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M A Edwards

Publications and source records attributed to M A Edwards.

At least 19 recordsLinked to original sources
PubMed1998

Modulation of the discriminative stimulus and rate-altering effects of cocaine by competitive and noncompetitive N-methyl-D-aspartate antagonists.

The purpose of this study was to determine the extent to which N-methyl-D-aspartic acid (NMDA) antagonists modified the discriminative stimulus effects of cocaine in rats trained to discriminate 5 mg/kg cocaine from vehicle on a fixed-ratio schedule of food presentation as well as the rate-altering effects of cocaine in rats maintained on a fixed-interval schedule of food presentation. NMDA-associated ion channel blockers (dizocilpine, phencyclidine, and magnesium chloride) and competitive NMDA antagonists (NPC 17742 and CGP 37849) displayed similar behavioral effects when administered alone: each drug engendered intermediate levels of cocaine-appropriate responses and rate-dependent effects on food-reinforced operant responding. Selected doses of dizocilpine, magnesium chloride, and phencyclidine given in combination with 1 mg/kg cocaine produced more cocaine-appropriate responses than this dose of cocaine alone. In addition, dizocilpine and magnesium chloride each attenuated the discriminative stimulus effects of higher doses of cocaine. The competitive NMDA antagonists did not appreciably modify the discriminative stimulus effects of any dose of cocaine. Under the fixed-interval schedule, each NMDA antagonist attenuated the effects of 3 mg/kg cocaine, which normally produced maximal increases in response rate. Attenuation of the rate-decreasing effects of the highest dose of cocaine (30 mg/kg) also were observed after pretreatment with dizocilpine and magnesium chloride. These findings demonstrated differences in the way that NMDA-associated ion channel blockers and competitive NMDA antagonists interact with cocaine, and suggest that some NMDA-associated ion channel blockers may either enhance or antagonize the effects of cocaine, depending on the dose and type of behavioral procedure.

2-Amino-5-phosphonovalerate↗
PubMed1997

Discriminative stimulus effects of magnesium chloride: substitution studies with monoamine uptake inhibitors and N-methyl-D-aspartate antagonists.

Previous studies suggest that magnesium chloride may have discriminative stimulus effects that partially overlap with those of noncompetitive N-methyl-D-aspartate antagonists as well as certain monoamine uptake inhibitors. In our study, rats were trained to discriminate 100 mg/kg magnesium chloride from saline and its discriminative stimulus effects were characterized with respect to N-methyl-D-aspartate receptor and monoamine transporter functions in substitution tests. The discriminative stimulus effects of magnesium chloride were acquired within a moderate number of training sessions and showed dose-related substitution after either subcutaneous (3-300 mg/kg) or intracerebroventricular (0.3-300 microg) administration. The intracerebroventricular administration of magnesium chloride was over 4000 times more potent than its s.c. administration. The monoamine uptake inhibitors cocaine, GBR 12909, talsupram and citalopram fully substituted (> or =90% magnesium-appropriate responses) for magnesium chloride in the majority of subjects tested and the group averages reached a maximum of 72 to 82% responses on the magnesium-appropriate lever. Based on relative potency analysis, the rank order of potency of these four drugs for producing magnesium-appropriate responses was talsupram = cocaine > citalopram = GBR 12909. The N-methyl-D-aspartate receptor antagonists dizocilpine, phencyclidine and NPC 17742 engendered maximum group averages of 49 to 65% responses on the magnesium-appropriate lever. The results suggest that the centrally mediated discriminative stimulus effects of magnesium chloride may be more directly related to interactions with monoamine neurotransmitter functions than to N-methyl-D-aspartate receptor blockade.

Amino Acids↗
PubMed1996

Efficacy of a therapeutic cocaine vaccine in rodent models.

Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.

Animals↗
PubMed1995

Effects of N-methyl-D-aspartate antagonists in rats discriminating different doses of cocaine: comparison with direct and indirect dopamine agonists.

