bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopamine receptors and the dopamine hypothesis of schizophrenia
Authors: Seeman Philip 
Published: December 2004

AbstractThe discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked “monoamine receptors” or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)‐butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]‐dopamine or [3H]‐haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase).Based on the fact that dopamine‐mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2‐selective blockade by all neuroleptics (except the monoamine‐depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug‐naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low‐affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.
Comparative immunohistochemical demonstration of peptide F‐ and other enkephalin‐containing neurons in the enteric nervous system of the rat
Authors: Wang Yen‐Nung , Wyatt Richard Jed 
Published: December 2004

AbstractThe immunohistochemical localization of peptide F and the related enkephalins met5‐enkephalin (met‐enk), leu5‐enkephalin (leu‐enk), met5‐enkephalin‐arg6‐Phe7(met‐enk‐arg‐phe); and met5‐enkephalin‐arg6‐gly7‐leg8 (met‐enk‐arg‐gly‐leu) was in vestigated by means of the indirect immunofluorescence technique in the enteric nervous system of the rat. Peptide F‐like immunoreactivity was widely distributed within neuronal structures throughout the gastrointestinal (GI) tract of the rat. Peptide F‐containing nerve cell bodies were meinly located in the myenteric plexus, and only rarely were seen in the submucosal plexus. Peptide F‐immunoreactive nerve fibers were principally present in the myenteric plexus and circular muscle layer; few were found in the submucosal plexus, longitudinal muscle layer, muscularis mucosa, and mucosa. No peptide F‐containing fibers were found associated with blood vessels in the gut. By comparing the distribution of immunoreactive peptide F with other related enkephalins met‐enk, leu‐enk, metenk‐arg‐phe, and met‐enk‐arg‐gly‐leu, we observed that there was a remarkable similarity in the distribution of peptide F and the other enkephalins in the GI tract. These data, combined with our previous studies, indicate that peptide F may coexist with other related enkephalins in the same neurons of the enteric nervous system. The results suggest that peptide F, a product of the proenkephalin A gene, may play a physiological role within the enteric nervous system.
Effects of a behaviorally active LHRH fragment and septal area stimulation on the activity of mediobasal hypothalamic neurons
Authors: Dudley Carol A. , Moss Robert L. 
Published: December 2004

AbstractThe effect of Ac‐LHRH5–10, An LHRH fragment capable of facilitating lordosis, and LHRH on the firing rate of mediobasal hypothalamic neurons receiving input from the septal area, (a site containing the majority of LHRH perikarya) was studied via conventional extracellular recording techniques. A multibarrelled glass electrode assembly was lowered through the dorsomedial and ventromedial hypothalamus to detect single units responsive to septal area stimulation, and to iontophoretically apply Ac‐LHRH5–10 and LHRH. Ovariectomized rats were primed with estradiol benzoate (EB; n = 21) or left untreated (n = 34) to determine if the neuronal responsiveness to septal area stimulation and/or to the two peptides was subject to estrogenic modulation.Of the total number of 228 neurons recorded in the study, 51 units (22.4%) were orthodromically responsive to septal area stimulation. The orthodromic responses in EB‐primed animals (n = 20) were characterized by a short‐latency, short‐duration increase in membrane excitability. When spontaneous activity was sufficiently high, the excitatory response was followed by, or superimposed upon, an inhibitory response of longer duration. Similar orthodromic excitatory and inhibitory response characteristics were observed in 21 of the 31 neurons recorded in nonprimed animals. In the remaining ten neurons, however, the excitatory component was absent.Iontophoretic application of both Ac‐LHRH5–10 and LHRH was found to produce predominantly an inhibitory effect on cell firing. Most neurons responded to the two peptides in a similar manner (i.e., inhibited by both peptides, excited by both peptides, or not effected by either peptide). However, 39.5% of the neurons exhibited a different response to the two agents. Responsiveness to Ac‐LHRH5–10, but not to LHRH, was enhanced by estrogen priming. Iontophoretically applied Ac‐LHRH5–10, was found to mimic the inhibitory component of the orthodromic response in 21 of the 30 neurons tested. The same was true for LHRH in 15 of the 27 neurons tested.Taken together, these results indicate that the septal‐stimulation‐evoked inhibition of mediobasal hypothalamic neurons may be mediated by the LHRH fragment and/or LHRH and that this input is subject to estrogenic modulation. Furthermore, the results suggest that Ac‐LHRH5–10 may act to facilitate lordotic responding by inhibiting the firing rate of mediobasal hypothalamic neurons.
Specific antagonism of behavioral action of “uncommon” amino acids linked to motor‐system diseases
Authors: Ross Stephen M. , Spencer Peter S. 
Published: December 2004

