bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of a vasopressin antagonist with vasopressin receptors in the septum of the rat brain
Authors: Dorsa Daniel M. , Brot Michelle D. , Shewey Linda M. , Meyers Kathleen M. , Szot Patricia , Miller Margaret A.
Published: January 2005

The ability of d(CH2)5‐Tyr(Me)‐arginine‐8‐vasopressin, an antagonist of peripheral pressoric (V1‐type) vasopressin receptors, to label vasopressin binding sites in the septum of the rat brain was evaluated. Using crude membrane preparations from the septum, 3H‐arginine‐8‐vasopressin (AVP) specifically labels a single class of binding sites with a Kd of 2.9nM and maximum binding site concentration of 19.8 fmole/mg protein. 3H‐Antag also labels a single class of membrane sites but with higher affinity (Kd=0.47nM) and lower capacity (10.1 fmole/mg protein) than 3H‐AVP. The rank order of potency of various competitor peptides for 3H‐AVP and 3H‐Antag binding was similar. Oxytocin was 100–1,000 fold less potent than AVP in competing for binding with both ligands. 3H‐AVP and 3H‐Antag showed similar labeling patterns when incubated with septal tissue slices. Unlabeled Antag also effectively antagonized vasopressin‐stimulated phosphatidylinositol hydrolysis in septal tissue slices.
Localization of substance P binding sites in submucous plexus of guinea pig ileum, using whole‐mount autoradiography
Authors: Burcher Elizabeth , Bornstein Joel C.
Published: January 2005

Whole mounts of guinea pig ileum submucosa were incubated with radiolabeled tachykinins, and binding sites were visualized using autoradiography. Very dense specific binding for [125I]‐Bolton‐Hunter substance P (BHSP) was observed over ganglia of the submucous plexus, with weaker binding over internodal strands. Dense specific binding was also seen over occasional strands of circular muscle, with weak binding over clumps of mucosa. Although very weak binding was seen over some large blood vessels, no binding was associated with smaller blood vessels. Localization of binding was absent in whole‐mounts coincubated with 1 nM substance P, used to define nonspecific binding. Localization of BHSP‐specific binding was also abolished in whole‐mounts coincubated with 1 nM substance P, but not with 1 nM neurokinin B, suggesting that binding was probably to an NK‐1 tachykinin receptor. In whole‐mounts incubated in [125I]‐iodohistidyl neurokinin A (INKA) or [125I]‐Bolton‐Hunter neurokinin B (BHNKB), no specific binding over ganglia was observed. These binding sites for BHSP are probably identical with the neuronal substance P receptors mediating mucosal ion transport.
SKF 38393 alters the rate‐dependent D2‐mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons
Authors: Kelland Mark D. , Freeman Arthur S. , Chiodo Louis A.
Published: January 2005

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single‐unit recording techniques to examine whether SKF 38393 can alter D2‐mediated inhibition of DA cell activity. Quinpirole induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl‐specific, feedback pathway‐dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2‐mediated inhibition of cell firing rate.
Direct demonstration of interactions between substance P immunoreactive terminals and tyrosine hydroxylase immunoreactive neurons in the substantia nigra of the rat: An ultrastructural study
Authors: Mahalik Thomas J.
Published: January 2005

The results of many anatomical, physiological, and pharmacological studies suggest that substance P‐containing neurons of the striatum project to the substantia nigra, and that substance P influences the activity of dopaminergic nigrostriatal neurons. The purpose of the present ultrastructural study was to employ dual immunocytochemical labeling to determine the morphological basis for the observed actions of substance P on nigral dopaminergic neurons.

Substance P‐like and tyrosine hydroxylase‐like immunoreactivities were localized simultaneously at the ultrastructural level in the substantia nigra of the rat. A double label method was utilized which relied on a combination of the peroxidase‐antiperoxidase method (Sternberger, 1979) for substance P, and immunogold or silver enhanced immunogold labeling for tyrosine hydroxylase.

The present results indicate that tyrosine hydroxylase immunoreactive (THLI) dendrites in the substantia nigra receive synaptic input from terminals exhibiting substance P‐like immunoreactivity. These findings support the idea that substance P is a major neurotransmitter in the striatonigral loop, and suggest that striatal substance P neurons act directly upon nigral dopaminergic cells.
Single Ca2+ entry and transmitter release systems at the neuromuscular synapse
Authors: Guan Y.‐Y. , Quastel D. M. J. , Saint D. A.
Published: January 2005

The possibility that there exists more than one voltage‐gated Ca2+ channel system subserving quantal release of neurotransmitter at nerve endings was examined by measuring the sensitivity of quantal release to agents that block Ca2+ or Ba2+ entry, namely Cd2+, Mg2+, neomycin, and bekanamycin. The results show equal effectiveness vs. release evoked by presynaptic action potentials, brief intense presynaptic depolarizations, or prolonged relatively mild depolarizations, from which it is concluded that the same channel system is involved in each case. In the presence of Ba2+ and no Ca2+ there occur essentially normal (but small) endplate potentials (epps), while in the presence of Ba2+ epp amplitude and frequency of miniature epps co‐modulate with stimulation frequency in a manner which corresponds to a residual Ba2+ model for augmentation. It is therefore also concluded that a single transmitter release system is responsible for normal phasic release and the asynchronous release that is mediated by Ba2+.
Immunocytochemical evidence for substance P and serotonin input to medullary bulbospinal adrenergic neurons
Authors: Nicholas Anthony P. , Hancock Michael B.
Published: January 2005