Dose-response functions for selected N-methyl-D-aspartate (NMDA) antagonists and direct and indirect dopamine agonists were compared in rats trained to discriminate either a low (2 mg/kg) or a high (10 mg/kg) dose of cocaine from vehicle. The NMDA-associated ion channel blockers, dizocilpine, phencyclidine and MgCl2, substituted fully for cocaine (> or = 90% cocaine-appropriate responses) in the majority of subjects under the low-dose training condition, but showed little or no substitution for cocaine under the high-dose training condition. The competitive NMDA antagonist [2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid)] did not substitute for cocaine under either training condition. Cocaine, 1-(2-[bis(4-fluorophenyl)methoxyl)-4-(3-phenylpropyl)piperazine, (+)-amphetamine and the D1 receptor agonist SKF 77434 engendered full substitution for cocaine under both training conditions. Dose-response functions for all four drugs were displaced to the left and average ED50 values were reduced by 3-fold or more under the low-dose compared to the high-dose training condition. The nonselective DA receptor agonist (-)-apomorphine substituted substantially for cocaine only under the low-dose training condition, whereas the D2 receptor agonist (+)-4-propyl-9-hydroxynapthoxazine substituted similarly for cocaine under both training conditions. The results show that change in the training dose of cocaine can affect both the shape and position of the dose-response functions for representative NMDA-associated ion channel blockers and direct and indirect dopamine agonists. The findings further show that under low-dose training conditions, NMDA-associated ion channel blockers can engender cocaine-like stimulus effects comparable to those of direct and indirect dopamine agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Purkinje cell compartments in the reeler mutant mouse as revealed by Zebrin II and 90-acetylated glycolipid antigen expression.

The cerebellum is organized into a series of parasagittally aligned bands that may be revealed histologically in the adult mouse by largely complementary immunostaining of Purkinje cells sets with the monoclonal antibodies Zebrin II (ZII; antigen:aldolase C) and P-path (PP; antigen:90-acetyl glycolipids). We compared the normal staining pattern using these markers and an antibody to calbindin with that found in the reeler mutants (rl/rl), in which most Purkinje cell migration is halted beneath the cerebellar white matter. The results revealed that Purkinje cells in reeler mutants, despite their ectopic location in large subcortical masses, show a clear tendency to distribute into alternating zones that either stain for Zebrin II or for P-path, with variable transition zones of mixed labeling. However, the estimated number of zones was fewer than in the normal adult cortex: roughly 7-9 zones are revealed per side in the mutant compared with 14 major divisions in wild type mice. These results raise the possibility that neurons destined to express these markers are segregated during their migration and that the final phase of migration into the cortex might involve further splitting or interdigitation between cell sets expressing the two antigens.

Animals↗
PubMed1994

Effects of nervous mutation on Purkinje cell compartments defined by Zebrin II and 9-O-acetylated gangliosides expression.

The cerebellum is organized into a series of parasagittally aligned bands which are well delineated in the adult mouse by the largely complementary immunostaining of Purkinje cell groups with the monoclonal antibodies Zebrin II (ZII; antigen: aldolase C) and P-path (antigen: 9-O-acetyl gangliosides). We examined the effect of nervous mutation on compartmental organization using these markers and an antibody to calbindin. In nervous mutant, up to 90% of Purkinje cells die in late postnatal development. The size of the cerebellum is about half that of normal, and caudal lobules appear to decrease in size more than anterior ones. Surviving Purkinje cells corresponded to P-path positive ones that were concentrated in two bilateral bands in the vermis and in medial portions of the hemispheres. Only small numbers of ZII positive cells remained, confirming the report by Wassef et al. with Zebrin I antibody. They were primarily located in caudal lobules IX, X and a portion of lobule IV, paraflocculus and flocculus, and their immunoreactivity was weak compared to that of normal. ZII positive cells are dominant in these caudal lobules, while P-path positive cells dominate in rostral lobules in normal mice, and the similar tendency remains in mutant. Thus, the nervous gene action respects not only sagittal compartments delineated by two antibodies, but also rostro-caudal gradient. The cause of the dominant survival of P-path positive cells awaits future study.

Animals↗
PubMed1993

Immunocytochemical demonstration of early appearing astroglial structures that form boundaries and pathways along axon tracts in the fetal brain.

