摘要:

AbstractThis study examined the relationship between the magnitude of tissue serotonin (5‐HT)depletion produced by treatment with the neurotoxin 5,7‐dihydroxytryptamine (5,7) and basal and fenfluramine‐induced 5‐HT release in the striatum. Separate groups of rats were treated with either vehicle or 5,7‐DHT (100μ 76% striatal 5‐HT depletion; or 200μ 93% styriatal 5‐HT depletion). four weeks after treatment 5‐HT release was measured in the ventral striatum using in vivo microdialysis in animals anesthetized with chloral hydrate. Basal 5‐HT levels were not significantly altered in any lesion group, whereas basal 5‐hydroxyindoleacetic acid levels were dosedependently reduced by 5,7‐DHT. In contrast, the increase of 5‐HT release produced by fenfluramine treatement (10 mg/kg) wa diminished significantly after 5‐HT neuronal destruction in correlation with the reduction of striatal tissue 5‐HT content. Fractional 5‐HT efflux, a measure of the 5‐HT release from surviving striatal nerve terminals, was also significantly elevated when tissue depletion of 5‐HT exceeded 95%. This study suggests that compensatory mechanisms may enable surviving 5‐HT terminals to maintain basal 5‐HT levels in th striatum with as little as 5% of the terminals remaining, but those mechanisms are not sufficient to allow the damaged system to respond to a pharmacolo

ISSN:0887-4476    

DOI:10.1002/syn.890200202

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

年代:1995

数据来源: WILEY

摘要:

AbstractAutoradiographic studies from our laboratory have previously demonstrated a selective association of high affinity neurotensin (NT) binding sites with basal forebrain cholinergic neurons. In search of an in vitro model for further characterization of the role and regulation of these sites, we have examined the binding and internalization of125I‐Tyr3I‐NT(125I‐NT) and fluorescein isothiocyanate (FITC)‐conjugated NT (fluo‐ NT) on SN17 hybrid cells, produced by fusion of embryonic murine septa1 cells with neuroblastoma.125I‐NT binding to SN17 membrane preparations was specific and saturable. Scatchard analysis of the data was suggestive of an interaction with a single population of sites, the affinity (Kd= 1.7 nM) and pharmacological profile of which were comparable to those of neural NT receptors. No specific binding was observed on the parent neuroblastoma cell line, confirming that the expression of those sites is a neuronal trait. Incubation of whole SN17 cells with125I‐NT resulted in a time‐ and temperature‐dependent internalization of the specifically bound peptide. The t½of this internalization was estimated at 13 min, a value nearly identical to that reported for neurons in culture. Confocal microscopic analyses using fluo‐NT indicated that the internalization process was endocytic in nature in that: (1)it was entirely blocked by the endocytosis inhibitor phenylarsine oxide; and (2) it was mediated through small intracytoplasmic particles the size and maturation of which corresponded to that of endosomes. It is proposed that the expression and internalization of NT receptors by SN17 hybrid cells represent a new facet of these cells' cholinergic phenotype that makes them amenable to the study of NT interactions with cholinergic cells. ©

ISSN:0887-4476    

DOI:10.1002/syn.890200203

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe hypothalamic‐pituitary‐adrenocortical (HPA) axis controls the levels of plasma corticosterone (CT) in the rat and the levels of cortisol in man. CT is important in maintaining homeostasis and regulating energy production. Homeostasis is maintained by basal activation of the hippocampal‐HPA axis. In response to stress CT secretion is increased. CT activation of receptors in the hippocampus provides feedback inhibition of the HPA axis to return the system to basal activity. There are two types of CT receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). CT has a 10‐fold higher affinity for MR than GR. Normal basal levels of CT occupy the majority of the MR. During the diurnal surge of CT and following the presentation of a stressful stimulus, the MR and GR are both maximally occupied. To begin to understand how CT influences the hippocampal‐HPA axis, intracellular recording techniques in the hippocampal brain slice preparation were used to determine how high concentrations of CT may alter cell characteristics and/or evoked synaptic activity. Two treatment groups were used, i.e., adrenalectomized (ADX) and ADX with CT pellet replacement (ADX + CT) that produced plasma blood levels equal to that seen in a normal rat in the morning. Acute administration of 100 nM CT decreased action potential threshold and the number of action potentials elicited by a depolarizing current pulse in cells from both the ADX and ADX + CT treated rats. The amplitude of the evoked excitatory postsynaptic potentials (EPSP) or inhibitory postsynaptic potentials (IPSP) declined in cells recorded from ADX animals and ADX rats acutely treated with high concentrations of CT (ADWCT). The EPSPs and IPSPs were stable in cells from ADX + CT rats exposed to high CT concentrations. We conclude from these data that chronic CT treatment is necessary to maintain EPSP and IPSP amplitude. Also, acute administration of a high concentration of CT alters the output of the CA1 hippocampal pyramidal cells by increasing the number of action potentials elicited by a depolarizing current pulse but does not alter the amplitude of subthreshold EPSPs and IPSPs. © 1995 Wiley