AbstractBeta‐N‐methylamino‐L‐alanine (BMAA) and beta‐N‐oxalylamino‐L‐alanine (BOAA) are chemically related amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA; a form of primary lateral sclerosis). A single large dose of BOAA or BMAA causes seizures in newborn mice and postsynaptic neuronal edema and degeneration in CNS explants. We report that the acute neurotoxic actions of these amino acids are blocked selectively by specific glutamate‐receptor antagonists (administered intracerebroventricularly) (i.c.v.) prior to the amino acid. Administration of BOAA i.c.v. to neonatal mice (ED100 = 50 μg) elicits a spectrum of time‐dependent behavioral states including arm and leg rigidity, convulsions, and resting tremor. These are blocked in a dose‐dependent manner by cis‐2,3‐piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)‐preferring (A2) and kainate (KA)‐preferring (A3) glutamate receptors (ED50s; 2.8 μg, rigidity; 1.4 μg, convulsions; 2.4 μg, resting tremor). BMAA induces a transitory hyperexcitable state followed by a long‐lasting whole‐body shake/wobble (ED100 = 1,000 μg, i.c.v.). These responses are antagonized selectively and dose‐dependently by 2‐amino‐7‐phosphonoheptanoic acid (AP7), an N‐methyl‐D‐aspartate (NMDA) or A1 glutamate‐receptor antagonist (ED50 = 0.45 μg). Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate‐receptor species. BMAA likely exerts most of its action indirectly via the A1 glutamate receptor, while BOAA acts principally at the A2 and/or A3 receptor.
Release‐regulating GABAA receptors are present on noradrenergic nerve terminals in selective areas of the rat brain
Authors: Bonanno G. , Raiteri M. 
Published: December 2004

AbstractThe effects of γ‐aminobutyric acid (GABA) on the spontaneous release of [3H]‐norepinephrine ([3H]‐NE) were investigated by means of superfused synaptosomes prepared from different areas of the rat brain and prelabeled with [3H]‐NE. GABA increased in a concentration‐dependent way (1–300 μM) the release of [3H]‐NE in hippocampal synaptosomes. The effect of GABA was mimicked in part by muscimol. Similar effects were observed in cerebral cortex synaptosomes where GABA and muscimol were however less potent than in hippocampus. No effect could be observed in hypothalamic synaptosomes. Bicuculline antagonized the effect of muscimol and that of low concentrations of GABA (below 10 μM). Above 10 μM, the [3H]‐NE releasing effects of GABA became progressively less sensitive to bicuculline. (−)‐Baclofen did not affect the spontaneous release of [3H]‐NE. It is concluded that release‐regulating receptors of the GABAA subtype are present on NE nerve terminals in selective areas of the rat brain.
Sexual dimorphism in the synaptogenic effect of estradiol in prepuberal female rats
Authors: Rodriguez‐Sierra J. F. , Clough R. W. 
Published: December 2004

