摘要:

AbstractAntibodies to Ca channels in ALS patients IgG can be demonstrated to enhance Ca current and cause cell injury and death in a motoneuron cell line in vitro. To determine whether these antibodies can alter neuronal calcium homeostasis in vivo IgG fractions from six ALS patients were injected intraperitoneally into mice, and neurons assayed by ultrastructural techniques for calcium content. After 24 h, all six ALS IgG (40 mg/animal) increased vesicle number in spinal motoneuron axon terminals, and in boutons synapsing on spinal motoneurons. Using the oxalate‐pyroantimonate technique for calcium precipitation, these antibodies produced dose‐dependent calcium increases either in axon terminal synaptic vesicles and mitochondria, or in rough endoplasmic reticulum, mitochondria, and Golgi complex of spinal motoneuron and frontal cortex pyramidal cells. ALS IgG was itself internalized and also induced neurofilament H phosphorylation. The observed changes in ultrastructure and calcium compartmentation were restricted to motoneurons; normal and disease control IgG, which did not possess antibodies enhancing calcium entry, did not exert similar effects. These data demonstrate that ALS IgG containing Ca‐channel antibodies can alter calcium homeostasis of motoneurons in vivo. © 1995 Wiley‐L

ISSN:0887-4476    

DOI:10.1002/syn.890200302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe variability of D2‐dopamine receptor binding parameters in man was determined using Positron Emission Tomography (PET) and [11C]raclopride. A saturation analysis based on five PET‐experiments was performed in each of ten men and ten women. The mean density of D2‐dopamine receptors (Bmax) was 28 ± 6.9 pmol/ml (mean ± S.D.) and the apparent affinity (Kdapp)9.1 ± 1.9 pmol/ml. The Hill coefficient was in all subjects close to unity (nH: 0.999 ± 0.020), thereby indicating binding to a homogeneous class of receptors. No significant differences between males and females were found in Bmaxor Kdapp. The interindividual difference in Bmaxwas statistically significant (α = 0.01). The difference in Kdappwas not significant. Upregulation of the receptor density (Bmax) has been widely discussed as a mechanism for increased dopaminergic neurotransmission in schizophrenia. This study indicates that receptor density varies considerably in a group of healthy subjects. © 1995 Wile

ISSN:0887-4476    

DOI:10.1002/syn.890200303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractRepeated treatment with the non‐selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D2‐type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D2‐type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty‐four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4‐dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD‐1015, was enhanced in the striatum, but not nucleus accumbensolfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D1antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) × two (vehicle or SCH 23390) design. Quinpirolealone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390‐alone and quinpirole‐SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect. In Experiment 3, rats were treated for 10 days with vehicle, 3.0 mg/kg quinpirole or the D2antagonist eticlopride (1.0 mg/kg) in a two (vehicle or quinpirole) × two (vehicle or eticlopride) design. As in the first two experiments, repeated quinpirolealone treatment resulted in a reduction of the locomotor suppressant effects of the drug; however, locomotor activity in this group was enhanced compared to vehicle controls on day 10. Eticlopridealone and eticlopride‐quinpirole treated rats had suppressed locomotor activity across the 10 days. DOPA accumulation was enhanced by both repeated quinpirole and repeated eticlopride treatment in the striatum and NAOT. DOPA accumulation in eticlopride‐quinpirole treated rats was not different from vehicle control levels in the NAOT, while no significant difference was obtained between the eticlopridealone and eticlopride‐quinpirole groups in the striatum. The locomotor activity data suggest that repeated quinpirole treatment results in tolerance to the locomotor suppressant effect of the drug. Evidence for sensitization was obtained in two out of three of the experiments. These results suggest that enhanced dopamine synthesis after repeated non‐selective dopamine agonist treatment is modulated by D2‐type dopamine recept

