bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAA‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits
Authors: Fritschy Jean‐Marc , Mohler Hanns
Published: January 2005

GABAA‐receptors display an extensive structural heterogeneity based on the differential assembly of a family of at least 15 subunits (α1–6, β1–3, γ1–3, θ, ρl–2) into distinct heteromeric receptor complexes. The subunit composition of receptor subtypes is expected to determine their physiological properties andipharmacological profiles, thereby contributing to flexibility in signal transduction and allosteric modulation. In heterologous expression systems, functional receptors require a combination of α‐, β‐, and γ‐subunit variants, the γ2‐subunit being essential to convey a classical benzodiazepine site to the receptor. The subunit composition and stoichiometry of native GABAA‐receptor subtypes remain unknown. The aim of this study was to identify immunohistochemically the main subunit combinations expressed in the adult rat brain and to allocate them to identified neurons. The regional and cellular distribution of seven major subunits (α1, α2, α3, α5, β2,3, γ2, δ) was visualized by immunoperoxidase staining with subunit‐specific antibodies (the β2‐ and β3‐subunits were covisualized with the monoclonal antibody bd‐17). Putative receptor subtypes were identified on the basis of colocalization of subunits within individual neurons, as analyzed by confocal laser microscopy in double‐ and triple‐immunofluoreseence staining expeximents. The results reveal an extraordinary heterogeneity in the distribution of GABAA‐receptor subunits, as evidenced by abrupt changes in immunoreactivity along well‐defined cytoarchitectonic boundaries and by pronounced differences in the cellular distribution of subunits among various types of neurons. Thus, functionally and morphologically diverse neurons were characterized by a distinct GABAA‐receptor subunit repertoire. The pultiple staining experiments identified 12 subunit combinations in defined neurons. The most prevalent combination was the triplet α1/β2,3/γ2, detected in numerous cell types throughout the brain. An additional subunit (α2, α3, or δ) sometimes was associated with this triplet, pointing to the existence of receptors containing four subunits. The triplets α2/β2,3/γ2, α3/β2,3/γ2, and α5/β2,3/γ2 were also identified in discrete cell populations. The prevalence of these seven combinations suggest that they represent major GABAA‐receptor subtypes. Five combinations also apparently lacked the β2,3‐subunits, including one devoid of γ2‐subunit (α1/α2/γ2, α2/γ2, α3/γ2, α2/α3/γ2, α2/α5/δ). These combinations were selectively associated with small neuron populations, thereby representing minor GABAA receptor subtypes. These results provide the basis for a functional analysis of GABAA‐receptor subtypes of known subunit composition and may open the way for unproved therapeutic approaches based on the development of subtype‐selective drugs. © 1995 Wiley‐Liss, Inc.
Compartmental organization of layer IVA in human primary visual cortex
Authors: Yoshioka Takashi , Hendry Stewart H. C.
Published: January 2005

Immunostaining for three neuronal proteins, nonphosphorylated neurofilament protein (with antibody SMI‐32), calbindin, and parvalbumin, was used to examine the organization of layer IV in human primary visual cortex (area 17 or V1) specifically to determine whether, similar to the case in macaque V1, layer IVA is present and is divided into neurochemically distinct compartments. All three proteins are expressed by neurons that are unevenly distributed in layer IV of human V1; immunostaining for each protein includes a thin band corresponding to layer IVA of classic cytoarchitectonic studies. In this band, nonphosphorylated neurofilament protein immunoreactivity is present in relatively broad clusters of pyramidal cell somata and dendrites that appear as upwardly protruding parts of intense immunostaining in layer IVB, whereas immunoreactivity for calbindin and parvalbumin exists in somata of nonpyramidal neurons and in thin, dense clusters of punctate profiles. In tangential sections through layer IVA, the three proteins are seen in distinct compartments. Calbindin‐ and parvalbumin‐immunostained neurons make up a thinly walled honeycomb or lattice, whereas neurons immunostained for nonphosphorylated neurofilament protein occupy the central lacunae. Direct comparison shows that neurons immunostained for calbindin occupy regions in layer IVA complementary to those immunostained for nonphosphorylated neurofilament protein. These data demonstrate a basic similarity in the organization of layer IV in macaques and humans. Layer IVA specifically is organized into complementary and neurochemically distinct compartments, including what appears to be a geniculocortically innervated and parvicellular‐driven lattice and the interstitial lacunae formed by the periodic, upward protrusion of magnocellular‐dominated layer IVB neurons. © 1995 Wiley‐Liss, Inc.
Complementary expression of parvalbumin and calbindin D‐28k delineates subdivisions of the rabbit medial geniculate body
Authors: de Venecia Ronald K. , Smelser Chad B. , Lossman Scott D. , McMullen Nathaniel T.
Published: January 2005