AbstractA study has been made of the effects of estradiol benzoate (EB) on synaptogenic induction in the hypothalamic arcuate nucleus (ARC), medial preoptic area (MPOA), and medial septal area (MSA) of prepuberal male and female rats. Subcutaneous administration of EB to 25‐day‐old female rats induces accelerated synaptogenesis in the ARC concomitant with a precocious surge of plasma luteinizing hormone (LH) at 1600 h on day 27 of age. The synaptic area densities (No. synapses/unit area of tissue section) of the MPOA and MSA are not increased at 27 days of age in rats treated with EB on day 25 of age. The synaptic area densities of the ARC, MPOA, and MSA are significantly higher on day 31 compared to day 27. However, only the ARC exhibits a further increase of synaptic numbers in EB‐treated female rats. Similar estrogen treatment to prepuberal male rats induces neither an LH surge in plasma nor increased synaptogenesis in the ARC, MPOA, or MSA. Male 27‐day‐old rats of both estrogen‐treated and control groups exhibit a synaptic area density in the ARC similar to 27‐day‐old control female rats. These data indicate that the sexually dimorphic positive response to estrogen with LH secretion has an equally sexually dimorphic neuromorphological response in rats. In addition, the synaptogenic effect of EB in the prepuberal female rat ARC remains manifest for at least 6 days after estrogen treatment.
Induction of hippocampal long‐term potentiation in the absence of extracellular Ca2+
Authors: May P. B. Y. , Goh J. W. , Sastry B. R. 
Published: December 2004

AbstractExtracellular Ca2+, synaptic transmission, and the activation of subsynaptic receptors are not required for the induction of long‐term potentiation of excitatory synaptic transmission at stratum radiatum‐‐CA1 neuron junctions as long as sufficient depolarizations of the presynaptic terminals and the postsynaptic neurons co‐occur.
Retinal neurons lack an acetylcholine receptor aggregating factor
Authors: Thompson Jeffrey M. , Rapoport Stanley I. 
Published: December 2004

AbstractSpinal cord neurons form stable synapses on muscle cells in culture, whereas retinal neurons, an inappropriate presynaptic partner for muscle cells, form synapses that are transient. We have hypothesized that a trophic influence of neurons on muscle is involved in the stabilization of synapses. Because other neural tissues that form stable synapses on muscle cells contain factors that aggregate acetylcholine receptors (AChR) into clusters on the surface of muscle cells. It may be that these aggregation factors are necessary for stabilization of neuron‐muscle synapses. Therefore, we determined the AChR‐aggregating activity of retinal neurons. The results showed that cocultures of retinal neurons and muscle cells and retinal‐conditioned medium do not show increases in the number of AChR on muscle cells. Conversely, spinal cord‐muscle cocultures and spinal cord‐conditioned medium produce increases in the number of AChR clusters. These data, along with previous studies demonstrating that retinal neurons are unable to affect the electrical membrane properties of cultured muscle cells, whereas spinal cord neurons do elicit such changes, add support to the above hypothesis of a trophic influence of neurons in synapse stabilization.
Central and peripheral effects of iminodipropionitrile on catecholamine metabolism in rats
Authors: Cadet J. L. , Karoum F. 
Published: December 2004

AbstractChronic treatment with iminodipropionitrile (IDPN) causes a behavioral syndrome characterized by lateral and vertical neck dyskinesias, hyperactivity, random circling, and increased startle response (the “ECC syndrome”). The effects of the neurotoxin on norepinephrine (NE), dopamine (DA), and their metabolites were evaluated in the hypothalamus and the striatum of IDPN‐treated animals. Urinary excretion of the amines was also measured. There was no significant persistent change in central metabolism of dopamine. There was a transient increase in NE metabolism in the hypothalamus after the third injection of IDPN that lasted until the development of the syndrome at 7 days of drug treatment. Urinary excretion of NE and its metabolites was increased on the day that the syndrome developed. Urinary excretion of homovanillic acid was persistently decreased throughout and after cessation of drug treatment. There was no change in the excretion of either dopamine or dihydroxyphenyl acetic acid. The ratio of total NE/total DA excreted by IDPN‐treated rats was the inverse of that of control animals. These results suggest that persistent dyskinesias may be associated with a relative increase in facilitatory NE‐dependent mechanisms at the cortical, subcortical, or spinal cord level.
Organization of glutamate‐like immunoreactivity in the rat superficial dorsal horn: Light and electron microscopic observations
Authors: Miller Kenneth E. , Clements Jane R. , Larson Alice A. , Beitz Alvin J. 
Published: December 2004

