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PubMed2003

Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system.

Voltage-dependent K(+) channels play a pivotal role in controlling cellular excitability within the nervous system. The aim of the present study was to investigate the expression in the adult rat brain of the three ether-a-gogo-related gene (ERG) family members ERG1, ERG2, and ERG3, encoding for K(+) channel subunits. To this aim, the distribution of ERG transcripts was studied by means of reverse-transcription polymerase chain reaction (RT-PCR) and nonradioactive in situ hybridization histochemistry (NR-ISH). Furthermore, ERG1 subunit distribution was studied by immunohistochemical analysis. RT-PCR analysis revealed ERG1, ERG2, and ERG3 expression in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, and cerebellum. NR-ISH experiments detected transcripts encoded by all three ERG genes in the cerebral cortex and in all CA subfields and in the granular cell layer of the dentate gyrus of the hippocampus; strong ERG1 signals were also detected in scattered large elements throughout the oriens, pyramidal, and radiatum layers, and in the hilus of the dentate gyrus. In the thalamus, positively labeled neurons were detected in the reticular nucleus with ERG1 and ERG3 and in the anterodorsal nucleus with ERG2 riboprobes. Transcripts for ERG1 and, to a lesser degree, also for ERG3, were detected in the basal ganglia and in several brainstem nuclei. All three ERG genes appeared to be expressed in cerebellar Purkinje cells. Finally, ERG1 expression was also revealed in non-neuronal elements such as ependymal and subependymal cells along the ventricular walls and hippocampal astrocytes. These results suggest that the K(+) channel isoforms of the ERG family appear to be expressed in different central nervous system regions where they might differentially control the firing of neurons engaged in several networks.

Action Potentials↗
PubMed2001

Distribution of galaninergic immunoreactivity in the brain of the mouse.

The distribution of galaninergic immunoreactive (-ir) profiles was studied in the brain of colchicine-pretreated and non-pretreated mice. Galanin (GAL)-ir neurons and fibers were observed throughout all encephalic vesicles. Telencephalic GAL-ir neurons were found in the olfactory bulb, cerebral cortex, lateral and medial septum, diagonal band of Broca, nucleus basalis of Meynert, bed nucleus of stria terminalis, amygdala, and hippocampus. The thalamus displayed GAL-ir neurons within the anterodorsal, paraventricular, central lateral, paracentral, and central medial nuclei. GAL-ir neurons were found in several regions of the hypothalamus. In the midbrain, GAL-ir neurons appeared in the pretectal olivary nucleus, oculomotor nucleus, the medial and lateral lemniscus, periaqueductal gray, and the interpeduncular nucleus. The pons contained GAL-ir neurons within the dorsal subcoeruleus, locus coeruleus, and dorsal raphe. In the medulla oblongata, GAL-ir neurons appear in the anterodorsal and dorsal cochlear nuclei, salivatory nucleus, A5 noradrenergic cells, gigantocellular nucleus, inferior olive, solitary tract nucleus, dorsal vagal motor and hypoglossal nuclei. Only GAL-ir fibers were seen in the lateral habenula nucleus, substantia nigra, parabrachial complex, cerebellum, spinal trigeminal tract, as well as the motor root of the trigeminal and facial nerves. GAL-ir was also observed in several circumventricular organs. The widespread distribution of galanin in the mouse brain suggests that this neuropeptide plays a role in the regulation of cognitive and homeostatic functions.

Animals↗
PubMed2005

Constitutive neuronal expression of CCR2 chemokine receptor and its colocalization with neurotransmitters in normal rat brain: functional effect of MCP-1/CCL2 on calcium mobilization in primary cultured neurons.