During normal development of the mammalian forebrain, the paired cerebral hemispheres are initially separated midsagittally by the connective tissue-filled longitudinal fissure. During subsequent stages, the hemispheres fuse as basal lamina is remodeled and fibroblasts are eliminated from the fissure to create new central nervous system (CNS) territory in the midline. Two axon pathways, the corpus callosum and dorsal callosal stria, eventually use this region as part of their pathway. In order to assess the possible role of glial cells in the fusion process and in the guidance of axons in this and several other areas of the forebrain, we have analyzed the developing brain in timed cat and mouse embryos with immunohistochemical and morphological techniques. With the use of astroglial-specific antibodies and electron microscopy, we have visualized two distinct, primitive astroglial structures associated with the cerebral midline, and seven more associated with other specific brain regions. The way in which one of these structures moves as a column along the hemispheric midline in synchrony with seam formation suggests the possibility that during morphogenesis of the telencephalon, astrocytes may aid in the fusion process. In addition, the compact assemblage, early appearance and location of this and the other glial structures in relation to well defined neuroanatomical landmarks or axon pathways suggest that they may transiently compartmentalize relatively large regions of the CNS and organize certain developing fiber systems by acting as guides or barriers at critical stages of ontogeny.

Animals↗
PubMed1991

Initial stages of retinofugal axon development in the hamster: evidence for two distinct modes of growth.

In order to characterize differences in growth patterns of axons as they elongate toward their targets and during the initial stages of terminal arbor formation within the targets, we examined the primary visual system of fetal and newborn hamsters using three morphological methods: the Cajal-deCastro reduced silver method, the rapid Golgi technique, and anterograde transport of HRP. Axons emerge from the retina between the 10th and 11th embryonic days (E10-E11). The front of retinal axons crosses the chiasm, extends over the primitive dorsal nucleus of the lateral geniculate body (LGBd) by E13, and advances to the back of the superior colliculus (SC) by E13.5-E14. The rate of axon growth during this advance is nearly 2 mm/day. Collateral sprouts appear on axons around E15.5. In the LGBd and SC, these sprouts arise from multiple sites along the parent axons. Only one or a few of the sprouts continue to grow and branch, while others are eliminated. The net rate of axon collateral advance in this second phase is an order of magnitude slower than during the stage of axon elongation. Thus, formation of CNS projections may involve two qualitatively distinct modes of axon growth. The arborization mode contrasts with the elongation mode by the presence of branching, a lack of fasciculation and a slower average rate of extension. The stereotypic direct advance of axons during elongation also differs from the remodelling which occurs during arborization. The delay between axon arrival at targets and onset of arborization could be a reflection of axons "waiting" for a maturational change to occur in the retina or in targets. Arborization in the LGBd and SC is initiated around the same time, implicating the former possibility. However, a slower differentiation of retinal arbors in the SC, in addition to morphological differences of arbors in the two structures, suggests that alterations in substrate factors also play a critical role in triggering the early stages of arbor formation.

Aging↗
PubMed1990

Organization of radial glia and related cells in the developing murine CNS. An analysis based upon a new monoclonal antibody marker.

A monoclonal antibody, RC1, has been generated which provides a selective and sensitive immunohistochemical marker of radial glial cells and related cell forms during development of the mouse CNS. Beginning on embryonic day E10, immunocytochemistry performed on cryostat sections stains throughout the CNS a subpopulation of cells in the ventricular zone with radial processes that terminate with endfeet at the pial surface. These processes become fasciculated and attain maximal densities by E12-14 in the spinal cord and lower brainstem and by E14-16 in the midbrain, cerebellum and forebrain. Fasciculation is especially prominent for a subclass of these cells at the midline of the brainstem and spinal cord. As nuclear and cortical structures develop, the trajectories of the radial fiber fascicles undergo systematic and region-specific distortions in their initially simple linear configuration, in the process maintaining a consistent spatial registration of germinal ventricular zones with distal sites of assembly of post-migratory neurons. In the late fetal period, radial glial progressively disappear and scattered immature astrocytes bearing multiple fine processes appear in most regions of the CNS. In the spinal cord, a transitional unipolar radial form is identified in the emerging ventral and lateral funiculi between E13 and E17. In the cerebellum, precursors to the unipolar Bergmann glial cell are identified by E15, and in the retina, precursors of the bipolar Müller cell are identified by E16. Postnatally, RC1-stained radial glia become sparse, and after one week, immunoreactive cells include only ependymal cells, hypothalamic tanycytes, Bergmann glia, Müller cells, a unipolar radial form in the dentate gyrus, and a subpopulation of white matter astrocytes. These results suggest that radial cells of astroglial lineage comprise a diverse set of cell classes which subserve multiple functions in the developing and adult brain.

Animals↗
PubMed1989

Early axonal differentiation in mouse CNS delineated by an antibody recognizing extracted neurofilaments.