AbstractGlutamate has been shown to be a neurotransmitter in the central nervous system of vertebrates, and it has been hypothesized that glutamate is functional as a neurotransmitter in the spinal cord dorsal horn. A monoclonal antibody to fixativemodified glutamate was used in this study to examine the light microscopic and ultrastructural profiles of glutamate‐like immunoreactivity in the superficial dorsal horn of the rat spinal cord. Glutamate‐like immunoreactivity was observed in neurons, fibers, and terminals of both laminae I and II. Marginal zone immunoreactive neurons ranged from 10 to 30 μm in diameter and received many nonimmunoreactive somatic synapses. In substantia gelatinosa, immunoreactive neurons were observed in both inner and outer layers, ranged 5 to 10 μm in diameter, and received few nonimmunoreactive somatic synapses. Glutamate‐like immunoreactive dendrites were observed in both laminae and were contacted primarily by nonimmunoreactive synaptic terminals that generally contained small clear vesicles. Both myelinated and unmyelinated immunoreactive axons were observed in Lissauer's tract. Immunoreactive terminals contained small (40 nm) clear vesicles and generally formed simple synaptic contacts with nonimmunoreactive dendrites in laminae I and II. The results of this study corroborate the importance of glutamate as a neurotransmitter in spinal sensory mechanisms.
Muscarinic agonists modulate spontaneous and evoked unit discharge in auditory cortex of cat
Authors: McKenna Thomas M. , Ashe John H. , Hui Gabriel K. , Weinberger Norman M. 
Published: December 2004

AbstractThe present experiments studied the effects of cholinergic agonists and antagonists on the spontaneous and acoustic‐evoked discharge of auditory cortical neurons and examined whether these effects were mediated by muscarinic cholinergic receptors. A primary focus of this report is the analysis of specific effects of these agents on the spontaneous and tone‐evoked discharge and on different temporal components of the evoked discharge. Single neurons were recorded in the auditory cortex of chronically prepared, awake cats with multibarrel micropipette electrodes. The responses to acoustic stimuli were obtained before, during, and following continuous ejection of cholinergic agonist or antagonists by micropressure. The mean rate of discharge of the neurons was analyzed quantitatively for spontaneous discharge and for different peaks of the tone‐evoked PSTH corresponding to tone “on,” “through,” and “off” responses. Acetylcholine (ACh) and acetyl‐β‐methacholine (MCh) produced significant effects on spontaneous activity in 72% and 68% of neurons tested, respectively. Tone‐evoked responses were effected in 92% and 82% of cells tested, respectively. The ability of these agonists to modify spontaneous or evoked activity was dose‐dependent. Agonist effects on spontaneous and evoked activity were often different in the same cell; however, effects on spontaneous activity did predict effects on “through” responses. The most common effect of ACh or MCh on evoked activity was facilitation of the tone “on” responses. For neurons with multicomponent discharge patterns in response to tones, the agonists had nonuniform effects on different response components. However, the effects of ACh on the “on” and “off” responses covaried. Hence cholinergic agonists produce heterogenous, selective effects on different components of the responses of auditory cortical neurons rather than simple increases or decreases in discharge level. The effects of cholinergic agonists were modified in the presence of atropine. The effects of MCh were blocked by atropine in a higher proportion of cases than those of ACh.
Dendritic development and preferential growth into synaptogenic fields: A quantitative study of Golgi‐impregnated spinal motor neurons
Authors: Vaughn James E. , Barber Robert P. , Sims Terry J. 
Published: December 2004