Chemokines and their receptors are well described in the immune system, where they promote cell migration and activation. In the central nervous system, chemokine has been implicated in neuroinflammatory processes. However, an increasing number of evidence suggests that they have regulatory functions in the normal nervous system, where they could participate in cell communication. In this work, using a semiquantitative immunohistochemistry approach, we provide the first neuroanatomical mapping of constitutive neuronal CCR2 localization. Neuronal expression of CCR2 was observed in the anterior olfactory nucleus, cerebral cortex, hippocampal formation, caudate putamen, globus pallidus, supraoptic and paraventricular hypothalamic nuclei, amygdala, substantia nigra, ventral tegmental area, and in the brainstem and cerebellum. These data are largely in accordance with results obtained using quantitative autoradiography with [(125)I]MCP-1/CCL2 and RT-PCR CCR2 mRNA analysis. Furthermore, using dual fluorescent immunohistochemistry we studied the chemical phenotype of labeled neurons and demonstrated the coexistence of CCR2 with classical neurotransmitters. Indeed, localization of CCR2 immunostaining is observed in dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area as well as in cholinergic neurons in the substantia innominata and caudate putamen. Finally, we show that the preferential CCR2 ligand, MCP-1/CCL2, elicits Ca(2+) transients in primary cultured neurons from various rat brain regions including the cortex, hippocampus, hypothalamus, and mesencephalon. In conclusion, the constitutive neuronal CCR2 expression in selective brain structures suggests that this receptor could be involved in neuronal communication and possibly associated with cholinergic and dopaminergic neurotransmission and related disorders.

Animals↗
PubMed2006

A study of the rat neuropeptide B/neuropeptide W system using in situ techniques.

In the rat, the neuropeptide B/neuropeptide W (NPB/NPW) system is composed of two ligands, neuropeptide B (NPB) and neuropeptide W (NPW), and one receptor, GPR7. Although preliminary analyses show roles in feeding, hormone secretion, and analgesia, the lack of a detailed anatomical map impairs our understanding of the NPB/NPW system. We demonstrate in this report the expression patterns of GPR7, NPB, and NPW precursor messenger ribonucleic acid (mRNA) in the rat brain by using in situ hybridization and in situ binding experiments. The amygdala expresses the highest levels of GPR7 mRNA and binding signals. Other nuclei with high levels of expression and binding are the suprachiasmatic and the ventral tuberomamillary nuclei. Moderate levels are seen in the dorsal endopiriform, dorsal tenia tecta, bed nucleus, and the red nucleus. Low levels are in the olfactory bulb, parastrial nucleus, hypothalamus, laterodorsal tegmentum, superior colliculus, locus coeruleus, and the nucleus of the solitary tract. Although the NPB precursor is mostly expressed at low levels in the brain, moderate expression is seen in anterior olfactory nucleus, piriform cortex, median preoptic nucleus, basolateral amygdala, hippocampus, medial tuberal nucleus, substantia nigra, dorsal raphe nucleus, Edinger-Westphal nucleus, and the locus coeruleus. To our surprise, the expression of NPW precursor was not detected. Our study greatly expands the preliminary in situ data previously reported. With this map of the NPB/NPW system in the rat brain, a better understanding of the functional implications of the system in various behavioral paradigms is now possible.

Animals↗
PubMed2007

Species differences in the localization of soluble guanylyl cyclase subunits in monkey and rat brain.

Nitric oxide (NO) exerts most of its physiological effects through activation of a predominantly soluble guanylyl cyclase (sGC). In mammalian cells sGC exists as a heterodimer of alpha and beta subunits. Currently, four subunits (alpha1, alpha2, beta1, and beta2) have been characterized. We used in situ hybridization with subunit-specific 33P-labeled oligonucleotide probes to compare the anatomical distribution of sGC subunit mRNAs in rat and monkey brains. Message for all subunits except beta2 was detected in both species. The sGC subunit showing the highest expression and widest distribution was beta1. High expression for all subunits was found in basal ganglia, olfactory system, hippocampus, cortex, and cerebellum. Minor species differences in the relative distribution of alpha subunits were observed. In general, the alpha1 message was more prominent in monkey brain and the alpha2 message in rat brain. This was more evident in limbic areas and cerebellar cortex. Some differences were also observed in subunit laminar distribution in cerebral cortex. The limited species differences in sGC subunit distribution suggest that in primates, as occurs in rodents, the NO-cGMP signaling pathway will be involved in important brain functions such as memory formation, sensory processing, and behavior.

Animals↗
PubMed1987

Corticotropin releasing factor-like immunoreactivity in the rat brain as revealed by a modified cobalt-glucose oxidase-diaminobenzidine method.

