provides experimental evidence to support the neuroprotective effects of statins in neonatal ischemic stroke.     

Polymorphisms of platelet adhesive receptors: do they play a role in primary intracerebral hemorrhage?

BACKGROUND: Several reports suggested that polymorphisms affecting the structure or level of the main adhesive platelet glycoproteins (GPs) could behave as genetic risk factors for arterial thrombotic disorders. However, very few reports analyzed the significance of these polymorphisms in bleeding disorders. Interestingly, one study suggested a role of the 807 C/T polymorphism of the collagen receptor GP Ia in the severity of the bleeding manifestations in von Willebrand disease. The aim of this study was to evaluate the role of frequent polymorphisms affecting platelet GPs in primary intracerebral hemorrhage (PIH), the third most frequent cause of cerebrovascular disorder. METHODS: We evaluated the role of four putative prothrombotic polymorphisms: GP Ia [807 C/T, and human platelet alloantigen system 5 (HPA-5)], GP Ibalpha (variable number of tandem repeats), and GP IIIa (HPA-1) in 141 Caucasian patients diagnosed of PIH, 141 race-, age-, sex- and risk factor-matched controls, and 446 subjects from the general population. RESULTS: The frequency of genotypes and alleles were similar between patients and controls. CONCLUSIONS: Our results suggest that these polymorphisms play a minor role in PIH.     

Cholesterol and triglyceride levels in the serum of muricidal male Wistar rats: indices of mitochondrial benzodiazepine receptors?

Cholesterol and triglyceride levels were studied in the serum of aggressive muricidal and non-muricidal male Wistar rats. The muricidal behavior was either spontaneous or induced by a long-term isolation or by adrenalectomy. Cholesterol levels were slightly higher in the whole population of muricidal rats; this was mainly observed in spontaneously and in adrenalectomized muricidal rats, as compared to non-muricidal rats of the same series. As regards triglyceride levels, they were significantly higher in the whole population of muricidal rats, mainly in isolation- and adrenalectomy-induced muricidal rats; the ratio of triglycerides to body weight was higher in the serum of muricidal rats of all series. The possible significance of these results is discussed in light of the data of the literature and related to the functional role of either mitochondrial benzodiazepine receptors or serotonin.     

Changes of evoked potential in different hippocampal regions induced by electrostimulation at medial mamillary nucleus of rats

IN T R O D U C T IO N The hippocam pus is im portant constituent of the lim bic system , re- lating w ith various functions such as taking in food, activity of inter- nal organs, sleep and w ake, study and m em ory as w ell as the acupuncture analgesia, e…     

Death receptors on reactive astrocytes: a key role in the fine tuning of brain inflammation?

Immune responses protect the CNS against pathogens. However, the fact that there is little dispensable tissue in the brain makes regulation necessary to avoid disastrous immune-mediated damage. Astrocytes respond vigorously to any brain injury (e.g., tumor, stroke, AD, MS, HIV) and are postulated to play an important role in the fine tuning of brain inflammation. The authors propose that astrocytes use death receptors to modulate pro- and anti-inflammatory effects.     

Anterior thalamic lesions stop immediate early gene activation in selective laminae of the retrosplenial cortex: evidence of covert pathology in rats?

