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PubMed1988

[3H]MK-801 labels a site on the N-methyl-D-aspartate receptor channel complex in rat brain membranes.

The potent noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist [3H]MK-801 bound with nanomolar affinity to rat brain membranes in a reversible, saturable, and stereospecific manner. The affinity of [3H]MK-801 was considerably higher in 5 mM Tris-HCl (pH 7.4) than in previous studies using Krebs-Henseleit buffer. [3H]MK-801 labels a homogeneous population of sites in rat cerebral cortical membranes with KD of 6.3 nM and Bmax of 2.37 pmol/mg of protein. This binding was unevenly distributed among brain regions, with hippocampus greater than cortex greater than olfactory bulb = striatum greater than medulla-pons, and the cerebellum failing to show significant binding. Detailed pharmacological characterization indicated [3H]MK-801 binding to a site which was competitively and potently inhibited by known noncompetitive NMDA receptor antagonists, such as phencyclidine, thienylcyclohexylpiperidine (TCP), ketamine, N-allylnormetazocine (SKF 10,047), cyclazocine, and etoxadrol, a specificity similar to sites labelled by [3H]TCP. These sites were distinct from the high-affinity sites labelled by the sigma receptor ligand (+)-[3H]SKF 10,047. [3H]MK-801 binding was allosterically modulated by the endogenous NMDA receptor antagonist Mg2+ and by other active divalent cations. These data suggest that [3H]MK-801 labels a high-affinity site on the NMDA receptor channel complex, distinct from the NMDA recognition site, which is responsible for the blocking action of MK-801 and other noncompetitive NMDA receptor antagonists.

Animals↗
PubMed1991

Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5-HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives.

The cerebral cortex of the rat and other mammals is innervated by two morphologically distinct classes of serotoninergic (5-HT) axon terminals: fine axons with minute varicosities and beaded axons characterized by large, spherical varicosities. Fine and beaded 5-HT axons exhibit different regional and laminar distributions in forebrain and arise from separate brainstem nuclei, the dorsal and median raphe nuclei, respectively. The present neuroanatomic study, based on immunocytochemical methods to visualize 5-HT axons, demonstrates that the two axon types differ markedly in their vulnerability to the neurotoxic amphetamine derivatives, methylenedioxyamphetamine (MDA), and p-chloroamphetamine (PCA). While both drugs cause extensive degeneration of fine 5-HT axons throughout forebrain, beaded 5-HT axons are consistently spared. Fine 5-HT axons, which richly innervate most regions of dorsal forebrain in control rats, are rarely seen 2 weeks after treatment with MDA or PCA; this loss of fine axons reflects a marked denervation that persists for months after drug administration. The serotoninergic axon terminals remaining after MDA or PCA administration are almost entirely of the beaded type and appear to be unaffected by both drugs. Over a wide range of doses (2.5-40 mg/kg PCA) and survival times (2 weeks to 2 months), these spared 5-HT axons with large, spherical varicosities cannot be distinguished from the normal, beaded 5-HT axons in control rats by morphologic criteria. Moreover, beaded 5-HT axons exhibit a highly characteristic regional distribution which is the same in control as in MDA- and PCA-treated rats: these axons innervate specific zones or layers within parietal and occipital cortex, hippocampus, cingulate cortex, entorhinal cortex, and the olfactory bulb, among other forebrain areas, and they form a dense plexus lining the ventricular system. Taken together, the results of this study demonstrate that fine 5-HT axons are highly vulnerable to the neurotoxic effects of the amphetamine derivatives MDA and PCA, while beaded 5-HT axons are markedly resistant. These findings are consistent with the hypothesis that there are two anatomically and functionally distinct sets of serotoninergic neurons projecting to forebrain. While both of these neuronal systems utilize 5-HT as a neurotransmitter, they differ in several features: 1) origin from separate nuclei in the brainstem (the dorsal and median raphe), 2) two types of morphologically distinct axon terminals, 3) markedly different distribution and innervation patterns in forebrain, and 4) dissimilar pharmacological properties. The results further suggest that psychotropic amphetamine derivatives have a selective action upon fine serotoninergic axons that arise from the dorsal raphe nucleus.

3,4-Methylenedioxyamphetamine↗
PubMed2006

Enhanced cyclooxygenase-2 expression in olfactory-limbic forebrain following kainate-induced seizures.