A cobalt-glucose-oxidase diaminobenzidine (Co-GOD) method, employing a specific antiserum against rat corticotropin releasing factor (CRF), was applied to determine immunohistochemically a widespread and detailed localization of corticotropin releasing factor-like immunoreactivity (CRFI) in the rat brain. Besides the CRFI cells in the paraventricular hypothalamic nucleus that project to the median eminence, CRFI cells were demonstrated in many brain regions, including the olfactory bulb, cerebral cortex, septal nuclei, hippocampus, amygdala, thalamic nuclei, medial hypothalamic nuclei, lateral hypothalamic area, perifornical area, central gray, cuneiform nucleus, inferior colliculus, raphe nuclei, mesencephalic reticular formation, laterodorsal tegmental nucleus, locus coeruleus, parabrachial nuclei, mesencephalic tract of the trigeminal nerve, pontine reticular formation, lateral superior olive, vestibular nuclei, prepositus hypoglossal nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus, lateral reticular nucleus, nucleus of the spinal tract of the trigeminal nerve, external cuneate nucleus, inferior olive, and medullary reticular formation. CRFI-reacting neural processes were also detected in these same areas. In particular, the median eminence, lateral septum, bed nucleus of the stria terminalis, mesencephalic reticular formation, parabrachial nuclei, and nucleus of the solitary tract contained large numbers of CRFI fibres. The widespread localization of CRFI demonstrated in the present study strongly suggests that CRF, like many other neurohormones and peptides, may act as a neurotransmitter and/or neuromodulator in numerous extrahypothalamic circuits, as well as participate in neuroendocrine regulation.

3,3'-Diaminobenzidine↗
PubMed1993

Light and electron microscopic immunocytochemical localization of PKC delta immunoreactivity in the rat central nervous system.

Protein kinase C (PKC) is one of the major cellular signal transduction systems. Since at least nine different PKC isoenzymes have been described, the purpose of the present studies was to identify the regional, cellular, and subcellular distributions of PKC delta in the rat central nervous system (CNS) by light and electron microscopic immunocytochemistry. We have found that PKC delta immunoreactivity is present in all major subdivisions of the rat CNS. Within each of the subdivisions, PKC delta immunoreactivity is localized to perikarya that monitor sensory and motor functions. More specifically, PKC delta is found in the olfactory bulb, cerebral cortex, lateral septum, thalamus, vestibular and cochlear nuclei, inferior olive, nucleus of the solitary tract, cerebellum, and superficial layers of the dorsal horn in the spinal cord. In most cases, the distribution of this isoenzyme is distinct from that of the conventional isoforms. Within the CNS, PKC delta is localized primarily in neurons; however, neurons of the same type are not uniformly labeled. This is most evident in the cerebellum, where alternating columns of Purkinje cells are immunostained. While PKC delta is prominent in perikarya, occasional immunostaining is seen in dendrites, fibers or axons, and nerve terminal. Electron microscopic analysis of the posterolateral nucleus of the thalamus reveals that the cell nucleus, the rough endoplasmic reticulum, and the plasma membrane are all immunopositive. Since each of the PKC subspecies may have different substrate, lipid, and other co-factor requirements, the regional, cellular, and subcellular distribution of each of these isoforms should help to define their functional environments.

Animals↗
PubMed1994

Histological and ultrastructural localization of the kainate receptor subunits, KA2 and GluR6/7, in the rat nervous system using selective antipeptide antibodies.