Lesions involving the anterior thalamic nuclei stopped immediate early gene (IEG) activity in specific regions of the rat retrosplenial cortex, even though there were no apparent cytoarchitectonic changes. Discrete anterior thalamic lesions were made either by excitotoxin (Experiment 1) or radiofrequency (Experiment 2) and, following recovery, the rats foraged in a radial-arm maze in a novel room. Measurements made 6-12 weeks postsurgery showed that, in comparison with surgical controls, the thalamic lesions produced the same, selective patterns of Fos changes irrespective of method. Granular (caudal granular cortex and rostral granular cortex), but not dysgranular (dysgranular cortex), retrosplenial cortex showed a striking loss of Fos-positive cells. While a loss of between 79 and 89% of Fos-positive cells was found in the superficial laminae, the deeper layers appeared normal. In Experiments 3 and 4, rats 9-10 months postsurgery were placed in an activity box for 30 min. Anterior thalamic lesions (Experiment 3) led to a pronounced IEG decrease of both Fos and zif268 throughout the retrosplenial cortex that now included the dysgranular area. These IEG losses were found even though the same regions appeared normal using standard histological techniques. Lesions of the postrhinal cortex (Experiment 4) did not bring about a loss of retrosplenial IEG activity even though this region is also reciprocally connected with the retrosplenial cortex. This selective effect of anterior thalamic damage upon retrosplenial activity may both amplify the disruptive effects of anterior thalamic lesions and help to explain the posterior cingulate hypoactivity found in Alzheimer's disease.     

Cytoskeletal dynamics in dendritic spines: direct modulation by glutamate receptors?

A wide heterogeneity in dendritic-spine morphology is observed and ultrastructural changes can be induced following experimental stimulation of neurons. Morphological adaptation of a given spine might, thus, reflect its history or the current state of synaptic activity. These changes could conceivably result from rearrangements of the cytoskeleton that is subjacent to excitatory synapses. This article dicusses the direct and indirect interactions, between glutamate receptors and the cytoskeletal proteins, which include PDZ-containing proteins, actin and tubulin, as well as associated proteins. In fact, the synaptic-activity-controlled balancing of monomeric, dimeric and polymeric forms of actin and tubulin might underlie the changes in spine shape. These continuous adaptations could be relevant for physiological events, such as learning and the formation of memory.     

Comparison of the severity of injury of hippocampal neuron in rats induced by simulated push-pull maneuver at various degrees

IN T R O D U C T IO N Push-pullcannotbe avoided during aviation,and the harm is severe. ±G z is alw ays exposured under the accelerative environm ent, and the m axim alvalue ranges from 11 G z to -8 G z. G z can be foundalternatively, and push-pulleffec…     

Desensitization of α7 nicotinic receptors potentiated the inhibitory effect on M-current induced by stimulation of muscarinic receptors in rat superior cervical ganglion neurons

Summary. Whole-cell patch-clamp recording from rat superior cervical ganglion neurons in culture was used to investigate the modulatory effect of desensitized α7-nAChRs on mAChRs. An inward α-bungarotoxin and methyllycaconitine sensitive current was elicited by rapid application of choline, which consisted of a fast and a slow desensitizing component. The amplitude of choline-evoked currents recorded 0.5, 1, 2, and 3 min after the prolonged application of choline (10 mM, 30 s) decreased to 25.3 ± 9.2%, 45.9 ± 11.8%, 66.3 ± 14.5%, and 73.9 ± 13.3% of their baseline levels, respectively. The amplitudes of M-currents, recorded at the same time intervals after the similar prolonged stimulation with choline, were decreased to 52.7 ± 17.4%, 63.9 ± 4.2%, 70.9 ± 2.8%, and 72.9 ± 17.3% of initial values respectively by focal application of pilocarpine (1 mM, 5 s) onto the soma of neurons. By contrast, before the desensitization of α7-nAChRs, M-currents were only decreased to 79.8 ± 13.7% of baseline levels by pilocarpine (1 mM, 5 s). Whereas the desensitization of α7-nAChRs had no direct effects on M-currents, and the facilitated effects on muscarinic agonists on the M-currents induced by desensitized α7-nAChRs, were removed in the presence of α-bungarotoxin and methyllycaconitine. These results indicated that desensitization of α7-nAChRs could potentiate the inhibitory effect on M-current by stimulation of mAChRs with their agonist.     

Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food?