Using two‐color immunoperoxidase staining combined with the retrograde transport of horseradish peroxidase injected into the rostral thoracic spinal cord, substance P‐immunoreactive (SPI) and serotonin‐immunoreactive (5HTI) variocosities have been observed in contiguity with medullary bulbospinal phenylethanolamine N‐methyl transferase‐immunoreactive (PNMTI) neurons of the C1, C2, and C3 cell groups. Since PNMTI terminals in the spinal cord are concentrated among sympathetic preganglionic neurons (SPGN) in the intermediolateral cell column, the close anatomical associations shown in the present study indicate that substance P‐ and serotonin‐containing pathways in the medulla likely affect activity of SPGN via adrenergic bulbospinal neurons.
Physiological correlates of responses to gamma‐aminobutyric acid (GABA) recorded from rat visual cortical neurons in vitro
Authors: Scharfman Helen E. , Sarvey John M.
Published: January 2005

Responses to focal application of gamma‐aminobutyric acid (GABA) were compared to synaptic potentials elicited by afferent stimulation of rat visual cortical neurons, using a slice preparation and conventional intracellular recording techniques. GABA produced three types of responses: a brief hyperpolarization (mean reversal potential, −72 mV), brief depolarization (mean reversal potential, −50 mV), or a prolonged hyperpolarization (mean reversal potential, −80 mV). Synaptic potentials included simple or complex EPSPs and EPSPs followed by mono‐ or biphasic IPSPs. A comparison of the characteristics of the GABA responses and synaptic potentials indicated that GABA may mediate both phases of the IPSP in these cells. Our results suggest that despite differences in the circuitry of the visual cortex as opposed to other neocortical and allocortical (hippocampal) areas (Mountcastle and Poggio, 1968; Colonnier and Rossignol, 1969; Creutzfeldt, 1978; Kuhlenbeck, 1978), the inhibitory control of cortical pyramidal and nonpyramidal neurons by GABA is quite similar.
Changes in miniature end‐plate currents due to high potassium and calcium at the frog neuromuscular junction
Authors: Glavinovic M. I.
Published: January 2005

Elevation of extracellular potassium concentration ([K+]0) in cutaneous pectoris neuromuscular junction from 2 to 20 mM slowly increased the variability of the amplitudes of miniature end‐plate currents (AMEPC‐s), (coefficient of variation of AMEPC‐s increased by 73%). Mean AMEPC‐s, however, decreased but not markedly (by 14%). Comparable MEPC changes were observed when [K+] was raised in the presence of choline chloride (50 μM), arguing that MEPC changes were not primarily due to a lower and less uniform vesicular filling. Channel kinetics were not altered by high [K+]O, since the time constant of decay of miniature end‐plate currents (TMEPC‐s) did not change. Acetylcholine clearance from the synaptic cleft, however, appeared to be faster in high [K+ O since with cholinesterase blocked throughout, TMEPC‐s were shortened. The changes of spontaneous quantal discharge induced by high [K+]0] can be almost entirely explained by altered spatial distribution of vesicular release if, as recent reports suggest, at high [K+],0, exocytosis appears randomly not only at but also in between the active zones. However, relatively greater frequency of large MEPCs suggests that in high [K+]0 some, and possibly all, quanta are filled above normal levels.

High [Ca2+]0 appears to counteract, although not always completely, all changes in spontaneous quantal secretion induced by high [K+]0. It is possible that high [Ca2+]0 reverses the changes in the spatial distribution of vesicular release induced by high [K+]0. However, high [Ca2+]0 also leads to other pre‐ and postsynaptic changes.
Adaptive changes of β‐adrenergic receptors after neonatal locus coeruleus lesion: Regulation of serotoninergic unit activity
Authors: Lanfumey Laurence , Adrien Joëlle
Published: January 2005

Spontaneous activity of 5‐hydroxytryptamine (5‐HT) neurons in the dorsal raphe nucleus (DRN) was recorded in adult rats that had undergone a bilateral locus coeruleus (LC) lesion during the neonatal period. The susceptibility of this neuronal firing to β‐adrenergic manipulation was tested. Microiontophoretic application of the β‐blockers d,l‐propranolol and acebutolol inhibited the firing of DRN cells in lesioned rats but not in control animals. This effect was specific to β‐receptors since the effects of pharmacological manipulation of other receptors—5‐HT, γ‐aminobutyric acid (GABA), γ‐adrenoceptors— were identical in lesioned and control animals. The present data demonstrate that a neonatal noradrenergic lesion allowed the persistence of a β‐regulation of DRN neuronal firing, which in young rats is normally only transient.
Presence of ghost doublets of coded neuronal patterns: Relation to synaptic memory storage
Authors: Strehler Bernard L. , Lestienne Remy
Published: January 2005