Cyclooxygenase-2 is expressed at low levels in a subset of neurons in CNS and is rapidly induced by a multiplicity of factors including seizure activity. A putative relationship exists between cyclooxygenase-2 induction and glutamatergic neurotransmission. Cyclooxygenase-1 is constitutively expressed in glial cells and has been specifically linked to microglia. In this study we evaluated cyclooxygenase-2 protein immunocytochemically and found markedly enhanced immunostaining primarily in olfactory-limbic regions at 2, 6 and 24 h following kainate-induced status epilepticus. Impressive enhanced cyclooxygenase-2 immunoreactivity was localized in anterior olfactory nucleus, tenia tecta, nucleus of the lateral olfactory tract, piriform cortex, lateral and basolateral amygdala, orbital frontal cortex, nucleus accumbens (shell) and associated areas of ventral striatum, entorhinal cortex, dentate gyrus granule cells and hilar neurons, hippocampal CA subfields and subiculum. Alternate sections were processed for dual immunocytochemical analysis utilizing c-Fos and cyclooxygenase-2 antiserum to examine the possibility that the neuronal induction of cyclooxygenase-2 was associated with seizure activity. Neurons that showed a timeline of cyclooxygenase-2 upregulation were found to possess c-Fos immunopositive nuclei. Additional results from all seizure groups showed cyclooxygenase-1 induction in microglia, which was confirmed by Western blot analysis of hippocampus. Western blot and real-time quantitative RT-PCR analysis showed significant upregulation of cyclooxygenase-2 expression, confirming its induction in neurons. These data indicate that cyclooxygenase-2 induction in a neuronal network can be a useful marker for pathways associated with seizure activity.

Animals↗
PubMed1993

Expression of multiple alpha adrenergic receptor subtype messenger RNAs in the adult rat brain.

Multiple subtypes of alpha adrenergic receptors with CNS expression (alpha 1A, alpha 1B, alpha 2A and alpha 2C) have been identified through pharmacological and molecular biological means. To characterize the localization of these subtypes and attempt to correlate subtype expression with physiological significance, the expression of the mRNAs encoding the alpha 1A, alpha 1B, alpha 2A and alpha 2C adrenergic receptor subtypes was examined in the adult rat brain by in situ hybridization histochemistry. Each subtype demonstrated a unique pattern of distribution, with the alpha 1 adrenergic receptors more restricted in their distribution and the alpha 2 receptors more widespread. The alpha 1A was primarily localized in the olfactory bulb, intermediate layers of the cortex, the hippocampus and the reticular nucleus of the thalamus. The alpha 1B was expressed in intermediate and deep layers of the cortex, thalamus, hippocampus, dorsal raphe and cerebellum. Although the alpha 2A message was relatively low in abundance, it was identified in the olfactory bulb, cortex, hippocampus, locus coeruleus, pons and cerebellum. The alpha 2C messenger RNA was localized in the cortex (particularly cingulate), hippocampus, caudoputamen, pons and cerebellum. Multiple alpha adrenergic receptor subtypes have significant sequence homology and similar pharmacologic properties; however, they each possess a unique pattern of messenger RNA distribution throughout the brain. The multiplicity of subtypes of alpha adrenergic receptors in specific brain regions may dictate the physiological and pharmacological responses to catecholamines.

Animals↗
PubMed1999

Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2.

The molecular mechanisms underlying the targeting and localization of glutamate receptors at postsynaptic sites is poorly understood. Recently, we have identified a PDZ domain-containing protein, glutamate receptor-interacting protein 1 (GRIP1), which specifically binds to the C termini of AMPA receptor subunits and may be involved in the synaptic targeting of these receptors. Here, we report the cloning of GRIP2, a homolog of GRIP1, and the characterization of the GRIP1 and GRIP2 proteins in the rat CNS. GRIP1 and GRIP2 are approximately 130 kDa proteins that are highly enriched in brain. GRIP1 and GRIP2 are widely expressed in brain, with the highest levels found in the cerebral cortex, hippocampus, and olfactory bulb. Biochemical studies show that GRIP1 and GRIP2 are enriched in synaptic plasma membrane and postsynaptic density fractions. GRIP1 is expressed early in embryonic development before the expression of AMPA receptors and peaks in expression at postnatal day 8-10. In contrast, GRIP2 is expressed relatively late in development and parallels the expression of AMPA receptors. Immunohistochemistry using the GRIP1 antibodies demonstrated that GRIP1 is expressed in neurons in a somatodendritic staining pattern. At the ultrastructural level, DAB and immunogold electromicroscopy studies showed that GRIP1 was enriched in dendritic spines near the postsynaptic density and was expressed in dendritic shafts and in peri-Golgi regions in the neuronal soma. GRIP1 appeared to be clustered at both glutamatergic and GABAergic synapses. These results suggest that GRIP1 and GRIP2 are AMPA receptor binding proteins potentially involved in the targeting of AMPA receptors to synapses. GRIP1 also may play functional roles at both excitatory and inhibitory synapses, as well as in early neuronal development.