The complementary pattern of immunohistochemical staining for the calcium‐binding proteins parvalbumin (PV) and calbindin D‐28k (CB) was used to delineate four major subdivisions of the rabbit medial geniculate body (MGB). PV immunoreactivity predominates in the ventral and medial divisions, whereas CB‐immunoreactiv cells characterize the dorsal and internal divisions. The ventral nucleus is strongly PV+ due to dense neuropil labeling and moderately labeled somata. The medial nucleus contains both medium‐sized and large PV+ somata, as well as thick PV+ axons and terminals. The wedge‐shaped internal nucleus, composed of densely labeled CB+ cells, separates the dorsal and ventral nuclei rostrally, and expands caudally to encapsulate the posterior MGV. Large multipolar CB+ neurons with radiate dendrites characterize the dorsal nucleus. The differential expression of PV and CB also distinguishes the deep dorsal and superficial dorsal subnuclei in the dorsal division and a ventrolateral component in the ventral division. A comparison with studies of MGB connectivity in a variety of species suggests that PV immunoreactivity is highest in subdivisions that receive a substantial input from the central nucleus of the inferior colliculus and that project to primary auditory cortex. In contrast, CB immunoreactivity characterizes nuclei that receive input primarily from other sources, such as the paracentral nuclei of the inferior colliculus, the lateral tegmentum, and the spinal cord, and that project to secondary auditory areas. The ability of calcium‐binding protein immunohistochemistry to delineate neuronal compartments across indistinct cytoarchitectonic borders makes it a powerful tool for guiding future connectional and physiological studies of the MGB. © 1995 Wiley‐Liss, Inc.
Projections from the cochlear nucleus to the superior paraolivary nucleus in guinea pigs
Authors: Schofield Brett R.
Published: January 2005

Axonal tracing techniques were used to study the projection from the cochlear nucleus to the superior paraolivary nucleus in guinea pigs. Different tracers were used to identify the cell types that give rise to the projections, the morphology of their axons, and the cell types that they contact in the superior paraolivary nucleus. Injections of Fluoro‐Gold or peroxidase‐labeled WGA and HRP into the superior paraolivary nucleus labeled multipolar cells and octopus cells bilaterally in the ventral cochlear nucleus, mainly on the contralateral side. Injections of PHAL into the ventral cochlear nucleus labeled two types of axons in the superior paraolivary nucleus. Thin axons branch infrequently and give rise primarily to small, en passant boutons. Thick axons have larger boutons, many of which are terminal boutons that arise from short collaterals. Thin axons appear to originate from multipolar cells, whereas thick axons probably originate from octopus cells. Both types are found bilaterally after an injection into the ventral cochlear nucleus on one side. Individual thick or thin axons may contact multiple cell types in the superior paraolivary nucleus. Individual cells in the superior paraolivary nucleus can receive convergent input from both thick and thin axons. Combined anterograde and retrograde transport of different fluorescent tracers was used to identify the projections of the cells in the superior paraolivary nucleus that receive inputs from the ventral cochlear nucleus. Cells in the superior paraolivary nucleus that projected to the ipsilateral cochlear nucleus or to the ipsilateral inferior colliculus appeared to be contacted by axons that were labeled by anterograde transport from the contralateral ventral cochlear nucleus. Thus the projections to the superior paraolivary nucleus are in a position to affect the activity in both ascending and descending auditory pathways. © 1995 Wiley‐Liss, Inc.
An atlas of aromatase mRNA expression in the zebra finch brain
Authors: Shen P. , Schlinger B. A. , Campagnoni A. T. , Arnold A. P.
Published: January 2005

Neurol conversion of androgen to estrogen by aromatase is an important step in the development and expression of masculine behavior in mammals and birds. In contrast to the low telencephalic levels of aromatase in adult mammals and nonsongbirds, the zebra finch telencephalon possesses high arornatase activity. This study maps, by in situ hybridization, cells that express aromatase mRNA in the adult zebra finch telencephalon, diencephalon, midbrain, and pons. High aromatase mRNA expression was observed in the caudal neostriatum, limbic archistriatum, and hypothalamus. The hippocampus, parahippocampal area, and hyperstria turn accessorium contained cells expressing moderate amounts of aromatase message. Weakly labeled cells were found in the rostral neostriatum, lobus parolfactorius, and mesencephalic reticular formation. These findings are consistent with aromatase activity measurements of zebra finch tissue and document with anatomical precision both the widespread expression of aromatase mRNA in the brain and novel sites of brain aromatase. This study identifies the caudal neostriatum as a major site of telencephalic Aromatase. A previous survey (Gahr et al., 1993: J. Comp. Neurol. 327:112–122) of several avian species found that the presence of estrogen receptors in parts of the caudal neostriatum is unique to songbirds, which are the only birds to possess the elaborated telencephalic song system. Together, these findings suggest that the heightened estrogen synthesis and estrogen sensitivity of the passerine caudal neostriatum may have some functional relation with the telencephalic circuits responsible for song. © 1995 Wiley‐Liss, Inc.
Ontogeny of the striatal neurons expressing neuropeptide genes in the human fetus and neonate
Authors: Brana C. , Charron G. , Aubert I. , Carles D. , Martin‐Negrier M. L. , Trouette H. , Fournier M. C. , Vital C. , Bloch B.
Published: January 2005

The distribution patterns of neurons expressing mRNAs for four neuropeptides in the human striatum were studied during ontogeny by the use of in situ hybridization. The results of our study demonstrate that somatostain, enkephalin, dynorphin, and substance P mRNAs are present in striatal neuronal populations from week 12 of fetal life. Each neuronal population undergoes a specific differentiation. Neurons containing somatostatin mRNA are scattered throughout the caudate‐putamen up until birth. Neurons containing enkephalin, dynorphin, or substance P mRNAs evolve throughout fetal life in relation to caudate‐putamen and patch‐matrix compartmentalization. Neurons containing enkephalin mRNA (distinct from those containing substance P or dynorphin mRNAs) are present in the matrix from week 12 of fetal life. These neurons are preferentially distributed in the matrix and, at birth, display higher enkephalin mRNA content in the matrix than in the patches. Dynorphin mRNA is found in the caudate and putamen, preferentially in the patch neurons; nevertheless, a low level of dynorphin mRNA is also present in neurons of the caudate matrix. Substance P mRNA is initially restricted to caudate neurons. At birth, both substance P and dynorphin mRNAs are expressed at high levels in the patches. These results demonstrate that each neuropeptide gene is expressed during human fetal life in neurons with a specific topology and pace of development in relation to caudate‐putamen and patch‐matrix differentiation. These results also contribute evidence that neurochemical evolution of the striatal neuronal populations is not complete at birth in humans. © 1995 Wiley‐Liss, Inc.
Chemoarchitectonics and corticocortical terminations within the superior temporal sulcus of the rhesus monkey: Evidence for subdivisions of superior temporal polysensory cortex
Authors: Cusick C. G. , Seltzer B. , Cola M. , Griggs E.
Published: January 2005