Recent evidence demonstrates that controlled visual stimuli cause the generation, in the primary visual cortex of rhesus monkey cells, of large numbers of very precisely replicating copies of complex patterns of discharge consisting of three or more spikes, the patterns of which presumedly code for specific qualities of the stimuli presented. We present evidence that the copies of precisely replicating triplets of spikes, generally not exceeding 100 ms in duration, occur in close time proximity to many copies of highly precise “ghost” doublets. These doublets are defined as patterns consisting of two pulses, with precise separations in time, specifically those that would be generated if any one of the pulses making up a given replicating triplet were missing. In striking contrast, nonreplicating triplets (also present in these records)–that is, triplets made up of intervals that are not present in replicating triplet–are not accompanied by such ghost doublets. The persistence (memory) of capacity to produce such ghost doublets decays according to two independent kinetic rules. The first of these results in the disappearance of such doublets within about 0.1 s as measured by two independent methods, whereas the second disappears only after several minutes or longer. These results provide strong evidence consistent with the notion that at least some parts of the brain transmit, store representations of, and retrieve qualitative information through the use of a code consisting of specific patterns of nerve discharges in time.
Modelling afferent connectivity, postsynaptic plasticity, and signal discrimination
Authors: Chover Joshua
Published: January 2005

We model a small system of hypothetical neurons having ongoing afferent input (“stimulus”) short‐term refraction/inhibition, and brief‐latency intercellular excitatory feedback loops. We incorporate postsynaptic plasticity: synapses onto a given cell are grouped into dendritic “neighborhoods” wherein sufficiently large local postsynaptic potentials sums cause proportional changes in local synaptic efficacy. The efficacies record multiple cell‐to‐cell and time‐to‐time correlations. The efficacy patterns fall into several classes, for each of which there is a stereotypical relationship leading from “steady‐state” stimuli to corresponding sets of possible “responses” (periodic firing patterns). We examine the system's ability to discriminate between stimuli via firing patterns and to retain information during change of efficacies. There is an optimal region for efficacy configurations inside of which discrimination is good and outside of which the system can be inactive, particularly forgetful, of perseverative. We find that stimulus discrimination is enhanced by divergence and convergence in the pattern of afferent input. Perseverative firing patterns, invoked or suppressed by cotransmitters, can play a role in associative activities of the network.
Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel experimental model of intractable epilepsy
Authors: Turski Lechoslaw , Ikonomidou Chrysanthy , Turski Waldemar A. , Bortolotto Zuner A. , Cavalheiro Esper A.
Published: January 2005

High‐dose treatment with pilocarpine hydrochloride, a cholinergic muscarinic agonist, induces seizures in rodents following systemic or intracerebral administration. Pilocarpine seizures are characterized by a sequential development of behavioral patterns and electrographic activity. Hypoactivity, tremor, scratching, head bobbing, and myoclonic movements of the limbs progress to recurrent myoclonic convulsions with rearing, salivation, and falling, and status epilepticus. The sustained convulsions induced by pilocarpine are followed by widespread damage to the forebrain. The amygdala, thalamus, olfactory cortex, hippocampus, neocortex, and substantia nigra are the most sensitive regions to epilepsy‐related damage following convulsions produced by pilocarpine. Spontaneous seizures are observed in the long‐term period following the administration of convulsant doses of pilocarpine.

Developmental studies show age‐dependent differences in the response of rats to pilocarpine. Seizures are first noted in 7–12 day‐old rats, and the adult pattern of behavioral and electroencephalographic sequelae of pilocarpine is seen in 15–21‐day‐old rats. During the third week of life the rats show an increased susceptibility to the convulsant action of pilocarpine relative to older and younger animals. The developmental progress of the convulsive response to pilocarpine does not correlate with evolution of the brain damage. The adult pattern of the damage is seen after a delay of 1–2 weeks in comparison with the evolution of seizures and status epilepticus. The susceptibility to seizures induced by pilocarpine increases in rats aged over 4 months.

The basal ganglia curtail the generation and spread of seizures induced by pilocarpine. The caudate putamen, the substantia nigra, and the entopeduncular nucleus govern the propagation of pilocarpine‐induced seizures.

The antiepileptic drugs diazepam, clonazepam, phenobarbital, valproate, and trimethadione protect against pilocarpine‐induced convulsions, while diphenylhydantoin and carbamazepine are ineffective. Ethosuximide and acetazolamide increase the suspectibility to convulsant action of pilocarpine. Lithium, morphine, and aminophylline also increase the susceptibility of rats to pilocarpine seizures.

The pilocarpine seizure model may be of value in designing new therapeutic approaches to epilepsy.
Phorbol‐12,13‐dibutyrate antagonizes while forskolin potentiates the presynaptic autoreceptor‐mediated inhibition of [3H]‐5‐hydroxytryptamine release in rat hypothalamic slices
Authors: Ramdine R. , Galzin A.‐M. , Langer S. Z.
Published: January 2005

In superfused rat hypothalamic slices prelabeled with [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT), the 5‐HT autoreceptor agonists 5‐methoxytryptamine and RU 24969 inhibited in a concentration‐dependent manner the electrically evoked release of [3H]‐5‐HT. Exposure to phorbol‐12,13‐dibutyrate increased in a concentration‐dependent manner the stimulation‐evoked overflow of [3H]‐5‐HT and shifted to the right the 5‐methoxytryptamine inhibition curve. Exposure to forskolin, a potent activator of adenylate cyclase, increased the stimulation‐evoked [3H]‐5‐HT overflow and shifted to the left the 5‐methoxytryptamine or RU 24969 inhibitory curves on transmitter release. A similar interaction was observed in the presence of 1‐isobutyl,3‐methylxanthine (IBMX), a phosphodiesterase inhibitor, or 8‐bromo‐cyclic AMP and the serotonin autoreceptor agonist 5‐methoxytryptamine. In the presence of phorbol‐12,13‐dibutyrate or forskolin, the enhancing effect of the 5‐HT autoreceptor antagonist methiothepin on the stimulation‐evoked [3H]‐5‐HT overflow was significantly less pronounced than in the absence of these compounds. These results indicate that the presynaptic 5‐HT autoreceptors that modulate the release of [3H]‐5‐HT in rat hypothalamic slices may be coupled to the phosphoinositide cycle and protein kinase C‐dependent mechanisms. In addition, the increase in intracellular level of cyclic AMP by forskolin, IBMX, and 8‐bromo‐cyclic AMP potentiates the inhibitory effects of the autoreceptor agonist 5‐methoxytryptamine on [3H]‐5‐HT release, although the mechanism of the interaction remains to be elucidated.
Frequency and amplitude gradients of spontaneous release along the length of the frog neuromuscular junction
Authors: Robitaille R. , Tremblay J. P.
Published: January 2005