Kainate receptors are found throughout many regions of the brain and presumably contribute to responses of neurons to glutamate and other excitatory amino acids. Two affinity-purified polyclonal antibodies that recognize the kainate binding subunits, KA2 and GluR6, were made using C-terminus peptides. A previous study demonstrated that each antibody is specific for its subunit, although antibody to GluR6 recognizes GluR7 to some extent (hence the designation GluR6/7). Vibratome sections immunostained with either antibody showed light to moderate staining in many structures in the brain as well as in cervical spinal cord, dorsal root and vestibular ganglia, and pineal and pituitary glands. Moderate levels were seen in the olfactory bulb, cerebral cortex, caudate/putamen, and hypothalamus, whereas much of the thalamus was stained lightly. In the hippocampus, CA3 pyramidal cells were stained more densely than CA1 pyramidal cells--the difference more evident with antibody to GluR6/7. In addition, neuropilar staining was densest in the stratum lucidum of the CA3 region. In the brainstem, staining was moderate to moderately dense in a number of sensory, motor, and reticular nuclei. The moderately dense staining in the reticulothalamic nucleus and pontine nuclei with antibody to GluR6/7 may represent its recognition of GluR7. In the cerebellum, staining was moderate in granular and molecular layers with antibody to KA2 and in the molecular layer with antibody to GluR6/7, whereas it was moderately dense to dense in the granular layer with the GluR6/7 antibody. Outside of the brain, densest staining was seen with antibody to KA2 in the intermediate lobe of the pituitary gland. Ultrastructural localization of immunostaining was examined in the hippocampus, cerebral cortex, and cerebellar cortex. Typically, major staining was in postsynaptic densities apposed by unstained presynaptic terminals with round or mainly round vesicles and in associated dendrites. The light microscope pattern of staining was fairly similar to that of previous [3H]kainate binding and in situ hybridization studies. In addition, comparison with previous studies on distribution of other types of glutamate receptors indicates that KA2 and GluR6/7 are found with various other subunits in many of the same cell populations throughout the nervous system.

Amino Acid Sequence↗
PubMed2005

Comparative analysis of Six 3 and Six 6 distribution in the developing and adult mouse brain.

Six 3 and Six 6 genes are two closely related members of the Six/sine oculis family of homeobox containing transcription factors. Their expression and function at early stages of embryonic development has been widely addressed in a variety of species. However, their mRNA distribution during late embryonic, postnatal, and adult brain barely has been analyzed. Here, we show that despite their initial overlap in the anterior neural plate, the expression of Six 3 and Six 6 progressively segregates to different regions during mammalian brain development, maintaining only few areas of partial overlap in the thalamic and hypothalamic regions. Six 3, but not Six 6, is additionally expressed in the olfactory bulb, cerebral cortex, hippocampus, midbrain, and cerebellum. These distinct patterns support the idea that Six 3 and Six 6 are differentially required during forebrain development.

Aging↗
PubMed1992

The mouse 5HT5 receptor reveals a remarkable heterogeneity within the 5HT1D receptor family.

Serotonin (5-HT) is a neuromodulator that mediates a wide range of physiological functions by activating multiple receptors. Using a strategy based on amino acid sequence homology between 5-HT receptors that interact with G proteins, we have isolated a cDNA encoding a new serotonin receptor from a mouse brain library. Amino acid sequence comparisons revealed that this receptor was a distant relative of all previously identified 5-HT receptors; we therefore named it 5HT5. When expressed in Cos-7 cells and NIH-3T3 cells, the 5HT5 receptor displayed a high affinity for the serotonergic radioligand [125I]LSD. Surprisingly, its pharmacological profile resembled that of the 5HT1D receptor, which is a 5-HT receptor subtype which has been shown to inhibit adenylate cyclase and which is predominantly expressed in basal ganglia. However, unlike 5HT1D receptors, the 5HT5 receptor did not inhibit adenylate cyclase and its mRNA was not found in basal ganglia. On the contrary, in situ hybridization experiments revealed that the 5HT5 mRNA was expressed predominantly in cerebral cortex, hippocampus, habenula, olfactory bulb and granular layer of the cerebellum. Our results therefore demonstrate that the 5HT1D receptors constitute a heterogeneous family of receptors with distinct intracellular signalling properties and expression patterns.

3T3 Cells↗
PubMed2007

Manganese-enhanced magnetic resonance imaging (MEMRI) of rat brain after systemic administration of MnCl2: changes in T1 relaxation times during postnatal development.

