摘要:

AbstractFlumazer it is an imidazobenzodiazepine, an antagonist of central benzodiazepine (BDZ) receptors. BDZ binding sites are a modulatory component located on the gamma‐aminobutyric acid (GABA) receptor macromolecule. We studied the effect of monocular enucleation on [3H]flumazenil binding in deprived and intact visual areas and nonvisual areas of the adult mouse brain under in vivo conditions. [3H]flumazenil binding was examined at seven time points up to 56 days postenucleation. In some monocularly deprived mice, changes in local blood flow accompanied with the BDZ receptor response were evaluated by coinjection of [3H]flumazenil and9mTc‐HMPAO. Monocular enucleation produced a transient increase in [3H]flumazenil binding in the deprived visual cortex and superior colliculus. At 17 days postenucleation, [3H]flumazenil binding in the anterior and posterior portions of the visual cortex and the superior colliculus increased by 28%, 15% and 23%, respectively, and declined to control levels at 45 days postenucleation. The increase in [3H]flumazenil was accompanied with a decrease in blood flow. Alterations in BDZ receptors and blood flow were selective to deprived visual structures. The regional correlation between the metabolic deficit and the BDZ response provides further support that the increase in BDZ receptor binding is confined to regions of reduced neuronal activity. [11C]flumazenil is an excellent radiotracer for in vivo imaging of benzodiazepine receptors in human brain using positron emission tomography (PET). This study suggests the suitability of [11C]flumazenil for in vivo PET study of BDZ receptor response to deafferentation of visual structures in human brain. © 1994 Wiley‐Lis

ISSN:0887-4476    

DOI:10.1002/syn.890180202

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

年代:1994

数据来源: WILEY

摘要:

AbstractL‐Deprenyl (Selegeline) is an enzyme‐activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L‐deprenyl requires the synthesis of new enzyme. We have measured a 40 day half‐time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L‐deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L‐Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L‐deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use. © 1994 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United S

ISSN:0887-4476    

DOI:10.1002/syn.890180203

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

年代:1994

数据来源: WILEY

摘要:

AbstractPrevious electrophysiological studies have reported conflicting results concerning the effects of ethanol on γ‐aminobutyric acid‐A (GABAA) receptor‐mediated responses in the brain. To examine the variables that might explain these inconsistencies, the present study was designed to determine whether ethanol modulation of synaptically evoked GABA responses is brain region dependent, to identify factors that might regulate ethanol sensitivity, and to investigate the mechanism(s) underlying ethanol modulation of GABA responses. Whole‐cell voltage clamp methods were used to examine the effects of ethanol on synaptically evoked GABAAinhibitory postsynaptic currents (IPSCs) recorded from neurons in hippocampus, cerebral cortex, and intermediate lateral and medial septum from rat brain slice preparations. Bicuculline‐sensitive IPSCs elicited by local stimulation were pharmacologically isolated by pretreatment with the glutamate specific antagonists, DL‐(−)‐2‐amino‐5‐phosphonovaleric acid (APV) and 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX). Superfused ethanol (80 mM) potentiated evoked GABAAIPSCs in cortical neurons and in intermediate lateral and medial septal neurons but not in CA1 hippocampal neurons. However, the mechanism by which ethanol enhanced GABAAIPSC amplitudes differed between brain regions. In cortex, ethanol induced a hyperpolarizing shift in the GABAAIPSC reversal potential (EIPSC) without modifying the underlying GABAAreceptor‐mediated conductance (GIPSC). In contrast, ethanol enhanced GABAAIPSC amplitudes in lateral and medial septal neurons by increasing the GIPSCwithout modifying the EIPSCThese results suggest that ethanol differentially modulates responses to endogenous GABA released during synaptic activation and that important differences between various brain regions may reflect multiple mechanisms of ethanol

ISSN:0887-4476    

DOI:10.1002/syn.890180204

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe actions mediated by limbic system output projections of the basal ganglia were investigated by studying the effects of ventral pallidum (VP) stimulation on the activity of neurons in thalamic target nuclei, including several of the dorsal thalamic nuclei and the nucleus reticularis, using in vivo intracellular recordings in rats. Intracellular injection of Lucifer yellow was used in a subset of experiments to identify the neurons recorded and to confirm their location with respect to the specific thalamic nuclei targeted. Stimulation of the VP evoked ipsps in 79% of the mediodorsal cells recorded. In the reticular nucleus, 73% of the neurons tested responded with evoked ipsps. In contrast, in other dorsal thalamic nuclei VP stimulation evoked depolarizations in 58% of the cells recorded. The latency to onset of the ipsps in the mediodorsal nucleus and in the reticular nucleus were not substantially different (1.7 ± 1.1 msec vs. 2.7 ± 1.1 msec), whereas the depolarizing response evoked in dorsal thalamic nucleus neurons typically occurred at longer and more variable latencies (3.5 ± 2.7 mse