Experiments were done at the neuromuscular junctions (NMJs) of the cutaneous pectoris muscle of the frog to test the validity of the “spatial decay method” which uses simultaneous recording with two intracellular electrodes, each located in the muscle fiber near a distal end of the terminal. The miniature endplate potential (MEPP) peak amplitude recorded by each electrode is used to calculate the position of the release site producing it as well as its initial amplitude in front of its release site. The validity of the method was tested with a third focal electrode located between the two intracellular electrodes, at about 60–100 μm from one of the intracellular electrodes. the probability of spontaneous transmitter release was not uniform along the NMJ either in low or in normal Ca2+ + concentration. The release sites located in the region close to the first point of contact between the axon and the muscle fibre, usually close to the center of the NMJ, were spontaneously more active than the distal release sites. The degree of the steepness of proximodistal release gradients varied among different junctions. The less active regions tended to produce smaller MEPPs than did the more active ones. In fact, a correlation was found between the logarithm of MEPP frequency in a given region and the mean corrected MEPP amplitude in that region. These results also show that MEPP frequency was modulated to a greater extent than MEPP amplitude along the frog nerve terminal. The proximodistal gradient in MEPP frequency may be related to corresponding gradients in density and length of release sites along the junction, whereas MEPP amplitude gradients may be related to gradients in the length of release sites and/or postjunctional folds.
D1 receptor activation enhances sciatic nerve stimulation‐induced inhibition of nigrostriatal dopamine neurons
Authors: Kelland Mark D. , Freeman Arthur S. , Chiodo Louis A.
Published: January 2005

Nigrostriatal dopamine (NSDA) neurons have been hypothesized to play an important regulatory role in neostriatal sensorimotor integration. In order to provide further information on the nature of sensory modulation of NSDA cells, we have examined the pharmacology of the responsiveness of these neurons to peripheral nerve stimulation. The selective D1 dopamine receptor agonist SKF 38393 enhanced the normal inhibition of NSDA neurons produced by electrical stimulation of the sciatic nerve. The SKF 38393‐induced enhancement, but not the basal stimulation‐induced inhibition itself, was blocked by prior hemitransection of the forebrain and was reversed by the selective D1 antagonist SCH 23390 but not by the selective D2 antagonist 1‐sulpiride. SCH 23390 alone, however, exerted no effect on this inhibition. The selective D1 receptor agonist fenoldopam, which does not cross the blood‐brain barrier, also failed to alter the response to sciatic nerve stimulation (i.v. administration). Thus, central D1 receptors (rostral to the midbrain) appear to be involved in a system which mediates phasic control over sensory modulation of NSDA neuronal activity.
Dopamine transporter: Solubilization from dog caudate nucleus
Authors: Lew Robert , Grigoriadis Dimitri E. , Sharkey John , Kuhar Michael J.
Published: January 2005

3H‐GBR 12935 was used to label the digitonin‐solubilized dopamine transporter from dog caudate nucleus. Specific binding to soluble fractions was observed in dog caudate but was absent in rat cerebellum. Binding to the solubilized transporter sites was saturable and of high affinity (Bmax = 2.57 ± 0.60 pmol/mg protein, KD = 23.42 ± 2.24 nM, n = 4). Heating or addition of trypsin abolished specific binding in the soluble fractions. In competition studies, soluble 3H‐GBR 12935 binding was inhibited by mazindol, GBR 12909, nomifensine, dimethocaine, dopamine, (−) cocaine, and (+) cocaine in a manner typical of binding to the dopamine transporter. As expected, tomoxetine and citalopram, inhibitors of norepinephrine and serotonin uptake, respectively, were weak competitors of 3H‐GBR 12935 binding.
Cholinergic modulation of frequency receptive fields in auditory cortex: I. Frequency‐specific effects of muscarinic agonists
Authors: McKenna Thomas M. , Ashe John H. , Weinberger Norman M.
Published: January 2005