ISSN:0887-4476    

DOI:10.1002/syn.890200204

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe effects of neonatal excitotoxic ventral hippocampus (VH)lesions on dopamine release in response to repeated stress (saline injections) and to chronic haloperidol treatment were investigated in Sprague‐Dawley rats infused with ibotenic acid or vehicle into the VH on day 7 of postnatal life (PD7). Beginning on PD35, lesioned and sham‐operated rats were injected i.p. with saline (INJ) once daily for 3 weeks or were not treated (NO INJ). Another cohort of rats was given haloperidol (HAL, 0.4 mg/kg, i.p.) or vehicle beginning on PD35 and thereafter once daily for 3 weeks. 3‐Methoxytyramine (3‐MT) was measured by combined gas chromatography/mass spectrometry in the frontal cortex (FC), nucleus accumbens (NAcc), and striatum (STR) at PD56 following MA0 inhibition with pargyline. At baseline (NO INJ), 3‐MT was reduced in STR of lesioned rats. Repeated saline injections resulted in a further 3‐MT reduction in STR, FC, and NAcc of lesioned animals, but had no effect in sham rats. Chronic HAL, compared with vehicle, suppressed locomotor activity, and increased 3‐MT accumulation in the FC, NAcc, and STR in sham and lesioned rats. This increase was enhanced in the FC of lesioned rats. These data show that mild repeated stress attenuates dopamine release in FC, NAcc, and STR of lesioned rats, while chronic HAL augments it in FC of lesioned animals versus controls. We conclude that the neonatal excitotoxic lesion of VH alters the functioning of midbrain dopamine systems during environmental and pharmacological challenge. © 1995 W

ISSN:0887-4476    

DOI:10.1002/syn.890200205

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

年代:1995

数据来源: WILEY

摘要:

AbstractVoltage‐dependent potassium currents play a key role in shaping the firing pattern of central neurons. Their pharmacological and physiological identification is rather important in the structures which are involved in the filtering of inputloutput messages. In this regard, globus pallidus external segment (GPe) is indicated as a crucial station in the well‐known indirect pathway of the basal ganglia. Among the potassium conductances which have been indicated to condition the firing behavior and the neuronal integrative properties in many central neurons, we analysed the depolarization‐activated ones by means of patchclamp recordings in the whole‐cell configuration. Two main families of calcium‐independent outward potassium currents are activated by depolarization in GPe neurons acutely isolated from the adult rat. From depolarized holding potentials (−50/−45 mV), a slowly‐activating, sustained current is evoked; it manifests very little inactivation and it is available at rather depolarized potentials (−30 mV/−20 mV). This current is relatively resistant to 4‐aminopyridine (4‐AP)but it is blocked by tetraethilammonium ions (TEA) and consequently it resembles delayed rectifier current (Ik). From negative holding potentials (−8O/−lOO mV), on the other hand, A‐like conductances are activated. Together with a fast‐inactivating transient current, another component is observed in a significant proportion of recordings (45%). This current shows half‐inactivation voltage around −90 mV, peculiar sensitivity to micromolar doses of 4‐AF' and a slow rate of recovery from inactivation. The presence and the modulation of these A‐like currents may be a very critical aspect in the membrane physiology of p