ISSN:0887-4476    

DOI:10.1002/syn.890200304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractRecent evidence implicates a crucial role for the ventral tegmental area (VTA) in the initiation of behavioral sensitization produced by repeated psychostimulant exposure, while changes in the nucleus accumbens (NAcc) are not critical during the initiation stage. We investigated whether the development of behavioral sensitization to repeated daily cocaine could be prevented by daily administration of the protein synthesis inhibitor, anisomycin, delivered onto VTA neurons. Rats were given five daily treatments as follows: obturators containing crystalline anisomycin or no compound (sham) were placed directly into the VTA 15 min prior to a saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) injection. After withdrawal for 8–9 days, the locomotor response to the same dose of saline or cocaine was monitored. No differences in the locomotor response to an acute saline challenge were found across the four groups. Animals given sham treatments in the VTA and daily cocaine demonstrated a significant augmentation in the locomotor response to a cocaine challenge compared to saline controls. Anisomycin treatments alone produced no effects on acute cocaine‐induced locomotion. Further, a cocaine challenge in animals receiving daily anisomycin and cocaine elicited a non‐augmented response similar to that of saline controls. Thus, the sensitized locomotor response to a cocaine challenge in daily cocaine pretreated animals was completely blocked by daily anisomycin treatment in the VTA. When daily anisomycin was administered into the NAcc along with daily cocaine, no blockade of behavioral sensitization was observed. These results provide support for a critical role of long‐term changes in gene expression in the vicinity of VTA neurons mediating the development of sensitization to psychostimulants. © 1995 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890200305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractIn vivo microdialysis was used to examine the effects of peripheral uptake inhibition on extracellular serotonin (5‐HT). Previous results from this lab indicated that systemic fluoxetine caused a decrease in 5‐HT when terminal uptake was inhibited by local infusion of the uptake blocker. We hypothesized that the decrease in 5‐HT levels in the terminal region was due to an increase in 5‐HT in the vicinity of the inhibitory somatodendritic autoreceptors in the dorsal raphe nucleus (DRN). To test this prediction, rats were implanted with probes in both the basal diencephalon (a nerve terminal region) and the DRN (the cell body region). Fluoxetine (10 mg/kg i.p.) increased extracellular 5‐HT, in a depolarization‐dependent manner, by approximately 140% in both areas. In a separate experiment, fluoxetine was infused into the diencephalon overnight to block nerve terminal uptake sites. This pretreatment caused an eight‐ to 10‐fold increase in 5‐HT levels. Subsequent systemic fluoxetine, sertraline, or paroxetine, produced a 50% decrease in extracellular 5‐HT in the diencephalon, presumably due to activation of the 5‐HT1Asomatodendritic autoreceptors. Consistent with this hypothesis, systemic administration of the 5‐HT1antagonists spiperone, penbutolol, or WAY100135 reversed the fluoxetine‐induced decrease in 5‐HT to approximately 85% of the pre‐fluoxetine baseline levels. Likewise, pretreatment with penbutolol, but not selective ß‐adrenergic antagonists, blocked the fluoxetine‐induced decrease in release. These findings suggest that the ability of acute systemic 5‐HT uptake inhibition to elevate nerve terminal 5‐HT is limited by autoreceptor activation following elevation of 5

ISSN:0887-4476    

DOI:10.1002/syn.890200306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractNeuroleptics given chronically to rats induce behavioral sequelae which mimic tardive dyskinesia in some respects. The intent of this study was to investigate the ultrastructural correlates of oral dyskinesias (vacuous chewing movements [VCMs]), induced by chronic haloperidol treatment. After 6 months of treatment, rats were divided into low or high VCM groups. Rats in the high VCM group were either sacrificed on drug or were withdrawn from drug for 4 weeks. Ultrastructural analyses of the striatum indicated that synaptic density: (1) was significantly decreased in both the low and high VCM groups compared to normal controls; (2) was more profoundly decreased in the high VCM group as compared to the low VCM group; and (3) recovered to normal following drug withdrawal. Compared to controls, the density of asymmetric synapses was reduced by a similar magnitude in both the low and high VCM groups, suggesting that this change is a result of haloperidol treatment and independent of VCMs. Conversely, the density of symmetric synapses was reduced compared to normal, only in the high VCM group, suggesting that this change is specifically related to the expression of VCMs. In addition, mitochondria1 profiles were hypertrophied and less frequent in the high VCM group in comparison to controls; size, but not number, recovered following drug withdrawal. These results identify distinct ultrastructural correlates of chronic haloperidol treatment that are unique to rats that develop VCMs and suggest that these ultrastructural features may play a role in the pathophysiology of oral dyskinesias in rats. © 1995 Wiley‐Liss, I