PURPOSE: To measure regional T(1) changes in the postnatal rat brain following systemic administration of the contrast agent manganese chloride (MnCl(2)). MATERIALS AND METHODS: MnCl(2) (120 mM) was administered intravenously (i.v.) at 1.25 mL/hour to a dose of 175 mg/kg body weight. MRI experiments were performed on anaesthetized animals (32 male Wistar rats, postnatal days (PDs) 11, 16, 21, and 31) at 2.0 T. Regions of interest (ROIs) were drawn in sagittal slices and placed over five brain regions: olfactory bulb, cerebellum, cortex, thalamus, and hypothalamus. The signal intensities of each ROI were measured and fitted to a three-parameter function to estimate T(1) values. RESULTS: In the brains of animals who did not receive the contrast agent (control group), we observed a consistent age-dependent decrease in T(1) values. In the brains of manganese-infused animals (manganese group), however, T(1) values were significantly lower than in the control group, indicating the uptake of manganese, but no dependence of T(1) on age was found. CONCLUSION: Our T(1) measurements indicate that the relative Mn(2+) concentrations are higher in neonates and decrease with brain development. An estimate of the relative cortical concentration of manganese shows a two-fold drop from PD 11 to PD 31.

Analysis of Variance↗
PubMed1990

Developmental and regional expression of basic fibroblast growth factor mRNA in the rat central nervous system.

A cDNA clone encoding rat basic fibroblast growth factor (bFGF) was used as a hybridization probe to determine the level of bFGF mRNA during rat brain development as well as in different adult rat brain regions. In the rat brain, a 3.7kb bFGF mRNA was detected together with lower levels of two minor bFGF mRNA species of 1.8kb and 1.5kb, respectively. The 3.7kb bFGF mRNA was detected in the rat brain already at embryonic day 16, the earliest time point tested. The embryonic brain contained 1.5 to 2 times higher levels of the 3.7kb bFGF mRNA than the adult brain. The amount of the 3.7kb bFGF mRNA in the adult rat brain was approximately 50 times higher than the level of beta-nerve growth factor mRNA in the rat brain. bFGF mRNA was found in all 12 brain regions tested in the adult rat brain with the highest level in colliculi, cerebral cortex, thalamus, and olfactory bulb. The lowest levels were found in pons and medulla oblongata. All three bFGF mRNA species showed the same regional distribution in the brain. In contrast to nerve growth factor mRNA, the level of bFGF mRNA in the neonatal hippocampus was slightly decreased 10 days after a cholinergic denervation by transection of the fimbria-fornix.

Animals↗
PubMed1990

Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains.

The iron transport protein, transferrin, and the iron storage protein ferritin were examined immunohistochemically along with iron in a number of brain regions from normal and aged humans. Two age groups were examined: a middle-aged group (28-49 years), and an older group (60-90 years). Transferrin, ferritin, and iron are found throughout all brain regions examined, predominantly in the perikaryal cytoplasm of cells that are small and round, fitting the description of oligodendrocytes. These cells are present in the optic nerve and in both the gray and white matter of the cerebral cortex, cerebellum, and olfactory bulb in both age groups. Ferritin is also found in microglial cells in the gray matter of most of these brain regions. In the subcortical regions examined (corpus striatum, hippocampus, amygdala), in addition to oligodendrocytes, astrocytes can frequently be observed that contain transferrin, ferritin, and iron. There is an age-related alteration in cell labeling: astrocytes in both gray and white matter contained transferrin in the oldest age group, whereas in the younger group the subcortical transferrin immunoreactivity was confined mostly to oligodendrocytes. Ferritin in the subcortical brain regions is also present in astrocytes but is primarily confined to those in the gray matter, even in the oldest age group. Iron is found predominantly in oligodendrocytes, although a few iron-positive astrocytes and microglia can be identified. These results indicate that (1) normally oligodendrocytes contain much of the iron and iron-binding proteins found in the brain; and (2) an increase in age is associated with altered cellular distribution of iron-binding proteins, but the altered distribution is specific to glial cells. These results suggest glial cells may have previously undescribed functions related to metal regulation and sequestration.

Aging↗
PubMed1991

Developmental and regional expression of choline acetyltransferase mRNA in the rat central nervous system.