ISSN:0887-4476    

DOI:10.1002/syn.890200206

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe have previously shown that tracer concentrations of [11C]cocaine binding to the dopamine transporter (DAT) in human and baboon striatum can be visualized using positron emission tomography (PET). To determine whether the concentration of dopamine normally present in the synaptic cleft can compete with [11C]cocaine for transporter binding sites, we conducted baboon PET studies with drugs (sodium 4‐hydroxybutyrate, four studies, 200 mg/kg gamma‐vinylGABA, three studies, 300 mg/kg and citalopram, three studies, 2 mgkg) expected to decrease synaptic dopamine. Each study involved two [11C]cocaine injections and PET scans separated by 2‐4 h, with drug administration after the first injection, and without movement of the subject between scans. Time‐activity data from striatum and from cerebellum were used with the arterial plasma input function to determine graphically by Logan plotting [11C]cocaine distribution volumes for the brain regions. Specific binding of [11C]cocaine to DAT in striatum was calculated as the distribution volume ratio (DVR) for striatum and cerebellum. In nine of the ten studies drug treatment produced a small increase in DVR (range, 1‐ll%), and in seven of these studies the increase was>7%. The mean increase was 6.2 ± 4.1%. The reproducibility of the DVR measure was assessed by comparing [11C]cocaine studies conducted without pharmacological treatments using individual baboons on separate days, and thus involving possible repositioning errors, as well as long‐term changes in the state of the striatal dopamine system. For four individual baboons with three or four studies per animal the mean (±s.d.) values of DVR were 1.73 ± 0.03, 1.39 ± 0.03, 1.53 ± 0.06, and 1.54 ± 0.12. The maximum differences between baseline DVRs, expressed as percentage of the lowest value, were 5%, 5%, 9%, and 20%. For two other baboons with two studies each, the between study differences were 1% and 9%. Thus within‐subject variability was quite low, even with repositioning. The results suggest that [11C]cocaine binding to the DAT is sensitive to pharmacological alterations in the concentration of synaptic dopamine. However, the sensitivity of [11C]cocaine to dopamine‐depletion is less than that of the D2 receptor radioligand [11C]raclopride, in agreement with literature in vitro binding studies, and is unlikely to be a serious issue in PET evaluations of DAT density.

ISSN:0887-4476    

DOI:10.1002/syn.890200207

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe present study examines the effect of acute liver failure induced by a single intraperitoneal (i.p.) injection of D‐galactosamine‐HC1(3 gkg) on somatostatin (SS) binding and levels in the rat frontoparietal cortex and hippocampus. Neurobehavioural changes were evaluated by the method of Zieve et al. (1984)J. Lab. Clin. Med., 1046554641.The rats were decapitated as soon as they reached neurobehavioural stage I or 11. In stage I, rats had lethargy and in stage I1 they showed mild ataxia, mainly in the hind limbs. The administration of D‐galactosamine elevated serum transaminase levels (mean peak level 2,242 IU/1) but hypoglycemia, gross cerebral edema, or signs of sepsis were not detected in any of the animals studied. In addition, D‐galactosamine did not affect somatostatin‐like immunoreactivity (SSLI) levels in either brain area in any of the experimental groups as compared to the control groups. The rats sacrificed in stage I showed no change in the number or affinity of specific125I‐Tyr11‐somatostatin(125I‐Tyr11‐SS)receptors in synaptosomes from the frontoparietal cortex and hippocampus. The rats sacrificed in stage II showed a decrease in the number of specific125I‐Tyr11‐SS receptors in synaptosomes from both brain areas, with no change in receptor affinity. Binding studies were also conducted on synaptosomes from the frontoparietal cortex and hippocampus of rats that received D‐galactosamine but did not develop acute liver failure and consequently did not develop neurobehavioural changes. The SS receptors in these synaptosomes did not change in comparison with controls, indicating that the D‐galactosamine was not directly responsible for the changes in the cerebral SS receptors. SS caused a significantly lower inhibition in AC activity in frontoparietal cortex and hippocampal membranes of D‐galactosamine‐treated rats sacrificed in stage II. No significant differences were seen for the basal or for the forskolin (FK)‐stimulated AC activities in all groups. The results of this study indicate that D‐galactosamine‐induced acute liver failure in rats is associated with a decrease of the number of SS receptors and the inhibitory effect of SS on adenylyl cyclase (AC) activity in frontoparietal cortex and hippocampus when the animals showed neurobehavioural stage II from Zieve et al. [(1984)J. Lab. Clin. Med., 1