Cortex of the upper bank of the superior temporal sulcus (STS) in macaque monkeys, termed the superior temporal polysensory (STP) region, corresponds largely to architectonic area TPO and is connectionally distinct from adjacent visual areas. To investigate whether or not the STP region contains separate subdivisions, immunostaining for parvalbumin and neurofilament protein (using the SMI‐32 antibody) was compared with patterns of corticocortical terminations in the STS. Chemoarchitectonic results provided evidence for three caudal‐to rostral subdivisions: TPOc, TPOi, and TPOr. Area TPOc was characterized by patchy staining for parvalbumin and SMI‐32 in cortical layers IV/III and III, respectively. Area TPOi had more uniform chemoarchitectonic staining, whereas area TPOr had a thicker layer IV than TPOi. The connectional results showed prefrontal cortex in the location of the frontal eye fields (area8) and dorsal area 46 projected in a columnar pattern to all cortical layers of area TPOc, to layer IV of TPOi, and in a columanr fashion, with a moderate increase in density in layer IV, to TPOr. In TPOc, columns of frontal connections showed a peridicity similar to that of the SMI‐32 staining. The caudal inferior parietal lobule (area 7a) and superior temporal gyrus projected to each subdivision of area TPO, displaying either panlaminar or fourth‐layer terminations. In addition to STP cortex, parvalbumin and SMI‐32 immunostaining allowed identification of caudal visual areas of the STS, including MT, MST, FST, and V4t. These areas received first and sixth‐layer projections from prefrontal cortex and area 7a. © 1995 Wiley‐Liss, Inc.
Development of parvalbumin immunoreactivity in the chick Edinger Westphal nucleus
Authors: Fujii Joanne T. , Lucaj Zef , Peduzzi Jean D. , Crossland William J.
Published: January 2005

To determine when the calcium‐binding protein parvalbumin appears during development, neurons in the chick Edinger Westphal nucleus were examined for parvalbumin immunoreactivity at a variety of embryonic stages. Parvalbumin immunoreactivity appeared on embryonic day 14 (E14, Hamburger and Hamilton stage 40) in predominantly lateral Edinger Westphal neurons.

Cytochrome oxidase activity within the nucleus was examined throughout development, as an indicator of physiological activity, and expression of cytochrome oxidase was compared with that of parvalbumin. Cytochrome oxidase activity was found to be uniformly high in all parts of the Edinger Westphal nucleus throughout development. Either the Edinger Westphal nucleus in physiologically active quite early in its development or other energy demands mask the correlation of cytochrome oxidase with electrical activity. Cytochrome oxidase was expressed well before parvalbumin immunoreactivity appeared.

Voltage‐activated calcium currents were characterized in E12 Edinger Westphal neurons. In both amplitude and composition, E12 calcium currents resemble those in E16 neurons, excluding the possibility that calcium currents appear de novo during or just prior to the appearance of parvalbumin.

Both cytochrome oxidase activity and calcum currents are observed in Edinger Westphal neurons well before the appearance of parvalbumin during development. These findings do not exclude the possibility that physiological activity affects the expression of parvalbumin since other factors such as changing patterns of synaptic activity or the appearance of calcium conducting NMDA receptors have yet to be examined. However, they raise the possibility that additional factors such as an intrinsic developmental program or a change in the neuron's basal intracellular calcium requirements may also be involved. © 1995 Wiley‐Liss, Inc.
Molecular basis of interactions between regenerating adult rat thalamic axons and Schwann cells in peripheral nerve grafts I. Neural cell adhesion molecules
Authors: Zhang Y. , Campbell G. , Anderson P. N. , Martini R. , Schachner M. , Lieberman A. R.
Published: January 2005

To gain insight into the possible molecular mechanisms underlying axonal regeneration of neurons of the adult central nervous system (CNS), we have investigated, by in situ hybridization and by immunocytochemistry, the localization and sites of synthesis of the neurite outgrowth‐promoting cell surface molecules Li, N‐CAM and its highly sialylated form, N‐CAM‐PSA, in and around peripheral nerve grafts implanted into the thalamus of adult rats. Normal unoperated adult rat thalamus contains N‐CAM and L1 but no N‐CAM‐PSA immunoreactive axons. Between 7 days and 13 weeks after graft implantation, L1, N‐CAM and N‐CAM‐PSA were all present at the surface of axonal sprouts in the brain parenchyma close to grafts and in the central parts of Schwann cell columns within grafts. Schwann cell membranes were L1 and N‐CAM positive at all postgraft survival times, more strongly at 2–4 weeks than other times, but were associated with N‐CAM‐PSA reaction product only where they abutted N‐CAM‐PSA positive axons. Schwann cell membranes apposed to basal laminae (which wereavoided by regenerating CNS axons) were L1, N‐CAM and N‐CAM‐PSA negative. Between 3 days and 8 weeks after grafting, N‐CAM and L1 mRNA were generally weakly upregulated in neurons of the ipsilateral thalamus, but, most conspicuously, L1 mRNA was strongly upregulated in the neurons of the thalamic reticular nucleus; these neurons are known to regenerate axons very effectively into peripheral nerve grafts and are the probable source of most of the axons which enter thalamic grafts. N‐CAM and L1 mRNA were also strongly upregulated in presumptive Schwann cells in the graft. These results show that regenerating CNS axons (re)express N‐CAM‐PSA and upregulate L1 and N‐CAM, suggesting that all of these molecules may play a role in cellular interactions during the regeneration of CNS axons. Furthermore L1 synthesis appears to be particularly well correlated with the ability of CNS neurons to regenerate axons into peripheral nerve grafts. © 1995 Wiley‐Liss, Inc.
Patchy and laminar terminations of medial geniculate axons in monkey auditory cortex
Authors: Hashikawa T. , Molinari M. , Rausell E. , Jones E. G.
Published: January 2005