ISSN:0887-4476    

DOI:10.1002/syn.890200307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractIt has been well documented that treatment with haloperidol and other typical antipsychotic drugs increase neurotensin (NT) concentrations in the nucleus accumbens and caudate nucleus in adult rats. The NT neuronal system has been found to undergo distinct age‐related changes in the rat brain, and therefore, it is of interest to examine the ontogeny of the effects of antipsychotic drug treatment on NT concentrations. In order to determine when, or if, antipsychotic drug treatment has an effect on NT‐containing neurons in the developing rat, rat pups received a single dose of haloperidol (2.0 mg/kg, s.c.) or vehicle at 9, 14, or 20 days after birth. Regional brain NT concentrations were then measured using a sensitive and specific radioimmunoassay. Treatment with haloperidol had no effect on NT concentrations in any brain region in 10‐day‐old rat pups. At 15 days of age, haloperidol significantly increased NT concentrations in the caudate nucleus (120% of control, P<0.05). At 21 days of age, haloperidol increased NT concentrations in the caudate nucleus (193% of control, P<0.001) and nucleus accumbens (126% of control, P<0.005) similar to that seen in adult animals. There were no statistically significant gender‐related differences found in any age or treatment group studied. These findings indicate that there is a specific time point during postnatal development when rat brain NT systems become responsive to antipsychotic drug administration. © 1995 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890200308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractNerve growth factor (NGF) deficiency has been proposed as a possible pathogenetic mechanism underlying the sympathetic autonomic neuropathy which develops in clinical and experimental diabetes and aging. To determine if long‐term NGF deficiency alone would reproduce the distinctive sympathetic neuropathology of streptozocin‐induced diabetes or aging in rats, nondiabetic animals were deprived of NGF for 12 months using an autoimmune paradigm. Neuroaxonal dystrophy (NAD), the neuropathologic hallmark of experimental sympathetic diabetic neuropathy and aging, was not increased in frequency in prevertebral superior mesenteric or paravertebral superior cervical ganglia in comparison to age‐matched controls. Residual neurons in chronically NGF deprived sympathetic ganglia did not show significant atrophy, chromatolysis, active neuronal degeneration or intraganglionic debris. Postganglionic noradrenergic axons in ileal mesenteric nerves also failed to develop NAD in chronic autoimmune NGF‐deprived rats as they would have in animals diabetic for the same duration. These results suggest that simple, isolated NGF deficiency maintained for long periods of time in nondiabetic animals is not sufficient to produce NAD in the pattern of experimental rat diabetes and aging. © 1995 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890200309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractA detailed, light microscopic study on the distribution of the N‐methyl‐D‐aspartate receptor subunit 1(NMDAR1) was carried out with immunohistochemistry and in situ hybridization on the cerebellar cortex of the mouse. With a monoclonal antibody, labeling of Purkinje cell bodies varied from intense to negative, while heavy dendritic staining was limited to the proximal dendrites (unlike the rat, which also had heavily stained distal dendrites). In the granular layer, the cell bodies and the dendritic shafts of Golgi II cells were only moderately stained, but very intense labeling was associated with granule cell bodies, and with their dendrites and dendritic endings in the glomeruli. The mossy and climbing fibers were negative. In situ hybridization with a cRNA probe showed levels and spatial distributions of NMDAR1 mRNA consistent with the immunolabeling pattern, in that signals were strongest in the granular and Purkinje cell layers and relatively low or absent in the molecular layer and white matter. The findings are consistent with the hypothesis that NMDAR1 may be especially well concentrated at the synaptic target sites of the mossy and climbing fibers. In the mouse, NMDAR1 at the parallel fiber sites associated with Purkinje cell spiny branchlets may differ from the rat in its level of expression or in its molecular configuration. © 1995 Wiley‐L

ISSN:0887-4476    

DOI:10.1002/syn.890200310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY

摘要:

AbstractThe pharmacological regulation of evoked extracellular dopamine was compared in the basolateral amygdaloid nucleus (BAN) and caudate‐putamen (CP) of the urethane‐anesthetized rat. The effects of drugs, which alter dopamine uptake, release or degradation, were examined. Dopamine efflux was elicited by electrical stimulation of ascending dopamine fibers and was monitored by fast‐scan cyclic voltammetry at Nafioncoated, carbon‐fiber microelectrodes. Dopamine uptake inhibitors, nomifensine (25 mg/kg) and cocaine (20 mg/kg), and the dopamine receptor antagonist, haloperidol (0.5 mg/kg), robustly increased evoked extracellular dopamine in the CP. In sharp contrast, these drugs were much less effective in the BAN. The relative potencies of the uptake inhibitors varied between the two regions. Nomifensine was more potent than cocaine in the CP, whereas cocaine was more potent that nomifensine in the BAN. The monoamine oxidase inhibitor, pargyline (75 mg/kg), and the catechol‐O‐methyltransferase (COMT) inhibitor, Ro 40‐7592 (40 mg/kg), had small or negligible effects in either region. No electrochemical evidence was found for the formation of 3‐methoxytyramine, the dopamine metabolite formed by the action of COMT on released dopamine, on the time scale of the measurements in control or after pharmacological manipulation of the degradative enzymes for dopamine. The conclusions reached are: (1) potent mechanisms for uptake and autoreceptor inhibition of release, which exist in the CP to tightly control the concentration of extracellular dopamine, are considerably weaker in the BAN; (2) the extracellular clearance of evoked dopamine in the BAN and CP is the result of cellular uptake and not degradation; and (3) these results support the view that the pharmacological regulation of extracellular dopamine is regionally distinct in the brain. © 1995

ISSN:0887-4476    

DOI:10.1002/syn.890200311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1995

数据来源: WILEY