Previously we reported that acetylcholine (ACh) and acetyl‐beta‐methacholine (MCh) modify responses of neurons in auditory cortex to individual frequencies. The purpose of this study was to determine whether muscarinic agonists produce frequency‐specific alterations or general changes in cellular responses. Frequency‐specific modifications would be evident in alterations of frequency receptive fields (FRF) that differed across frequencies while general effects would be seen as changes that were more or less the same over frequencies. Responses of single neurons to designated sets of tones were recorded in the auditory cortex of chronically prepared awake cats before, during, and following ejection of ACh or MCh by iontophoresis or micropressure using multibarrel micropipettes. Frequency receptive fields were determined by presenting isointensity tones across a range of frequencies including the cell's best frequency (BF) to tone onset. FRF for “off” and “sustained (through)” responses were also determined quantitatively. The effects of ACh and MCh were predominantly frequency‐specific (77%, 39/51 cells); general changes (19%, 10/51) and no effects (4%, 2/51) were less likely. Frequency‐specific effects involved both facilitation and reduction of the same response component to different frequencies within the same neuron. For responses to tone onset (but not “through” and “off” responses), agonists were more likely to produce a decrease at the BF while simultaneously increasing responses to other frequencies. Agonists could increase or decrease frequency selectivity. Effects of agonists could be blocked by atropine, suggesting involvement of muscarinic receptors.
Quantitative autoradiographic distribution of [3H]AF‐DX 116 muscarinic‐M2 receptor binding sites in rat brain
Authors: Regenold William , Araujo Dalia M. , Quirion Remi
Published: January 2005

The distribution of muscarinic‐M2 receptors in rat brain was investigated by in vitro autoradiography using [3H]AF‐DX 116, a putative probe for the muscarinic‐M2 receptor subtype. Incubation of rat brain coronal sections with 10 nM [3H]AF‐DX 116 showed highest binding site densities in discrete areas such as the superior colliculus and certain thalamic and brainstem nuclei, similar to the distribution reported for [2H]acetylcholine/M2 sites. [3H]AF‐DX 116 site densities were markedly lower in forebrain areas such as cortex, striatum, and hippocampus, in contrast to the distribution seen for [3H]pirenzepine‐M1 binding sites, which were concentrated in these forebrain areas; however, differential patterns of labeling were observed for the two muscarinic‐M2 probes, [3H]AF‐DX 116 and [3H]acetylcholine, in the hippocampal formation. Although [3H]AF‐DX 116 binding was broadly distributed in multiple subfields of the hippocampus, [3H]acetylcholine binding was discretely distributed in a manner resembling that of acetylcholinesterase staining. This suggests the existence of muscarinic‐M2 subtypes in the CNS, especially in the hippocampal formation.
Substantia nigra 6‐hydroxydopamine lesions alter dopaminergic synaptic markers in the nucleus basalis magnocellularis and striatum of rats
Authors: Geula Changiz , Slevin John T.
Published: January 2005

Recent findings have demonstrated the existence of dopaminergic (DA) markers in the nbM of the human brain and a reduction of these markers in both the nbM and the striatum of patients suffering from Alzheimer's disease (AD). To investigate the source of the DA synaptic markers found in the nbM, rats received unilateral 6‐OHDA lesions of the substantia nigra pars compacta (SNc). The SNc lesions caused signigificant reductions in DA and DOPAC but not HVA in the nbM and the striaum; 3H‐sulpiride binding to D2 receptors ipsilateral to the SNc lesion was significantly increased in the stratum (16%), consistent with denervation supersensitivity, but single‐point analysis showed no significant changes in the nbM. These data suggest that the decreases in DA and 3H‐spiperone binding levels observed in the nbM of AD patients may be due to partial destruction of DA nbM afferent projections from the brainstem.
Changes in the structure of synaptic junctions during climbing fiber synaptogenesis
Authors: Landis Dennis M. D. , Payne H. Ross , Weinstein Lori A.
Published: January 2005

Synaptogenesis between climbing fiber axons and Purkinje cells involves both an orderly translocation of synaptic junctions over the Purkinje cell surface and an elimination of all but one innervating axon. We used thin‐section and freeze‐fracture electron microscopic techniques to study structural changes in synaptic junctions during this interval of synapse translocation and elimination. In freeze‐fractured preparations, virtually all climbing fiber synaptic junctions with the perisomatic processes and somatic spines lacked the particle aggregates that characterized the extracellular half of the postsynaptic membrane of mature synaptic junctions with dendritic spines. Some climbing fiber junctions with the dendritic shaft in the second postnatal week were associated with such aggregates, despite the fact that these junctions are transient. Thus, during the interval when Purkinje cells initially were innervated by multiple climbing fibers, and subsequently denervated of all but one climbing fiber afferent per cell, only a few of the transient synaptic junctions on the cell body and proximal dendrites have associated particles. The presence of a particle aggregate at a synaptic junction does not appear to be correlated with the permanence of that junction and probably is not correlated with the capacity to support synaptic transmission. The particle aggregates might be indicative of relatively long‐lived junctions, or might occur only at junctions formed by the climbing fiber that will persist in synaptic contact with the mature Purkinje cell.
Excitatory amino acid treatment of the ventromedial globus pallidus enhances dopamine utilization in the prefrontal cortex of the rat via the thalamic mediodorsal nucleus
Authors: Jones M. W. , Kilpatrick I. C. , Phillipson O. T.
Published: January 2005