The object of this study was to identify the terminal distributions of thalamocortical axons arising in chemically characterized subdivisions of the medial geriiculate complex. Large injections of wheat germ agglutinin‐conjugated horseradish peroxidase or small injections of Phaseolus vulgaris leucoagglutinin were made in the medial geniculate complex of Macaca fuscata. The terminal distributions of labeled axons in the cortex were correlated with auditory cortical fields demonstrable by different intensities of immunoreactivity for parvalbumin.

Fibers from the ventral nucleus terminated mainly in layer IV and deep portion of layer III (IIIB), with additional terminations in layers I‐IIIA and in layer VI. In layers IIIB‐IV, a major terminal plexus was formed by a small number of dense patches, 300–500 μm in diameter, surrounded by smaller satellite patches. The patches conformed to a similarly lobulated pattern of parvalbumin fiber immunoreactivity. Terminations of some individually labeled thalamocortical fibers were restricted to a single patch, whereas others innervated more than one patch by collateral branches. Fibers from the dorsal nuclei ending in areas of less dense parvalbumin immunoreactivity surrounding the primary auditory cortex formed much larger terminal patches centered largely in layer IIIB. Fibers from the magnocellular nucleus had relatively few terminal branches but innervated extremely wide areas by collaterals of single axons. Two types of axons arose from the magnocellular nucleus, one terminating preferentially in middle cortical layers and the other exclusively in layer I. These may arise respectively from parvalbumin‐ and calbindin‐immunoreactive cell populations in the magrnocellular nucleus. © Wiley‐Liss, Inc.
Developmental changes in calretinin expression in GABAergic and nonGABAergic neurons in monkey striate cortex
Authors: Yan Y.‐H. , Van Brederode J. F. M. , Hendrickson A. E.
Published: January 2005

The development of the calcium‐binding protein calretinin (CaR) and its co‐localization with GABA was studied in the striate cortex of Macaca monkeys from fetal day (Fd) 45 to adult. At Fd45, early neurons resembling Cajal‐Retizus cells are stained in the marginal zone (MZ). At Fd55 the MZ is filled with CaR+ Cajal‐Retzius cells and their processes, and scattered CaR+ cells are also found in deep cortical plate (CP), intermediate zone (IZ), and subventricular zone (SVZ). At Fd66, a band of CaR+ fibers appears in the IZ, corresponding to the location of the geniculocortical axons. This fiber band labels heavily until Fd130 but then ceases to be immunoreactive by postnatal (P) 16 weeks. At Fd85–101, the number of CaR+ cells in the CP, SVZ, and ventricular zone (VZ) reaches its highest cell density. After Fd130, CaR+ cells are concentrated in layer II and upper layer III, and this distribution changes little into adulthood. After mid‐gestation, there is a progressive loss of CaR+ cell bodies and processes in the MZ, and these are rare in the adult cortex. Just before birth, a weakly stained CaR+ cell band appears in layer NA at the border between layer NA and IVB, but this band disappears immediately after birth. Another CaR+ cell band appears transiently in upper layer V just below the border with layers IV at P6 months. These results suggest that CaR is expressed early in fetal development in the cell populations that are immunoreactive for CaR in the adult. However, developmental events related to cortical maturation during late prenatal and early postnatal stages result in transient expression of CaR in neurons that are not immunoreactive for CaR in the adult.

CaR‐immunoreactivity is colocalized with GABA in almost all CaR+ cells with the exception of Cajal‐Retzius cells in the MZ and some large cells observed at Fd70–101 in the VZ. The band of CaR+ fibers in the IZ is GABA‐. At Fd90, almost all (>96%) CaR+ cells are GABA+ in the CP and he first developed layers V/VI. This percentage declines later, so that on average 80% of CaR+ cells are GABA+ in adult cortex. At Fd135, 53% of GABA+ neurons located in layers II/III are CaR+; this percentage declines to 37% in the adult. These double‐label patterns suggest that early in fetal development the majority of GABA+ cells stain for CaR and that expres of CaR may be related to the migration of these neurons into the cortical plate, Once they attain their final position in the cortex many GABA+ cells loose CaR‐immunoreactivity, so that in postnatal life only a minority of GABA+ neurons contain this calcium‐binding protein. © 1995 Wiley‐Liss, Inc.
Axonal regeneration and limited functional recovery following hippocampal deafferentation
Authors: Eagle K. S. , Chalmers G. R. , Clary D. O. , Gage F. H.
Published: January 2005