A monoclonal antibody, C2, raised against chick embryo spinal cord, is shown by a solid phase immunoabsorbent assay to recognize a molecular species associated with neurofilaments extracted from adult mouse and rat brain. As immunoreactivity is lost following pre-treatment with alkaline phosphatase, the antibody probably recognizes a phosphorylated protein. Immunocytochemical staining in fetal mouse indicates that this antigen is expressed selectively in axons from the earliest stages of their development. Neuronal somata tend to show only weak immunoreactivity. The C2 antibody allowed visualization of the spatiotemporal pattern of axonal growth in the retina, neocortex and cerebellum with greater resolution than in previous light microscopic descriptions. The concept that the leading process of some classes of migratory neurons becomes transformed into an axon is supported by the expression of C2 immunoreactivity in radially ascending processes from principle neuron classes in the fetal retina and cerebellum.

Aging↗
PubMed1988

Identification of radial glial cells within the developing murine central nervous system: studies based upon a new immunohistochemical marker.

The monoclonal antibody RC2 was generated in mouse by conventional hybridoma methodology. The antigen recognized by RC2 is robust, allowing aldehyde fixation appropriate to high resolution light and electron microscopic analyses. From the neural tube stage of fetal development the antibody delineates throughout the central nervous system a subpopulation of neuroepithelial cells which have a radial bipolar morphology. A descending process extends to the ventricular margin, and an ascending process contacts the glial limiting membrane by one or more endfeet varicosities. The persistence of these cells through the neurogenetic period allows their identification as radial glial. From as early as E9-10 the fibers appear to be organized in simple straight fascicles. Later in fetal development these fascicles show marked region-specific transformations in density and trajectory, particularly in association with cerebral corticogenesis and with cerebellar and basal ganglia development. The bipolar forms continue to stain with RC2 until they disappear in the postnatal period. Concurrently with a progressive perinatal loss of stained bipolar radial glia, RC2 identifies multipolar cell forms at various levels of the brain wall, as consistent with the transformation of radial glia into astrocytes. RC2 also recognizes monopolar cell forms in the spinal cord and the cerebellum as early as E15, and in the dentate gyrus of the hippocampal formation from the day of birth. Monopolar forms in the cerebellum are inferred to be progenitors of Bergmann glia. Although Bergmann glia are known to persist in adult life, these cells do not stain with RC2 beyond the 2nd postnatal week. The robustness of the antigen recognized by RC2 makes this probe a valuable tool to study the morphological transformations of the bipolar radial glia during their mitotic turnover. It also provides a sensitive stain for the study of the organization and the histogenetic role of the overall radial fiber system.

Aging↗
PubMed1988

Mitotic cycling of radial glial cells of the fetal murine cerebral wall: a combined autoradiographic and immunohistochemical study.

Radial glial cells of the embryonic murine cerebral wall are selectively labeled by staining with antibody RC1. In order to study the mitotic cycling of these cells, we combined RC1 immunohistochemistry and autoradiographic analysis following [3H]thymidine injection at 1, 2, 6, 48 h prior to sacrifice. Many radial glial cells, i.e. RC1-positive cells, incorporate the DNA tracer and hence must be mitotically active. Other proliferative cells of the ventricular zone do not stain with RC1. With the transition from S to M phase, the nuclei of the radial glial cells participate in the interkinetic 'to-and-fro' nuclear translocation characteristic of the non-radial glial cells of the ventricular zone. The density of radioactive grains over nuclei of both RC1-positive and negative cells of the ventricular zone becomes similarly reduced in the 48 h following the [3H]thymidine incorporation. Thus, the subpopulation of radial glia with nuclei within the ventricular zone which have incorporated the DNA tracer does not appear to become arrested in a prolonged G1 phase. The results suggest that the ventricular zone includes at least two subpopulations of stem cells, neuronal and radial glial. Radial glial cells, i.e. RC1-positive cells, are inferred to serve initially as a progenitor population for new radial glial cells. Later in development, they probably become a source of other cells of astroglial lineage.

Animals↗
PubMed1987

Increased excretion of propan-1,3-diol and 3-hydroxypropionic acid apparently caused by abnormal bacterial metabolism in the gut.