ISSN:0887-4476    

DOI:10.1002/syn.890180205

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

年代:1994

数据来源: WILEY

摘要:

AbstractThe whole cell patch clamp technique was used to examine the electrophysiological properties of embryonic hippocampal neurons maintained in a very low density (VLD) culture prejparation. The goal of these experiments was to establish the viability of the VLD culture as a model system in which to study regulation of neurotransmission at single monosynaptic connections, in the absence of polysynaptic innervation. Depolarization of neurons in the VLD culture revealed voltage‐dependent sodium, calcium, and potassium currents which were blocked with, respectively, tetrodotoxin (TTX), cobalt, and tetraethylammonium and 4‐aminopyridine. When pairs of neurons were simultaneously recorded, action potentials evoked in presynaptic neurons elicited either excitatory or inhibitory postsynaptic currents (EPSCs or IPSCs, respectively). The dual component “EPSCs” were due to the activation of both types‐of postsynaptic, ionotropic glutamate receptors: N‐methyl‐D‐aspartate (NMDA) and non‐NMDA receptors. Evoked IPSCs were due to the activation of postsynaptic γ‐aminobutyric acid (GABA) receptors. Both excitatory and inhibitory synapses exhibited short term depression in response to high frequency stimulation, although IPSCs were routinely decreased to a much greater degree than EPSCs. Spontaneous miniature EPSCs and IPSCs were found to persist in TTX, were blocked by the same pharmacological antagonists which blocked evoked responses, increased in frequency in response to hyperosmotic solution, and were unaffected by changes in extracellular calcium concentration. mIPSCS were found to occur at a significantly lower frequency than mEPSCs. These experiments indicated that neurotransmission in the VLD cultures occurs in a manner consistent with the quantal hypothesis and, therefore, the VLD culture is a good model for studying excitatory and inhibitory neurotransmission between isolated pairs of neurons. In addition, these experiments, performed under comparable physiological conditions, demonstrated that there are fundamental differences underlying neurotransmitter release between excitatory and inhibitory neurons. ©

ISSN:0887-4476    

DOI:10.1002/syn.890180206

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

年代:1994

数据来源: WILEY

摘要:

Abstractdl‐threo‐Methylphenidate (Ritalin) was labeled with carbon‐11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [llC]dl‐threo‐methylphenidate ([llC]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5‐15 minutes post‐injection. The half‐time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed ≤8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43% The ratios of distribution volumes at the steady‐state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively. In contrast, pretreatment with tomoxetine (1.5 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, respectively, did not produce a significant change in the kinetics of [11C]MP and the ST/CB after pretreatment was similar to that for control. In one patient with Parkinson's disease, the striatum to cerebellum ratio of [11C]MP was markedly lower than that of an elderly normal subject. These results demonstrate the saturable [11C]MP binding to the dopamine transporter in the baboon brain and that [11C]MP is sensitive to dopamine neuron degeneration in Parkinson's disease. © 1994 Wiley‐Liss, IncThis article is a US Government work and, as such, is in the public domain in the Un

ISSN:0887-4476    

DOI:10.1002/syn.890180207

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

年代:1994

数据来源: WILEY

摘要:

AbstractImmediate‐early genes, such asc‐fos, are induced in the brain by cocaine and other psychotropic drugs. This induction is thought to be mediated via the activation of dopamine D1and glutamate N‐methyl‐D‐aspartate (NMDA) receptor subtypes. Because alcohol selectively blocks NMDA receptor function, we determined the ability of alcohol to block the expression ofc‐fosnormally induced by systemic cocaine exposure in perikarya of the rat striatum. Acute administration of alcohol (2 g/kg; IP) approximately 30 min prior to a single cocaine (20 mg/kg) injection significantly reduced the patchy appearance of intensely immunoreactive gene signal in dorsal‐central quadrants of the caudate putamen. Separate administration of three doses of alcohol alone (1, 2, or 3 g/kg) was ineffectual in inducing FOS‐like protein in this or other regions of the rat brain. The blockade of the encoded protein by alcohol was partial in magnitude reminiscent of that produced by MK‐801 and related NMDA receptor antagonist drugs. Furthermore, the blockade of cocaine‐induced FOS‐like protein by alcohol occurred at a dose which produced a blood alcohol concentration of approximately 180 mg/dl (40 mM), comparable to that detected in intoxicating humans. Considering the fact that the concomitant use of alcohol and cocaine is the most common substance abuse pattern found in the addictive population, the present results suggest an antagonistic effect exerted by these two drugs at the transcriptional level and further support the consensus that NMDA receptors are the plausible surface‐target elements mediating some of the effects of alcohol and cocaine.

ISSN:0887-4476    

DOI:10.1002/syn.890180208

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

年代:1994

数据来源: WILEY

ISSN:0887-4476    

DOI:10.1002/syn.890180201

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

年代:1994

数据来源: WILEY