Although central neurons do not naturally recover following injury, damaged adult septal neurons can regenerate when nerve growth factor (NGF) is provided along with a suitable cellular substrate. This study investigates the outgrowth of axotomized septal neurons grafted with primary fibroblasts genetically modified to produce NGF. Confocal microscope images of double staining for neuritic markers (neurofliament or low‐affinity NGF receptor) and the astrocytic marker glial fibrillary acidic protein (GFAP) demonstrated that regenerating neurites crossed dense buildups of astrocytic processes at the edges of NGF‐producing grafts and were in apposition with astrocytic processes within NGF‐producing grafts. Immunoreactivity for acetylcholinesterase and low‐(p75) and high‐affinity (TrkA) NGF receptors was dense in NGF‐producing grafts but absent in control grafts. NGF‐grafted rats exhibited significantly increased hippocampal density of p75‐immunoreactive fibers and significantly decreased ectopic hippocamoal sympathetic ingrowth as compared to control‐grafted rats. Rats with unilateral fimbria‐fornix lesions and NGF‐producing grafts exhibited ameliorated performance on a simple memory task. These findings demonstrate that implantation of NGFproducing grafts to the lesion cavity allows axotomized septal cholinergic neurons to reinnervate the hippocampus, and that rats receiving these grafts show a partial recovery of function. © 1995 Wiley‐Liss, Inc.
Topographical organization of the motoneuron pools that innervate the muscles of the pinna of the cat
Authors: Populin Luis C. , Yin Tom C. T.
Published: January 2005

The topographical organization of the 22 motoneuron pools that innervate the pinna muscles of the cat was examined by injecting the B‐subunit of cholera toxin conjugated to horseradish peroxidase into individual muscles. All 22 pools are found in the facial nucleus, organized as rostro‐caudally oriented columns, and arranged according to the action of the muscles they innervate. Pools innervating muscles that pull the pinna dorsally are located in the dorsal two thirds of the medio‐dorsal subdivision, and those innervating muscles that pull the pinna ventrally are located in the ventral one half of the nucleus. Motoneurons innervating muscles that pull the pinna cranially are located laterally, those that pull the pinna caudally are located medio‐ventrally, and those that change the shape of the pinna are located along the entire dorso‐ventral extent in the center of the medio‐dorsal subdivision. This topographical layout is consistent with the somatotopic organization of the entire facial nucleus as demonstrated in a variety of species. © 1995 Wiley‐Liss, Inc.
Sensory and premotor connections of the orbital and medial prefrontal cortex of macaque monkeys
Authors: Carmichael S. T. , Price Joseph L.
Published: January 2005

Sensory and premotor inputs to the orbital and medial prefrontal cortex (OMPFC) were studied with retrograde axonal tracers. Restricted areas of the lateral and posterior orbital cortex had specific connections with visual‐, somatosensory‐, olfactory‐, gustatory‐, and visceral‐related structures. More medial areas received few direct sensory inputs.

Within the lateral and posterior orbital cortex, area 121 received a substantial projection from visual areas in the inferior temporal cortex (TE). Area 12m received somatosensory input from face, digit, or forelimb regions in the opercular part of area 1–2, in area 7b, in the second somatosensory area (SII), and in the anterior infraparietal area (AIP). Areas 13m and 131 also received a projection from the opercular part of areas 1–2 and 3b. The posteromedial and lateral agranular insular areas (Iapm and Ial, respectively) received fibers from the ventral part of the parvicellular division of the ventroposterior medial nucleus of the thalamus (VPMpc) that may represent a visceral afferent system. The dorsal part of VPMpc projected to the adjacent gustatory cortex. These restricted inputs from several sensory modalities and the convergent corticocortical connections to orbital areas 13l and 13m suggest a network related to feeding.

The OMPFC was also connected to premotor cortex in ventral area 6 (areas 6va and 6vb), in cingulate area 24c, and probably in the supplementary eye field. Area 6va projected to area 12m, whereas a region of area 6vb projected to area 131. The region of the supplementary eye field projected to areas 121, 120, and 12r. Area lal received fibers from area 24c.

Lighter and more diffuse projections also reached wider areas of the OMPFC. For example, injections in several orbital areas labeled a few cells scattered through the anterior part of area TE and the superior temporalrus. There was also a projection to the intermediate agranular insular area (Iai) and to areas 13a and 12o from the apparently multimodal areas in the superior temporal sulcus and gyrus. © 1995 Wiley‐Liss, Inc.
Cellular expression of mRNAs encoding monoamine oxidases A and B in the rat central nervous system
Authors: Luque Juan M. , Kwan Sau‐Wah , Abell Creed W. , Prada Mosé Da , Richards J. Grayson
Published: January 2005

Monoamine oxidases A and B (MAO‐A and MAO‐B) oxidatively deaminate neurotransmitter and xenobiotic amines The cellular localization of these isoenzymes in the central nervous system (CNS) differs markedly and only partly reflects the distribution of their presumed natural substrates. In the present study, by using in situ hybridization with 35S‐labelled oligonucleotide probes, we examined the distribution of mRNAs encoding MAO‐A and MAO‐B in the rat CNS. Probes for tyrosine hydroxylase, histidine decarboxylase, and tryptophan hydroxylase mRNAs were used to demonstrate the catecholaminergic, histaminergic, or serotoninergic nature of some cell populations in adjacent sections. The radioligands [3H]‐Ro 41‐1049 and [3H]lazabemide (reversible and selective inhibitors of MAO‐A and MAO‐B, respectively) were used to reveal the protein distribution by enzyme radioautography. The distribution and abundance of transcripts for both isoenzymes in the tissues investigated differed markedly but, in general, correlated with the protein distribution. MAO‐A mRNA and protein were most abundant in noradrenergic neurons. However, moderate levels of transcript expression and protein were also detected in the serotoninergic neurons, and low but significant levels were detected in the dopaminergic neurons. An unexpectedly remarkable degree of hybridization signal was apparent in nonaminergic cell populations, e. g., in the cerebral cortices, the hippocampal formation (CA1–3, dentate gyrus), the cerebellar granule cell layer, and the spinal cord motoneurons. In contrast, MAO‐B mRNA and protein were most abundant in serotoninergic and histaminergic neurons, Bergmann glial cells, and circumventricular organs, including the ependyma. MAO‐B transcripts were also weakly expressed in nonaminergic cells, e. g., in the hippocampal formation (CA1‐2). A further nonneuronal localization of MAO‐B transcripts was also resolved, e. g., in the glia limitans, the olfactory nerve layer, and the cerebellar peduncle. These findings reveal further the potential of various cell populations to synthesize the isoenzymes, and homologous (aminergic) and heterologous (nonaminergic) patterns of expression as well as coexpression of MAO mRNAs are described. © 1995 Wiley‐Liss, Inc.
The number and size of the nerve fibers innervating the skin and muscles of the thigh in the frog (Rana virescens brachycephala, cope)
Authors: Dunn Elizabeth Hopkins
Published: January 2005