ISSN:0887-4476    

DOI:10.1002/syn.890200208

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

年代:1995

数据来源: WILEY

摘要:

AbstractSystemic administration of the putative selective D3receptor agonist 7‐hydroxy‐2‐(N, N‐di‐n‐propylamino)tetralin(7‐OH‐DPAT) consistently decreased extracellular dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and dopaminergic neuronal activity in the ventral tegmental area. 7‐OH‐DPAT inhibited dopamine release in the nucleus accumbens also when locally perfused through the dialysis probe. The results suggest the possibility that stimulation of dopamine D2receptors with 7‐OH‐DPAT mimic biochemical and electrophysiological actions previously ascribed to D2autoreceptor stimulation; however the lack of selective D3antagonist precludes any firm conclusion in this sens

ISSN:0887-4476    

DOI:10.1002/syn.890200209

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

年代:1995

数据来源: WILEY

摘要:

AbstractWe studied neuroprotective properties of 12 structurally different sigma site ligands in primary rat hippocampal cell cultures and analyzed whether they interfere with glutamate‐induced activation of the nitric oxide synthase (NOS) pathway. Neurotoxicity was triggered with 1mM glutamate on day 8 of culture. Cells were treated with various concentrations of the compounds for 7 days before glutamate exposure (prolonged pretreatment), or during glutamate exposure (acute treatment). Protection was seen after prolonged pretreatment (long‐term protection) with sabeluzole, opipramole, haloperidol, ifenprodil, fenpropimorph, carbetapentane, and tiospirone, with pIC50S of 7.30, 7.15, 6.87, 6.68, 6.66, 6.39, and 6.34, respectively. There was no protection with PD 128298, 1,3‐ortho‐di‐tolylguanidine, BMY‐14802, (+)3‐(3‐hydroxyphenyl)‐N‐l(propy1) piperidine, or dextromethorphan. Upon acute treatment, only ifenprodil was protective. Interference of the drugs with glutamate activation of the NOS pathway was determined by measuring glutamate‐activated cGMP formation and citrulline levels. Glutamate‐activated cGMP formation was reduced by all neuroprotective sigma ligands after prolonged pretreatment but not after acute treatment. Sigma ligands added to cell culture iysate did not reduce citrulline formation, evidence that there was no direct effect on the NOS enzyme. We conclude that some but not all sigma ligands exert long‐term protective properties against glutamate‐induced neurotoxicity in primary hippocampal cultures, and that this protection is accompanied by attenuation of cGMP formation in the NOS pathway. However, inhibition of cGMP formation by itself appeared not sufficient for obtaining neuroprotective effects, as inhibition of glutamate‐activated cGMP formation by N‐nitro‐L‐arginine, haemoglobin, or PD128298 did not provide neur

ISSN:0887-4476    

DOI:10.1002/syn.890200210

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

年代:1995

数据来源: WILEY

摘要:

AbstractThe γ‐aminobutyric acid‐A receptor consists of several subunits. In this immunohistochemical study we investigated the regional distribution of the α1 subunit with an antibody directed against a specific amino acid sequence (1‐9) of the α1 subunit. We compared the distribution pattern of the α1 subunit‐like immunoreactivity with that of substance P‐ and enkephalin‐like immunoreactivities in adjacent sections of the rat forebrain. α1 subunit‐like immunoreactivity appeared in the form of varicosities and fibers. A band‐like terminal staining pattern (woolly fibers) that has been shown by others for substance P‐ and enkephalin‐like immunoreactivity is also observed for α1 subunit‐like immunoreactivity. In contrast to substance P and enkephalin, numerous α1 subunit‐like immunoreactive perikarya were found. The highest density of α1 subunit‐like immunoreactive fibers and perikarya was found in the pallidal areas and the substantia nigra pars reticulata whereas the nucleus accumbens and the caudate putamen displayed a low density. α1 subunit‐like immunoreactive neurons resembled typical pallidal neurons. Some of these neurons were pericellularly stained with enkephalin‐like immunoreactive varicosities in the dorsal pallidum.The distribution pattern of α1 subunit‐like immunoreactivity reflects a partial overlap with the substance P and enkephalin system although a differential distribution to each of these peptides was observed for cell bodies, fibers, a

ISSN:0887-4476    

DOI:10.1002/syn.890200211

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

年代:1995

数据来源: WILEY