AbstractBranching patterns of dendrites may be modulated by the way in which dendritic growth cone filopodia come into initial synaptic relationships with afferent axons. This synaptotropic hypothesis of dendritic branching predicts that dendritic growth will be directed preferentially into regions containing numerous prospective presynaptic elements. The developing mouse spinal cord provides a natural experiment to test this prediction, because synapses are found exclusively within the marginal zones bordering the motor columns during the early (E11–14) period of synaptogenesis. During this time, therefore, most motor dendritic growth would be expected to be directed laterally or ventrally into the marginal zones, whereas internally directed growth should become more prevalent later, when synaptogenesis begins to take place within the intermediate zone, i.e., the motor columns proper. A computer‐assisted three dimensional reconstruction system has been used to test these expectations in Golgi preparations of developing mouse (C57BL/6J) spinal cords ranging in age from E13 through P1. Mean dendritic lengths and branch densities are significantly greater for marginal zone dendrites than for intermediate zone dendrites at early ages (E13–14), but there are no significant differences in these measures at later stages of development (PO,1). These findings are interpreted as meaning that motor dendritic growth is initially biased into the marginal zone by synaptogenic afferents and that this oreferential distribution is progressively lost as synapses develop within the intermediate zone to attract or to stabilize internally directed dendritic growth. Thus the findings of this study are consistent with predictions of the synaptotropic hypothesis of dendritic branching.
The ultrastructural localization of calcium‐activated protease “calpain” in rat brain
Authors: Perlmutter Lynn S. , Siman Robert , Gall Christine , Seubert Peter , Baudry Michel , Lynch Gary 
Published: December 2004

AbstractCalpain I, a calcium‐activated neutral protease which degrades a number of cytoskeletal proteins, has been implicated in the rapid turnover of structural proteins that may participate in synaptic plasticity. In the present study, an antibody raised against purified erythrocyte calpain I was biochemically characterized and demonstrated to specifically bind the Mr=80,000 subunit of both rat erythrocyte and brain calpain I. This antibody was used to examine the cellular distribution of calpain I at the electron microscopic level in rat brain and spinal cord using the avidin‐biotin immunocytochemical technique. Reaction product was observed throughout neuronal perikarya, within both axonal and dendritic processes, and within spine heads and necks. Postsynaptic densities in both shaft and spine synapses were also immunoreactive. Glial cell bodies and processes were densely stained. In both neurons and glia, the reaction product was deposited along cytoskeletal elements. The localization of calpain I immunoreactivity to glial processes suggests this degradative enzyme may play a role in the glial hypertrophy and process retraction seen in brain. The presence of the enzyme in spines and postsynaptic densities is consistent with the hypothesis that it is involved in the turnover of synaptic cytoskeleton, thus providing a means through which transient physiological events effect lasting changes in the chemistry and morphology of spines.
A reevaluation of the mathematical models for simulating single‐channel and whole‐cell ionic currents
Authors: Millhauser Glenn L. , Oswald Robert E. 
Published: December 2004

AbstractWe have developed a technique that allows for the simulation of both single‐channel and whole cell ionic currents given any arbitrary first‐order kinetic scheme for the conformational states of an ion channel. The procedure is based on the solution of the master equation, which, in turn, is a general expression for a Markov process. The solution is expressed in terms of the eigenvalues and eigenvectors of the kinetic system and the system's deviation from equilibrium. Our derived expression provides a general recipe for the calculation of whole‐cell currents. By further manipulation of this expression, we show how conditional probabilities are derived that can be used for the simulation of single‐channel currents. We discuss computer implementation of the results so that complicated kinetic schemes can be solved numerically. Finally, we demonstrate the procedure by providing a worked example of a simple model of activation followed by inactivation.