The innervation of the thigh in the American frog, Rana virescens, shows no marked variation from that of the European frog, Rana esculenta.

An enumeration of all the nerve fibers concerned in innervating the hind legs reveals only a slight numerical inequality for the two sides.

The nerve fibers concerned in the innervation of the skin and muscles of the thigh are more numerous and of greater average caliber than those innervating the remainder of the leg. Hence in the leg of the frog the fibers of greater diameter run the shorter course.

The nerve fibers to the muscles of the thigh surpass both in number and average diameter those which supply the skin of the thigh.

From the results of enumeration we conclude that of the fibers which innervate the thigh about 8% divide, one division passing in the main trunk of the sciatic nerve at least to the level S2 (Fig. II), distal to the last branch of the sciatic nerve. Direct observation reveals some large fibers dividing dichotomously where the branches from the sciatic to the thigh are given off. They are sufficient in number to render the explanation probably correct.

The cutaneous nerve fibers of the thigh bear to the cutaneous area which they supply a relation of one fiber to each 1.13‐1.58 square millimeter of this area.
Fabrication of polycrystalline LaAlO3 films on Si(100): An MOCVD application of the second‐generation La(hfa)3 · diglyme precursor
Authors: Malandrino Graziella , Frassica Amalia , Fragalà Ignazio L.
Published: December 2004

Communication: The integration of high Tc superconductors with silicon requires buffer layers, which can act as diffusion barriers. One suitable material is LaAlO3 and this paper reports on a simple, low cost technique for preparating buffer layers on Si(100) substrates by MOCVD with new lanthanum and aluminum precursors. This effects of deposition temperature with either a one‐step or two‐step process are investigated. Both methods produce polycrystalline, shiny thin films with good adhesion properties.
Enzyme inhibition as a source of new drugs
Authors: Kalman Thomas I.
Published: January 2005

The significance of enzymes as targets of drug action is discussed. New approaches to the rational design of enzyme inhibitors are characterized by a pronounced shift of emphasis toward the targets of drug action, as the structure and function of an increasing number of enzymes are described in great detail. The most promising of the recently developed approaches is the design of mechanism‐based enzyme inhibitors and, in particular, suicide inactivators. These require enzymic activation of “latent” functional groups to chemically reactive species. The various functionalities currently encountered are reviewed, grouped into chemical categories.

The various aspects of the selectivity and the specificity of mechanism‐based enzyme inhibitors, as well as the stability of drug‐enzyme complexes, are discussed in detail. Reversible covalent bond formation is demonstrated by the recovery of thymidylate synthetase activity after inactivation by various 5‐substituted pyrimidine analogs, using purified bacterial enzyme preparations or intact mammalian cells. The fragmentation and secondary reactions of the inhibitor within the complex are described using typical examples of the action of penicillin on its targets and clavulanate on /3‐lactamase, respectively.

The perspectives of enzyme inhibitory drug development are discussed, and some of the many areas currently undergoing rapid exploration are mentioned.

It is concluded that the rational design of enzyme inhibitors will play an ever‐increasing and significant role in new drug discovery and development.
Effect of a new eburnamenine derivative (RU 24722) on EEG recovery in the conscious gerbil after cerebral ischemia
Authors: Barzaghi Fernando , Dragonetti Marco , Robert Boissier Jacques
Published: January 2005

The efficacy of a new eburnamenine derivative (RU 24722) on cerebral insufficiency was studied by evaluation of postischemic EEG recovery in the conscious gerbil. Ischemias of different durations were obtained by clamping both common carotids. This method required only brief anesthesia, thereby permitting the recording of EEG recovery in unanesthetized and unrestrained animals during the 24 hr following arterial occlusion. The EEG was analyzed by the Fast Fourier Transform. Mortality rate and clinical status were also evaluated. After a 5‐min ischemia the initial return of EEG was characterized by very high amplitude slow waves (1–2 Hz) and the EEG became normal 24 hr after ischemia. No mortality was observed. After a 10‐min ischemia the early recovery phase was characterized by a decrease in the power spectrum and a rebound of slow frequency waves after 2–4 hr. After 24 hr the EEG was not yet completely normal and 1 animal out of 10 died. A 15‐min ischemia killed 50% of the animals, and the EEGs of the survivors were abnormal even after 24 hr. Treatment with RU 24722 (10 mg/kg/s.c.) significantly improved the electrocortical recovery of gerbils submitted to a 10‐min ischemia. In this group the EEG was normalized 6 hr after ischemia in the same way as in the controls submitted to a 5‐min ischemia. These findings suggest that RU 24722 may have a therapeutic effect in cerebral insufficiency.
An automated descending rate‐intensity self‐stimulation paradigm: Usefulness for distinguishing antidepressants from neuroleptics
Authors: Goldstein Jeffrey M. , Malick Jeffrey B.
Published: January 2005