Heat shock proteins (HSPs) have been shown to act as inhibitors of apoptosis, but this anti-apoptotic effect is not known in the central nervous system. Prior heat shock has been demonstrated to protect astrocytes from cell death in a model of reperfusion injury (Brain Res. 735 (1996) 265). The present study examines the mechanism underlying the protective effect of the heat shock. Preincubation of astrocytes at 40 degrees C for 10 min attenuated the hydrogen peroxide (H(2)O(2))-induced decrease in cell viability, DNA ladder formation and nuclear condensation, and these effects were blocked by the protein synthesis inhibitor cycloheximide. The thermal stress inhibited the H(2)O(2)-induced increase in caspase-3 like protease activity, but it did not affect the H(2)O(2)-induced loss of mitochondrial membrane potential. The cytosol prepared from preheated cells did not affect Ca(2+)-induced swelling of mitochondria, a marker of the permeable transition pore. The protective effect of the thermal stress on the H(2)O(2)-induced decrease in cell viability was not affected by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor 2'-amino-3'-methoxyflavone, the phosphatidylinositol-3 kinase inhibitor wortmannin and the NF-kappaB inhibitor pyrrolidinedithiocarbamate. These findings suggest that HSPs inhibit apoptosis via an inhibition of caspase-3 activation without effect on mitochondrial dysfunction.     

Inhibition of myopia development in chicks using himbacine: a role for M(4) receptors?

The success of the M(1)-selective muscarinic antagonist pirenzepine in preventing myopia development in animal models implicates a role for the M(1) receptor. However, the relatively high dose of pirenzepine required may indicate that the drug acts through another receptor subtype. This study examined whether the M(4)-selective antagonist, himbacine, could also prevent myopia. Daily intravitreal injections of himbacine inhibited the inducement of myopia in chick eyes in a dose- dependent manner. Doses < or = 200 microg caused no significant inhibition of induced myopia compared to controls (-13.7 +/- 2.3 vs -16.2 +/- 0.9D, ANOVA p = 0.37), whilst a dose of 800 microg almost completely inhibited the induced myopia (-2.4 +/- 2.0, p < 0.01). Findings demonstrate himbacine is effective at preventing the development of myopia in chick and implicates a role for the M4 receptor.     

Serotonin‐induced phase advances of SCN neuronal firing in vitro: A possible role for 5‐HT5A receptors?

Spontaneous firing rates of neurons in the suprachiasmatic nuclei (SCN) follow a consistent pattern, peaking near the midpoint of the light phase in a 12:12 light/dark schedule, and repeating this brief period of increased activity in subsequent circadian cycles. These carefully timed fluctuations reflect the output signal of the SCN, long recognized as the site of the endogenous biological clock in mammals. In rat hypothalamic slices, bath incubations of 8-OH-DPAT had previously been shown to elicit phase advances when applied at ZT6 (or 6 h following the onset of light), an action that could readily be attributed to 5-HT7 receptor activation. The present studies set out with the simple goal of establishing that the same receptor mechanism was responsible for the phase-shifting actions of 5-HT itself. Surprisingly, the phase advances elicited by 5-HT (0.5 microM, 1 h) at ZT6 were reduced by one 5-HT7 antagonist, ritanserin (10 microM), but not by another, mesulergine (10 microM). Receptor binding studies demonstrated a 25-fold greater affinity of ritanserin for h5-HT5A sites compared to mesulergine (Ki = 71 nM vs. 1,800 nM), an observation suggestive of a 5-HT5A mechanism for 5-HT and consistent with earlier observations of robust labeling of 5-HT5A sites in the SCN. 5-HT generated by the addition of L-tryptophan (10 microM, 1 h) to the slices displayed the same pattern of sensitivity, that is, blockade by ritanserin but not by mesulergine. Rp-cAMPS, a cAMP antagonist, failed to block the phase shifts elicited by 5-HT at a concentration (1 microM) previously shown to be effective against 8-OH-DPAT-induced phase shifts, in keeping with the proposed negative coupling of 5-HT5A receptors to cAMP production. Taken together, these results suggest that activation of both 5-HT5A and 5-HT7 receptors can produce phase advances of the circadian clock in vitro when they occur during mid-subjective day.