Amino Acid Sequence↗
PubMed1998

Immunohistochemical localization of metabotropic glutamate receptors, mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: a light and electron microscopic study.

The distributions of two alternative splicing variants of metabotropic glutamate receptor mGluR7, mGluR7a and mGluR7b, were examined immunohistochemically in the rat and mouse by using variant-specific antibodies raised against C-terminal portions of rat mGluR7a and human mGluR7b. Many regions throughout the central nervous system (CNS) showed mGluR7-like immunoreactivities (LI). The distribution patterns of mGluR7-LI in the rat were substantially the same as those in the mouse, although some species differences were observed in a few regions. Intense mGluR7a-LI was seen in the main and accessory olfactory bulbs, anterior olfactory nucleus, islands of Calleja, superficial layers of the olfactory tubercle, piriform cortex and entorhinal cortex, periamygdaloid cortex, amygdalohippocampal area, hippocampus, layer I of the neocortical regions, globus pallidus, superficial layers of the superior colliculus, locus coeruleus, and superficial layers of the medullary and spinal dorsal horns. The distribution of mGluR7b was more restricted. It was intense in the islands of Calleja, substantia innominata, hippocampus, ventral pallidum, and globus pallidus. The medial habenular nucleus also showed intense mGluR7a-LI in the rat but not in the mouse. For both mGluR7a- and mGluR7b-LI, localization in the active zones of presynaptic axon terminals was confirmed electron microscopically at synapses of both the asymmetrical and symmetrical types. It is noteworthy that mGluR7a-LI is seen preferentially in relay nuclei of the sensory pathways and that both mGluR7a- and mGluR7b-LI are observed not only in presumed glutamatergic axon terminals, but also in non-glutamatergic axon terminals including presumed inhibitory ones. Thus, mGluR7 may play roles not only as an autoreceptor in glutamatergic axon terminals, but also as a presynaptic heteroreceptor in non-glutamatergic axon terminals in various CNS regions.

Amygdala↗
PubMed1994

Facilitatory effect of olfactory bulbectomy on 2-deoxyglucose uptake in rat amygdala slices.

The aim of the present study was to determine whether the 2-deoxyglucose uptake of amygdala slices was affected by olfactory bulbectomy. At 7, 14 and 21 days post-lesion, bilateral olfactory bulbectomized rats exhibited a significant increase of 2-deoxyglucose uptake in amygdala slices, but not in the cerebral cortex. In addition, unilateral olfactory bulbectomized rats showed a high uptake of 2-deoxyglucose uptake in the ipsilateral amygdala, but not in the contralateral amygdala. These results suggest that the enhancement of 2-deoxyglucose uptake is related to the hyperexcitability of amygdala neurons following bulbectomy, and that this enhancement may be responsible for the behavioral changes in olfactory bulbectomized rats.

Amygdala↗
PubMed1989

A new method to estimate time delays between EEG signals applied to beta activity of the olfactory cortical areas.

A method based on coherence and phase spectra was developed to characterize the transmission of signals through neural networks that were assumed to have linear filter properties. The system is thought to consist of a frequency independent delay in series with a network that gives rise to a frequency dependent lag, the so-called minimum phase shift. The latter was estimated from the gain of the transfer function by means of Hilbert transform pairs. By subtracting the minimum phase shift from the phase differences between input and output, a corrected phase spectrum was obtained that represents the frequency independent delay. The slope of this spectrum was calculated and converted into the time delay. This method was applied to EEG signals recorded from different parts of the olfactory basal forebrain structures of the cat, in order to determine time delays for the beta activity. The results showed that the beta activity was propagated in a rostro-caudal direction. Along this rostro-caudal axis the conduction velocity slowed down from approximately 3 m/sec for the pathways between olfactory bulb and prepyriform cortex to 0.5 m/sec within the EC. These findings were compared to estimates of the conduction velocities in the lateral olfactory tract fibres and collaterals using transient responses. It is concluded that, to a first approximation, the linear approach gives physiologically meaningful results.