Rats with medial forebrain bundle electrodes were trained to self‐stimulate during successive no‐cue periods in which the stimulating current remained constant for the first ten minutes and then decreased in small steps every two minutes for the next 30 minutes. Control response profiles generated in this manner were compared to drug dose‐response profiles. Tricyclic anti‐depressants (imipramine, amitriptyline) and neuroleptics (chlorpromazine, haloperidol) suppressed intracranial self‐stimulation (ICSS) responding in the fixed (F) and descending (DES) current periods. However, in combination with amphetamine, antidepressants potentiated amphetamine's effect in the DES periods only, whereas neuroleptics blocked amphetamine's effect in the DES periods. Both classes of drugs blocked amphetamine's effect in the F period. On the basis of these results, it is suggested that the ICSS model presented in this report can distinguish between antidepressant and neuroleptic drugs.
Influence of neuroleptics on pharmacokinetic parameters of amphetamine in rat after single and double injections
Authors: Shah Nandkumar S. , Shah Arunkumar B. , Patel V. O.
Published: January 2005

Sprague‐Dawley rats (90–100 g) were injected i.p. with saline, iprindole (10 mg/kg), clozapine (10 mg/kg), pimozide (10 mg/kg), or molindone (10 mg/kg), and 30 min later with dextro‐3H‐amphetamine (5 mg/kg). For two dose studies, a second injection of 3H‐amphetamine (5 mg/kg) was administered 3 hr after the first dose in saline or iprindole pretreated rats. In both studies, brain and hepatic levels of amphetamine paralleled the plasma levels, were highest at 1 hr in single dose and at 4 hr in two dose study, and thereafter, started declining. Iprindole markedly increased tissue amphetamine levels in single dose experiments and further raised and prolonged them up to 24 hr in two dose experiments. Both pimozide and molindone significantly enhanced amphetamine levels, and this effect lasted for 1 and 3 hr, respectively (single dose study); clozapine was ineffective. From the data, it appears that several chemically unrelated neuroleptics alter the distribution and elimination of amphetamine; such alterations need to be assessed in clinical situations, since neuroleptics are used in amphetamine intoxication.
Hypnotic benzodiazepines: Relationship between sleep parameters and pharmacokinetics of loprazolam
Authors: Krieger J. , Perianu M. , Bertagna C. , Mangin P. , Kurtz D.
Published: January 2005

In the search for a relationship between subjective and electrophysiologic sleep parameters and blood levels of loprazolam during night sleep after single and repeated administration, eight normal volunteers took loprazolam, a novel imidazo‐benzodiazepine, on eight consecutive evenings. The assessment of the pharmacokinetics of the drug was done by two different methods: a high‐pressure liquid chromatography‐gas chromatography (HPLC‐GC) measuring the parent drug specifically and a radioreceptor assay (RRA) measuring both the parent drug and the metabolites binding to the benzodiazepine‐receptor; the latter gave slightly higher values indicating the existence of metabolites binding to the benzodiazepine‐receptor. The elimination half‐life of the parent drug was about eight hr and did not significantly increase after repeated administration; the half‐life when using the RRA was some‐what longer since steady state was not reached until the fourth day. A relationship was looked for between pharmacokinetic data and either self‐evaluated or polygraphic sleep parameters obtained from all‐night recordings on the first and eighth treatment nights. No correspondence could be demonstrated, suggesting that the drug does not act directly on sleep systems and that its hypnotic effects may be indirect, secondary to anxiolytic effects or to deactivation of wake systems.
Effects of UP 614‐04, a potential antidepressant, on cerebral monoamine oxidase activity
Authors: Cloarec Alix , Chevalier Ghislaine , Delchambre Chantal , Tremblay Dominique
Published: January 2005

The effects of UP 614‐04, a potential antidepressant agent, and those of some known antidepressant agents on cerebral monoamine oxidase (MAO) activity were compared in rats and mice. Using ex vivo and in vitro techniques, it was shown that UP 614‐04, a viloxazine analogue, inhibited cerebral MAO activity in rats and mice ex vivo, but that it was not effective in vitro. Time‐course studies revealed that the action of UP 614‐04 was more sustained than that of viloxazine, but much less potent or sustained than those of pargyline or isocarboxazide. The effect of UP 614‐04 was not selective to the A or B forms of MAO.
Effect of 3‐PPP, a putative dopamine autoreceptor agonist, on [3H]ligand binding to dopamine receptors of calf and rat striatum
Authors: Wong David T. , Threlkeld Penny G. , Reid Leroy R.
Published: January 2005

3‐(3‐Hydroxyphenyl)‐N‐n‐propyliperidine (3‐PPP) is most effective in inhibiting [3H]apomorphine binding in rat striatal membranes, with Ki values of 63 nM. 3‐PPP was six to 27 times less effective when it competed with the binding of [3H]dopamine or [3H]spiperone in calf and rat striatal membranes. At concentrations up to 10 μM, 3‐PPP failed to substitute for dopamine in the activation of adenylate cyclase in rat striatal membranes. 3‐PPP at 4.8‐5 μM caused 50% inhibition of catecholamine uptake in synaptosomes of corpus striatum and hypothalamus, therefore appearing to be a relatively weak uptake inhibitor. The higher affinity of 3‐PPP for [3H]apomorphine binding sites is consistent with its binding to a subset of dopamine receptors which are characterized by a high affinity for both the agonist and antagonist of dopamine.
Perspectives on the in vitro evaluation of anti‐anaphylactic agents
Authors: Weinryb Ira , Coutts Stephen M. , Khandwala Atul S.
Published: January 2005