Infusion of a low dose (5 μM) of the cell‐selective chemical excitant quisqualic acid (QUIS) into rostral ventromedial globus pallidus (GP) had no immediate effect on DA utilization (assessed as [DOPAC]:[DA] and [HVA]:[DA] ratios) in either the medial bank of the prefrontal cortex (FCx) or the agranular insular cortex (AgCx). In contrast, a larger dose (630 μM) of another excitant sodium ibotenate (IBO) produced an immediate bilaterally symmetrical increase in both indices of DA utilization in FCx. There was also a marked trend towards a bilateral increase in these indices of DA utilization in AgCx. In order to determine whether these effects on cortical DA utilization are mediated by a direct cortical route or via the thalamic mediodorsal nucleus (lateral division, MDL), infusions of IBO into GP were repeated in animals with a 1‐week‐old N‐methyl‐D‐aspartate lesion of MDL. The increase in DA utilization of FCx following infusion of IBO into GP was abolished, although the trend towards increased DA utilization in AgCx was still maintained. Since MDL innervates FCx but not AgCx and since we have previously shown that MDL lesions alone have no effect on DA utilization in either cortical region, the present results suggest that the changes in cortical DA utilization are probably mediated via MD. Thus in addition to the well‐documented control exerted by the thalamus over brain DA function, this has now been extended in the present study to include GP, which projects both directly and indirectly to the thalamus.
1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine‐Induced neurotoxicity in the rat: Characterization and age‐dependent effects
Authors: Jarvis Michael F. , Wagner George C.
Published: January 2005

1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) is a potent dopaminergic toxin that has been found to produce Parkinson's disease‐like symptoms in humans and monkeys. The neurotoxic effects of MPTP appear to be reduced in rodents where multiple dosing procedures are required to demonstrate long‐lasting neuronal deficits. In the present study, the neurotoxic effects of MPTP were further characterized in the rat. Following the repeated administration of MPTP, pronounced (60–80%) and dose‐dependent depletions of striatal dopamine and serotonin concentrations were found in the rat brain. Time‐course studies revealed that while striatal dopamine concentrations remained consistently reduced for at least 8 weeks following MPTP treatment, striatal serotonin depletions as well as MPTP‐induced monoamine depletions in other brain regions were transient in nature. Pretreatment with the MAO‐B inhibitor pargyline afforded a selective and complete protection of striatal dopamine levels without significantly affecting MPTP‐induced striatal serotonin depletions. Similarly, treatment with ascorbic acid was found to selectively attenuate MPTP‐induced dopamine depletions in rats. The neurotoxic effects of MPTP were also found to increase in the developing rat. No significant brain monoamine depletions were observed in neonatal rats following the repeated administration of MPTP. However, MPTP‐induced neurotoxicity progressively increased in older rats. The present results indicate that when appropriate treatment procedures are used, a pronounced, selective, age‐dependent, and long‐lasting MPTP‐induced reduction in striatal dopamine concentrations can be observed in the rat brain. The present results are discussed in references to the putative mechanisms and species differences of MPTP‐induced neurotoxicity.
Pargyline‐Sensitive selective accumulation of a radiolabeled MPTP analog in the primate cerebral cortex and basal ganglia
Authors: Efange S. M. N. , Kung H. F. , Mash D. C. , Jabir M. , Billings J. , Pablo J. , Dutta A. , Freshler A.
Published: January 2005

The distribution of radioiodinated N‐methyl‐4‐(4‐hyroxy‐3‐iodobenzyl)‐1,2,3,6‐tetrahydropyridine (MHTP), an analog of the reportedly nontoxic N‐methyl‐4‐benzyl‐1,2,3,6‐tetrahydropyridine, (4‐homo‐MPTP), has been studied in the primate. [123I]‐MHTP‐derived radioactivity exhibited a progressive accumulation and prolonged retention within the primateeye. Following injection, [123I]MHTP rapidly accumulated within the primate brain and was subssequently oxidized to a radiolabeled metabolite. The half‐life of [123I]MHTP‐derived radioactivity within the primate brain was 50 min. The highest concentrations of radioactivity were found in the caudate‐putamen and the frontal, temproal and cingulate cortices; the substantia nigra and inferior olivary nucleus were labeled with medium intensity. Very low concentrations of radiolabel were detected in the cerebellum and white matter, Selective accumulation of [125I]MHTP‐derived radioactivity within these structures was blocked by pretreatment with pargyline, suggesting that nonoamine oxidase B is involved in the bioactivation of radioiodinated MHTP.
Statistical analysis of dose‐response curves in extracellular electrophysiological studies of single neurons
Authors: Pitts David K. , Kelland Mark D. , Shen Roh‐Yu , Freeman Arthur S. , Chiodo Louis A.
Published: January 2005

The application of polynomial regression and the analysis of covariance (ANCOVA) to dose‐response (DR) data derived from extracellular electrophysiological studies of midbrain dopamine neurons and noradrenergic locus coeruleus neurons in vivo is demonstrated and discussed. Third‐order polyomial regression was found to be a better method for estimating ED50 values than probit analysis or linear regression. ANCOVA provides a more powerful statistical method than ANOVA for detecting significant differences in ED50 values or DR curves when a confounding variable such as basal discharge rate is present. The methods of analysis presented herein should be useful in the analysis of other types of neurons in electrophysiol studies.
Regultion of adrenergic receptors in intraocular hippocampal transplants: Role of Noradrenergic Innervation
Authors: Mynlieff Michelle , Curella Pamela , Zahniser Nancy R. , Gerhardt Greg A. , Seiger Ake , Dunwiddie Thomas V.
Published: January 2005