Animals↗
PubMed2005

Age-related expression of sigma1 receptors and antidepressant efficacy of a selective agonist in the senescence-accelerated (SAM) mouse.

The sigma1 receptor is a unique intracellular receptor whose activation results in an efficient modulation of several neurotransmitter responses. Its role as a target for the rapid nongenomic effects of neuro(active)steroids and the age-related diminutions in steroid levels suggested that targeting the sigma1 receptor might allow alleviation of age-related neuronal dysfunctions. We examined here the expression and behavioral efficacy of sigma1 receptors in the senescence-accelerated (SAM) mouse model. The sigma1 receptor mRNA expression was measured by using comparative RT-PCR in the olfactory bulb, hippocampus, hypothalamus, cortex, or cerebellum of senescence-prone SAMP/8 and senescence-resistant SAMR/1 control animals. No difference was observed between substrains in 6-, 9-, and 12-month-old (m.o.) mice. The sigma1 protein expression was analyzed by using immunohistochemical techniques. Labeling was intense in the olfactory bulb, hippocampus, hypothalamus, and midbrain of both SAMR/1 and SAMP/8 mice, and the distribution appeared unchanged in 6-, 9-, and 12-m.o. animals. The receptor's in vivo availability was examined by using in vivo [3H](+)-SKF-10,047 binding. No age-related difference was observed in the olfactory bulb, hippocampus, hypothalamus, cortex, cerebellum, and brainstem of 6- or 12-m.o. SAMR/1 or SAMP/8 mice. The antidepressant efficacy of the selective agonist igmesine was examined in the forced-swimming test. The compound decreased significantly the immobility duration at 60 mg/kg in 6- and 12-m.o. SAMR/1 and in 6-m.o. SAMP/8 mice. In 12-m.o. SAMP/8 mice, the drug efficacy was facilitated; a significant effect was measured at 30 mg/kg. Decreased neurosteroid levels, particularly of progesterone, were seen in 12-m.o. SAMP/8 mice that might explain the enhanced efficacy of igmesine. Preserved sigma1 receptor expression and enhanced behavioral efficacy of sigma1 agonists were measured in SAM animals, confirming the therapeutic opportunities for selective ligands against age-related mood disorders.

Age Factors↗
PubMedDate not supplied

Acetylcholine and olfactory perceptual learning.

Olfactory perceptual learning is a relatively long-term, learned increase in perceptual acuity, and has been described in both humans and animals. Data from recent electrophysiological studies have indicated that olfactory perceptual learning may be correlated with changes in odorant receptive fields of neurons in the olfactory bulb and piriform cortex. These changes include enhanced representation of the molecular features of familiar odors by mitral cells in the olfactory bulb, and synthetic coding of multiple coincident odorant features into odor objects by cortical neurons. In this paper, data are reviewed that show the critical role of acetylcholine (Ach) in olfactory system function and plasticity, and cholinergic modulation of olfactory perceptual learning at both the behavioral and cortical level.

Acetylcholine↗
PubMed1996

Regional distribution of cytochrome P450 2D1 in the rat central nervous system.

Cytochrome P450s are enzymes involved in the oxidative metabolism of numerous endogenous and exogenous molecules. The enzyme cytochrome debrisoquine/sparteine-type monoxygenase is a specific form of cytochrome P450 and is found in the liver and the brain (in the rat the enzyme is known as CYP2D1). CYP2D1 has no established role in the brain; however, it has been shown to share substrate and inhibitor specificities with the dopamine transporter and the enzyme monoamine oxygenase B. Using CYP2D-specific deoxyoligonucleotide probes and a polyclonal antibody to CYP2D1, we have mapped the distribution of CYP2D mRNA and CYP2D1-like immunoreactivity in the rat central nervous system. CYP2D1 immunoreactivity and the CYP2D1 mRNA signal were heterogenously distributed between brain areas. There were moderate to high levels of immunoreactivity and mRNA signal in the olfactory bulb, olfactory tubercle, cerebral cortex, hippocampus, dentate gyrus, piriform cortex, caudate putamen, supraoptic nucleus, medial habenula, hypothalamus, thalamus, medial mammilliary nucleus and superior colliculus. In the brainstem, strong CYP2D1 immunoreactivity and CYP2D mRNA signal were observed in the substantia nigra compacta, red nucleus, interpeduncular nucleus, pontine grey, locus coeruleus, cerebellum, and the ventral horn of the spinal cord. This study indicates that CYP2D1 is widely and constitutively expressed in neuronal and some glial populations in the rat brain. The localization of CYP2D1 in several regions known to harbor catecholamines and serotonin may suggest a role for CYP2D1 in the metabolism of monoamines.