Three patients who died in infancy showed an unusual urinary organic acid pattern with excessive excretion of 3-hydroxypropionic acid but none of the other metabolites normally associated with propionyl-CoA carboxylase deficiency. Propan-1,3-diol was present in the urine in all three cases. In the two patients examined propionyl-CoA carboxylase activity was not deficient in cultured skin fibroblasts. A fourth patient, also severely ill, showed similar urinary abnormalities. Feeding a medium-chain triglyceride-rich diet to this patient increased the ratio of 3-hydroxypropionic acid to propan-1,3-diol and resulted also in the appearance of malonic acid in the urine. These abnormal metabolites disappeared on the administration of neomycin and presumably were produced by gut bacteria.

Aging↗
PubMed1987

Anatomical demonstration of ocular segregation in the retinogeniculocortical pathway of the New World capuchin monkey (Cebus apella).

We describe the architecture of the dorsal lateral geniculate nucleus and primary visual cortex (striate cortex; area 17) of the New World capuchin monkey (Cebus apella) on the basis of the distribution of cell bodies and cytochrome oxidase histochemistry. Changes in staining for cytochrome oxidase following unilateral enucleation served to indicate the organization of the representation of the two eyes in the retinogeniculocortical pathway. The number and disposition of eye-specific layers within the lateral geniculate nucleus of Cebus are consistent with the common plan of geniculate organization in anthropoid primates, and the radial organization of area 17 fits the pattern common to New World squirrel and Old World macaque monkeys, including the presence of cytochrome-oxidase-rich zones in supragranular and deeper cortical layers (Horton: Philos. Trans. R. Soc. Lond. [Biol.] 304:199-253, '84). Our principal finding is that cytochrome oxidase histochemistry following unilateral eye removal unequivocally reveals ocular dominance columns in the striate cortex of Cebus. As in the macaque (Hubel: Nature 292:762-764, '82), ocular dominance columns extend through the thickness of cortex and blobs are centered on columns, but the array of columns viewed tangentially is less orderly or more mosaic than in the macaque, and there is apparently significant overlap between columns. The presence of well-defined ocular dominance columns in Cebus, as in Ateles (Florence, Conley, and Casagrande: J. Comp. Neurol. 243:234-248, '86) but not in other New World monkeys examined previously, emphasizes the phylogenetic lability of binocular segregation in the primate visual cortex. In addition, the present results indicate significant differences with respect to the tangential organization of the ocular dominance domain between primate species in which ocular dominance columns are present.

Animals↗
PubMed1986

Development of cell and fiber lamination in the mouse superior colliculus.

The emergence of laminar organization in the superior colliculus was investigated in the mouse with several anatomical methods, including tritiated-thymidine autoradiography, Golgi impregnation, and general stains for cell bodies and for fibers. The sequence of neurogenesis, cell migration, and early morphological differentiation of neurons was shown to exhibit a discontinuity between the lower and upper divisions (i.e., between the deep and intermediate "gray" and "white" layers and the superficial "gray" and "white" layers). These events proceed in an inside-out order within the lower division, but the same events within the upper division commence in advance of the completion of this progression. Thus, peak generation times for layers of the lower division proceed from (embryonic day) E11 to E13 and for the upper division from E12 to E13. Cell migration, as monitored with tritiated-thymidine labelling, reflects closely the pattern of cytogenesis. This is most clearly evident on E15 when a population of E11-labelled cells is divided into superficial and deep layers (the strata superficiale and profundum--SS and SP) by the interposition of E13-labelled cells at an intermediate level (stratum intermedium--SI). A contingent of the latter cells continue their migration and join their predecessors within the SS on E17, a time point when cell migrations are largely complete. Paralleling this sequence of arrival of neurons and the formation of three primary layers, both the time course of accumulation of fiber fascicles and the early morphological differentiation of neurons in the interval from E13 to E17 tends to proceed from SP to SS and from SS to SI. Thus, the transverse fiber system and large multipolar neurons of SP develop in advance of the longitudinal fiber system and vertically oriented neurons of SS, which in turn develop precociously with respect to the longitudinal fibers and medium-sized multipolar neurons of SI. In contrast, later events of differentiation that underly a major radial growth and an architectonic sublamination of the primary strata proceed in a simpler inside-out sequence from E17 to (postnatal day) P6. The major morphogenetic events underlying the establishment of statification in the colliculus appear to involve the operation of relatively independent programs of assembly for the two basic subdivisions. It is probable that selective cell-cell interactions contribute to the delivery of concurrently generated neurons to different laminae as well as to the deployment of axons in a manner that respects laminar boundaries.

Animals↗