Hippocampal tissue transplanted into the anterior chamber of the eye offers a unique system in which development can be studied in the absensce of the noradrenergic innervation. This system was used to determine the extent to which noradrenergic innervation regulates the developement of adrenergic receptors. In addition to examining single denervated transplates, transplants grown with innervation from the superior cervical ganglia of the host rat or from locus coeruleus cotransplants were also examined to determine whether the source of norepinephrine and extent of innervation in oculo regulate the developement and density of adrenergic receptors. In vitro autoradiographic analysis of ligand binding to both α1‐ and β‐adrenergic receptors. In vitro autoradiographic analysis of ligand binding to both α1‐and β‐adrenergic receptors with 125‐I‐BE2254 and 125I‐pindolol, respectively, was used to charcterize aderenergic receptors in the intraocular transplants. Quantitative analysis of the receptors showed and up‐regulation of both α1‐ and β‐adrenergic receptors in tissue grown in the absence of norepinephrine, but in general there was not a high degree of correlation between norepinephrine content and receptor density. Although high‐performance liquid chromatography (HPLC) analysis of catecholamines revealed higher than normal amounts of norepinephrine in hippocampal transplants innervated by the superior cervical ganglia or a locus coeruleus cotransplant, the density of α1‐ and βreceptors was quite comparable with values found in the literature for normal adult hippocampus. These results suggest that the relationship between receptor number and density of innervation may differ significantly from what is observed in response to pharmacological manipultion of norepinephrne systems in the adult brain.
Electrophysiological identification of a pathway from the septal area to the medial amygdala: Sensitivity to estrogen and luteinzing hormone‐releasing hormone
Authors: Dudley Carol A. , Lee Yong , Moss Robert L.
Published: January 2005

Medial amygdala neurons responsive to electrical stimulationof the medial septal area were electrophysiologically identified in ovariectomized, urethane‐anesthetized female rats. Peristimulus time histograms were collected and used to define the orthodromic response. The action of iontophoretically applied luteinzing hormone‐releasing hormone (LHRH) and an LHRH fragment, Ac‐LHRH5–10, on the activity of were identified as orthodromically responsive. Three types of orthodromic responses were observed: excitatory, inhibitory, and complex. Priming the animals with 5 μg estradiol benzoate (EB) 48 hr prior to recording had no effect on the overall number of neurons responding to septal area stimulation, but EB priming did significantly reduce the percentage of orthodromically excited neurons. The firing rate of the majority of amygdala neurons responsive to septal area stimularion was not affected by iontophoretically applied LHRH (59 of 76) or LHRH fragment (41 of 65). In some cases, application of LHRH (10 of 76) or Ac‐LHRH5‐10 (12 of 55) produced a change in neuronal firing that was similar in direction to the orthodromically evoked response. When applied during the collection of peristimulus time histograms, both peptides were also able to modulate the orthodromically evoked response (five of 18 cells tested with LHRH and three of 14 cells tesed with Ac‐LHRH5‐10). The results demonstrate a large projection from the septal area to the amygdala, one component of which is altered by estrogen priming. The findings suggest that LHRH released from septal neurons may act as a neurotransmitter and a neuromodulator in the medial amygdala; however, the large number of neurons unaffected by the decapeptide indicates that the role of LHRH at this synapse is subservient to that of another tranmitter (s).
Identification of a subpopulation of neuropeptide Y‐containing locus coeruleus neurons that project to the entorhinal cortex
Authors: Wilcox Barbara J. , Unnerstall James R.
Published: January 2005

A Fundamental question important to the undersanding of the neuro‐chemical organization of the central nervous system focuses on the relationships between the differential phenotypic expression of multiple neurotransmitter markers in individual neuronal populations and the factors that regulate their expression. The first approach in studying this phenomenon is the determination of specifcic relationships between neuro‐chemically distinct neuronal subpopulations and their efferent targets. The pontine nucleus locus coeruleus (LC) provides a useful model for adressing this question since the projections of LC neurons are topographically organized and several neuropeptides are expressed along with noradrenergic markers in subsets of these neurons. In these studies, we have focused on defining the efferent targets of LC neurons that contain neuropeptide tyrosine (NPY)‐like immunoreactivity. The has been accomplished by injecting the retrograde fluorescent tracer fluorogold into specifec cortical and hippocampal targets in adult rats and identifying the proportion of retrogradely labeled LC neurons that are positive for NPY‐like immunoreactivity. In agreement with other investgators, no preferential cortical projections of NPY‐positive LC neurons were observed. However, when fluorogold injections included or were limited to the entorhinal cortex, a discrete cluster of round or ovoid neurons in the dorsomedial portion of the LC approximately 9.8 mm posterior to bregma were found to contain NPY‐like immunoreactivity. This observation demonstrates that some topographic organization of NPY‐containing LC neurons does exist. In fact, these data indicate that morphologic and topographic organisation exists even within neurochemically distinct subsets of neuronal populations.
Effect of short‐term serotonin depletion on the efficacy of serotonin neurotransmission: Electrophysiological Studies in the Rat central Nervous System
Authors: Chaput Yves , Lesieur Philippe , de Montigny Claude
Published: January 2005