The developmental and regional expression of choline acetyltransferase (ChAT) mRNA was examined in the rat brain and spinal cord by northern blot analysis and in situ hybridization. ChAT mRNA expression in the brain showed a biphasic increase during development, with a first peak at two weeks postnatally, a marked decrease by the third week, and a second increase between the third and fifth week after birth, indicating that emergence of the cholinergic phenotype occurs at different times in different brain regions. In the spinal cord, ChAT mRNA was detected at similar levels from embryonic stage 13 (E13) until birth, increasing thereafter until adulthood. In the adult rat central nervous system, high levels of ChAT mRNA were detected in the spinal cord and brain stem structures. Lower levels were seen in midbrain, septum, striatum, thalamus, and olfactory bulb. ChAT mRNA containing cells were identified by in situ hybridization in the olfactory tubercule, piriform cortex, striatum, several basal forebrain nuclei, and spinal cord. A nearly two-fold increase in adult spinal cord ChAT mRNA levels were seen one week after a bilateral crush lesion of the sciatic nerve, indicating that ChAT mRNA expression is regulated during motoneuron regeneration.

Animals↗
PubMed1992

Novel antigenic determinant expressed in neurons of the dorsolateral hypothalamus in rat and human.

Previous studies have identified a group of cells in the dorsolateral hypothalamus that project to many different areas in the CNS, such as thalamus, diagonal band of Broca, basal ganglia, cerebral cortex, hippocampus, and olfactory bulb. Their role is presently unknown, but the cells have been reported to stain for an intriguing array of putative neurotransmitter-related substances, including alpha-melanocyte-stimulating hormone (alpha MSH), melanin-concentrating hormone (MCH), human growth-hormone-releasing factor 1-37 (hGRF 1-37), corticotropin-releasing factor (CRF), metorphamide, and acetylcholine esterase. A monoclonal antibody produced in the present study, alpha C11, stains both the cell bodies of this system in hypothalamus, with a punctate pattern, and varicose fibers in the various target areas. In double-label immunocytochemical experiments in rat DLH, alpha C11 and MCH staining exactly overlaps. Concentrations of alpha MSH and MCH high enough to completely block staining with the corresponding antisera had no effect on staining with alpha C11. Similarly, CRF, hGRF 1-37, and metorphamide were unable to block alpha C11 staining. The results suggest that the antigenic epitope for alpha C11 is not contained in alpha MSH, MCH, CRF, hGRF, or metorphamide, and thus, that alpha C11 is detecting another antigen uniquely expressed in these neurons. The punctate appearance of staining in the hypothalamus and the concentration of staining in fiber varicosities suggests that the alpha C11 epitope may be involved in synaptic function.

Acetylcholinesterase↗
PubMed1994

Regional CNS uptake of blood-borne nerve growth factor.

Nerve growth factor (NGF), in addition to being a neurotrophic substance, has effects on the endocrine and immune systems. For example, intravenous injection of NGF results in a cascade of events leading to an increase in glucocorticoid secretion. While this response appears to be mediated centrally, there has been no evidence that circulating NGF has access to the CNS. Using intravenous injections of 125I-NGF, we find specific uptake at 1 hr but none at 6 hr, into homogenates of the basal forebrain, cerebellum, frontal cortex, hippocampus, and olfactory bulb. By autoradiography, uptake is localized to circumventricular organs, deep layers of the cerebellum, and all layers of the hippocampal region CA1, but not the dentate gyrus. Thus, uptake of blood-borne NGF could affect the hypothalamic-pituitary-adrenal axis via binding to NGF receptors present in the hippocampus. However, the sources of endogenous NGF, the mechanism of access through the blood-brain barrier, the eventual fate of NGF entering from the blood, and the physiological significance of this uptake remain to be elucidated.

Animals↗
PubMed1993

Pilocarpine-induced convulsions in rats: evidence for muscarinic receptor-mediated activation of locus coeruleus and norepinephrine release in cholinolytic seizure development.