In vitro models of anaphylaxis such as the release of mediators from the mast cell can do more than identify compounds with intrinsic anti‐allergic activity; they have the potential for development of a detailed profile of activity that may be compared and contrasted in several ways to that of disodium cromoglycate. These parameters include effects upon (a) immunologic versus nonimmunologic release, (b) IgE‐ versus IgG‐provoked release, (c) timing of compound addition relative to challenge, (d) repeated administration (presence or absence of tachyphylaxis), (e) wash‐out of agent (reversibility), and (f) other granulocyte models relative to the mast cell. Use of in vitro models of anaphylaxis in this way allows an early judgment to be made about the extent to which a new compound presents a novel anti‐allergic profile.
A comparison of naloxone and naltrexone in laboratory tests predictive of antipsychotic potential
Authors: Malick Jeffrey B. , Herman Raymond L. , Goldstein Jeffrey M.
Published: January 2005

Naloxone and naltrexone were compared neuropharmacologically, especially in several rodent models considered to be predictive of antipsychotic activity, since narcotic antagonists have been reported to be effective in the treatment of schizophrenia. Naltrexone was found to be a potent antagonist of amphetamine‐induced aggregate toxicity in mice; this was in marked contrast to naloxone, which enhanced amphetamine's toxicity. Both naloxone and naltrexone exhibited an unusual profile of activity in the apomorphine‐induced stereotypy test in mice in that they antagonized the chewing behavior but failed to antagonize the rearing; this is in contrast to the activity of standard neurolepitcs (e.g., haloperidol, clozapine) which antagonize both behaviors induced by apomorphine. Neither of the narcotic antagonists exhibited any activity in several other tests predictive of antipsychotic activity. Naltrexone was a potent inhibitor of spontaneous locomotor activity in mice; naloxone, although much weaker, also antagonized motor activity. Thus, endorphins may play a role in the modulation of exploratory or locomotor activity. The marked difference in activity between the two antagonists in the amphetamine aggregate toxicity study may indicate a significant neuropharmacological difference between these agents; i.e., naltrexone may be much more than merely a more potent naloxone. Furthermore, naltrexone's potent activity as an antagonist of amphetamine‐induced aggregate toxicity in mice may be predictive of a better therapeutic effect in schizophrenia than has been observed with naloxone.
Some in vitro and in vivo studies of a new angiotensin I‐converting enzyme inhibitor [[S‐(R*), S*]‐1‐[(3‐acetylthio)‐3‐benzoyl‐2‐methylpropionyl]‐L‐proline] (CL 242,817) in comparison with captopril
Authors: Lai F. M. , Cervoni P. , Tanikella T. , Shepherd C. , Quirk G. , Herzlinger H. , Stubbs C. S.
Published: January 2005

Some in vitro and in vivo properties of CL 242,817, a new angiotensin l‐converting enzyme (ACE) inhibitor, were studied and compared to those of captopril. In vitro CL 242,817 effectively inhibited rabbit lung ACE (IC50 54.9 nM), angiotensin l (Al)‐induced contractions (IC50 0.82 μM), and potentiated bradykinin (BK)‐induced contractions (EC50 0.383μM) of the guinea pig ileum. In these systems, CL 242,817 was approximately 3.5, 27, and 96 times less effective than captopril, respectively. In vivo, equimolar oral doses of CL 242,817 (8.36 mg/kg) and captopril (5 mg/kg) were equieffective in inhibiting the pressor responses to intravenously (i.v.) administered angiotensin l (Al) in normotensive rats and dogs. Similar equimolar oral doses of CL 242,817 and captopril were also equieffective in potentiating the depressor responses to i.v. administered BK in the rat. In the anesthetized dog 30 min after dosing, captopril (0.5 mg/kg i.v.) produced significantly greater potentiation of the BK response than a similar dose of CL 242,817. A single 1 mg/kg i.v. dose of Cl 242,817 or captopril effectively lowered mean arterial blood pressure of the aortic‐coarcted hypertensive rat (AHR) and markedly inhibited serum ACE activity after 1 hr. Serum from AHR treated with CL 242,817 or captopril exhibited an apparent loss in ACE inhibition upon cold storage. However, the loss of inhibition of ACE activity was faster with captopril than with CL 242,817. Kinetic studies indicate that CL 242,817 is a pure competive inhibitor of ACE with an estimated Ki of 24.3 nM.
Effect of chronic antidepressant treatment on α2‐adrenoreceptors
Authors: Sethy Vimala H. , Carlsson Robert W. , Harris Douglas W.
Published: January 2005

The effect of chronic (7‐day) intravenous infusion of antidepressants and psychostimulants like cocaine and amphetamine on density of presynaptic α‐adrenergic receptors (α2‐receptors) in rat cerebral cortex and brainstem has been investigated in this study. Antidepressants, cocaine, and amphetamine had no significant effect on the density of α2‐receptors either in the cerebral cortex or brainstem. The results have been discussed with respect to the role of noradrenergic system in regulation of α2‐receptors.
Has thioridazine a role in the treatment of anxious depressed neurotic outpatients?
Authors: Becker Robert E.
Published: January 2005

A 4‐wk double‐blind comparison of amitriptyline vs. thioridazine was conducted in 54 anxious depressed patients. Both drugs showed essentially equal efficacy in relieving target symptoms. Thioridazine may have a clinical role in the treatment of anxious depressive symptoms in selected patients.