The effects of short‐term serotonin (5‐HT) depletion by p‐chlorophenylalanine (PCPA) on the firing activity of dorsal raphe nucleus 5‐HT neurons, on the responsiveness of dorsal hippocampus pyramidal neurons to microiontophoretically applied 5‐HT and on the efficacy of the electrical stimulation of the ascending 5‐HT pathway in suppressing the firing activity of CA3 dorsal hippocampus pyramidal neurons were assessed in chloral hydrate‐anesthetized rats. PCPA (250 mg/kg/day i.p. for 2 days) reduced the 5‐HT content of the dorsal hippocampus by 90%. However, the number of spontaneously active 5‐HT neurons per microelectrode trajectory through the dorsal raphe or their average rate of firing was unaltered. The effect of afferent 5‐HT pathway stimulation was reduced in only 40% of treated rats, whereas the sensitivity of CA3 pyramidal neurons to microiontophoretic 5‐HT was not modified. The function of the terminal 5‐HT autoreceptor was assessed using methiothepin, an autoreceptor antagonist. Methiothepin (1 mg/kg, i.v.) significantly enhanced the efficacy of the stimulation in PCPA‐treated rats, although the degree of enhancement was much less than in controls. A greater reduction of the effectiveness of the stimulaiton was obtained by increasing the dose of PCPA (350 mg/kg/day i.p. for 2 days). This regimen reduced the 5‐HT content of the dorsal hippocampus by 95%. In these rats, the sensitivity of the terminal 5‐HT autoreceptor was assessed by increasing the frequency of the stimulation from 1 to 5 Hz. This procedure reduced to a similar extent the efficacy of the stimulation in treated and control rats, suggesting that the reduced effectiveness of the stimulation in treated and control rats, suggesting that the reduced effectiveness of methiothepin in enhancing 5‐HT synaptic transmission in PCPA‐treated rats is due to a lower degree of activation of the terminal 5‐HT autoreceptor. The present results showing that the 350 mg/kg/day regimen of PCPA, but not the 250 mg/kg/day regimen, reduced the efficacy of the stimulation of the ascending 5‐HT pathway suggest that a greater than 90% depletion is required to affect 5‐HT neurotransmission significantly. The reduced level of activation of terminal 5‐HT autoreceptors in rats treated with the lower dose of PCPA may facilitate the release of the remaining 5‐HT per stimulation‐triggered action potential, ensuring a virtually unaltered synaptic efficacy.
Tyrosine hydroxylase and galanin mRNA levels in locus coeruleus neurons are increased following reserpine administration
Authors: Austin Mark C. , Cottingham Sandra L. , Paul Steven M. , Crawley Jacqueline N.
Published: January 2005

The neuropeptide galanin coexists in 80–90% of the norepinephrine‐containing neurons in the locus coeruleus. In situ hybridization histochemistry was used to examine the effects of reserpine treatment or swim stress on tyrosine hydroxylase and galanin mRNA concentrations in locus coeruleus neurons. Reserpine administration significantly increased tyrosine hydroxylae and galanin mRNA levels in the locus coeruleus. The reserpine‐induced increase in tyrosine hydroxylase mRNA was significantly correlated with the reserpine‐induced increase in galanin mRNA. Three consecutive days of swim stress did not significantly alter either tyrosine hydroxylase or galanin mRNA concentration in the locus coeruleus. These data suggest that both tyrosine hydroxylase and galanin gene expression in locus coeruleus neurons may be regulated by a reserpine‐sensitive mechanism.
Transduction of the modulatory effect of catecholamines at the mammalian motor neuron terminal
Authors: Chen Hsinyo , Dryden William F. , Singh Yadhu N.
Published: January 2005

MEPP frequency (f) was measured in mouse phrenic nerve hemidialphragm preprations during exposure to adrenoceptor agonist and antagonist drugs. Epinehprine, norepinephrine (NE), and phenylephrine caused a concentration‐dependent increase in frequency that was blocked by prazosin but yohimbine or nadolol. Isoproterenol had no effect on MEPP(f). The response to NE was not affected by prior incubatin of the tissues with pretussis toxin. The response was, however, reduced or abolished by prior exposure to drugs, the actions of which include protein kinase inhibition, and also to a calmodulin inhibitory concentration of W‐7. H‐7, an inhibitor of protein kinase C and of cyclic nucleotide‐dependent kinases, was ineffective. The response to NE was enahanced by 10 mM Li+. The data indicate the existence of a presynaptic α1‐adrenoceptor in the motor neuron terminal and suggest that modulation of transmitter release might be mediated by inositol triphosphate liberation, Ca2+ release into the cytosol and activation of a clamodulin‐dependent system.
The contribution of endogenous benzodiazepine receptor ligands to the pathogenesis of hepatic encephalopathy
Authors: Basile Anthony S.
Published: January 2005

The involment of the γ‐aminobutyric acidA (GABAA) receptor complex in the pathogenesis of hepatic encephalopathy (HE) was examined in galactosaminetreated rabbits with HE caused by fulminant hepatic failure. Radioligand binding to the constituent components of the GABAA receptor complex was unchanged in rabbits with HE. However, Partially purified extracts from encephalopathic rabbit brain were approximately three times more potent in inhibiting [3H] Ro 15‐1788 binding to benzodiazepine (BZ) receptors than extracts from control rabbits. The inhibition of radioligand binding to the BZ receptor produced by these extracts was competitive and reversible and was significantly enhanced by GABA. Further purification of these extracts by high‐performance liquid chromatography (HPLC) indicated that the inhibitory activity was localized in several peaks, some of which has retention times corresponding to 1,4‐benzodiazepine standards. The presence of diazepam in these extracts was confirmed using mass spectroscopy. Both mass spectoroscopic and radiametric techniques demonstrated that the concentration of diazepam in brain exstracts from encephalopathic rabbits was approximately 4 time greater than control extracts. These findings link the presence of BZ receptor agonists to the development of a neuropathological condition, therby providing a rational basis for the use of BZ receptor antagonists in the management of HE in man.