We recently reported that systemic administration of the anticholinesterase, soman, caused rapid depletion of forebrain norepinephrine (NE) in convulsive but not in nonconvulsive rats. As neurons in nucleus locus coeruleus (LC) provide the bulk of NE innervation to most of the forebrain and the sole source of NE input to the cortex and the olfactory bulb, soman-induced NE depletion was hypothesized to result from activation of LC neurons. This activation was thought to be due to inhibition of acetylcholinesterase by soman, leading to rapid, sustained accumulation of acetylcholine in LC, causing these cells to fire at a high sustained rate. Support for this hypothesis was provided by neurophysiological findings showing that: (i) Systemic administration of soman in anesthetized rats caused a sustained, fivefold increase in the mean firing rate of LC neurons and (ii) microinjections of soman directly into LC caused a similar increase in the firing rate of LC neurons. Soman-induced activation of LC occurred prior to and even in the absence of seizures. As systemic administration of the muscarinic receptor antagonist, scopolamine, rapidly and completely reversed soman-induced activation of LC, it was further hypothesized that activation of LC neurons following soman administration is due to muscarinic receptor stimulation. The rapid release of NE by cholinolytic agents, thus, may play an important role in the initiation and/or maintenance of convulsions. To further test the hypothesis that NE release in soman-intoxicated rats is due to muscarinic activation of LC, we have investigated the effects of the muscarinic receptor agonist, pilocarpine, on NE release and LC discharge. In one set of experiments, rats were injected with a periconvulsive dose of pilocarpine (300 mg/kg, ip); both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h and monoamine levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. NE levels declined substantially only in convulsive rats; forebrain NE levels in convulsive rats rapidly decreased to 50% of control levels at 1 h and to 37% of controls level between 2 and 4 h. The time course and magnitude of these changes were similar to those observed following soman administration in our previous study. Recovery of forebrain NE began at 8 h and was complete by 96 h following pilocarpine administration. Neither dopamine (DA) nor serotonin (5-HT) levels were changed in the forebrain and olfactory bulb of either convulsive or nonconvulsive rats.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Rat beta 1-adrenergic receptor regulatory region containing consensus AP-2 elements recognizes novel transactivator proteins.

beta 1-Adrenergic receptors (beta1-ARs) serve as important regulators of central nervous system (CNS)-mediated behavior and several neural functions, including mood, memory, neuroendocrine control, and stimulation of autonomic function. Using beta 1-AR-luciferase reporter recombinants, we have previously determined that important beta 1-AR genetic elements controlling expression within the C6 glioma cell line are contained within the region -396 to -299, relative to the translational start site. By conducting progressive internal deletions of the rat beta 1-AR 5' flanking region and with the use of beta 1-AR-luciferase recombinants, we have verified that this region contains the primary beta 1-AR promoter and/or major regulatory elements. To begin the identification of protein factors involved in beta 1-AR transcriptional activity conferred by this beta 1-AR region and flanking sequences, we conducted electrophoretic mobility shift assays using defined beta 1-AR DNA subregion probes. One probe (GS-1), encompassing the region -396 to -367, was found to produce two major and two minor mobility shift complexes when bound to nuclear extracts from the beta 1-AR expresser C6 cell line. UV-crosslinking of DNA-protein complexes, coupled with DNase I digestion, indicated that this beta 1-AR region interacts with one major protein of approximately 117 kDa molecular weight and additional minor proteins. GS-1 DNA-protein complexes were observed using beta 1-AR expresser tissues in the CNS, including cortex, hippocampus, and olfactory bulb. No DNA-protein complexes were observed when using nuclear extracts from beta 1-AR nonexpresser tissues; in some cases, using L6 cells, previously characterized to express little or no beta1-ARs, a reduction in intensities of the DNA-protein complexes was observed. Competition experiments indicate that nuclear protein binds to one of two subregions within the GS-1 sequence that contain AP-2-like consensus elements. Recombinant AP-2 protein will bind to both the beta 1-AR GS-1 promoter fragment and commercially available AP-2 consensus element control probes. Interestingly, using antibody supershift and immunoblotting experiments, no supershifts were observed and the major 117-kDa protein was not immunoreactive to antibodies recognizing either AP-2 alpha or AP-2 beta. These results support our contention that this beta 1-AR regulatory region contains AP-2 consensus elements that recognize novel transactivator proteins.

Animals↗