Animals↗
PubMed1996

Distribution of alpha 2A-adrenergic receptor-like immunoreactivity in the rat central nervous system.

In this study, we analyzed immunohistochemically the distribution of the A subtype of alpha 2-adrenergic receptor (alpha 2A-AR) in the rat central nervous system using light level immunohistochemistry. By using affinity-purified antisera, we found perikaryal labeling was diffuse and/or punctate; immunoreactive puncta were heterogeneous in size and number in a region-specific manner. Dense deposits of immunoreaction product were found associated with neuropil also, particularly in the lateral parabrachial nucleus, locus coeruleus, lateral septum, diagonal band, stratum lacunosum-moleculare of CA1, and various nuclei of the amygdala and extended amygdala. Prominently immunoreactive olfactory structures include the anterior olfactory nucleus and the granular layer of the olfactory bulb. The cortex was generally light to moderately labeled with greater immunoreactivity in the cingulate and insular cortices. alpha 2A-AR-like immunoreactivity was intense in the basal forebrain and continuous from the nucleus accumbens through the substantia innominata and fundus of the striatum. Most immunoreactivity in the diencephalon was restricted to the hypothalamus with light to moderate labeling in the thalamus. Generally light immunoreactivity was observed in midbrain structures. In the pons and medulla, both perikaryal and neuropil labeling were observed. Together with the accompanying paper describing the neural distribution of alpha 2C-AR-like immunoreactivity, our results provide an extensive immunohistochemical cartography of alpha 2-ARs in the adult rat central nervous system.

Animals↗
PubMed1996

Distribution of alpha 2C-adrenergic receptor-like immunoreactivity in the rat central nervous system.

The distribution of alpha 2C-adrenergic receptors (ARs) in rat brain and spinal cord was examined immunohistochemically by using an affinity purified polyclonal antibody. The antibody was directed against a recombinant fusion protein consisting of a 70-amino-acid polypeptide portion of the third intracellular loop of the alpha 2C-AR fused to glutathione-S-transferase. Selectivity and subtype specificity of the antibody were demonstrated by immunoprecipitation of [125I]-photoaffinity-labeled alpha 2-AR and by immunohistochemical labeling of COS cells expressing the individual rat alpha 2-AR subtypes. In both cases the antibody recognized only the alpha 2C-AR subtype, and immunoreactivity was eliminated by preadsorption of the antibody with excess antigen. In rat brain, alpha 2C-AR-like immunoreactivity (alpha 2C-AR-LI) was found primarily in neuronal perikarya, with some labeling of proximal dendrites; analysis by confocal microscopy revealed the intracellular localization of some of the immunoreactivity. Areas of dense immunoreactivity include anterior olfactory nucleus, piriform cortex, septum, diagonal band, pallidum, preoptic areas, supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, amygdala, hippocampus (CA1 and dentate gyrus), substantia nigra, ventral tegmental area, raphe (pontine and medullary), motor trigeminal nucleus, facial nucleus, vestibular nucleus, dorsal motor nucleus of the vagus, and hypoglossal nucleus. Labeling was found in specific laminae throughout the cortex, and a sparse distribution of very darkly labeled cells was observed in the striatum. At all levels of the spinal cord there were small numbers of large, darkly labeled cells in layer IX and much smaller cells in layer X. In general, the pattern of alpha 2C-LI throughout the neuraxis is consistent with previously published reports of the distribution of receptor mRNA detected by hybridization histochemistry.

Animals↗
PubMed1999

Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system.

Glucagon-like peptide-1 (GLP-1) is derived from the peptide precursor pre-pro-glucagon (PPG) by enzymatic cleavage and acts via its receptor, glucagon-like peptide-1 receptor (GLP-1R). By using riboprobes complementary to PPG and GLP-1R, we described the distribution of PPG and GLP-1R messenger RNAs (mRNAs) in the central nervous system of the rat. PPG mRNA-expressing perikarya were restricted to the nucleus of the solitary tact or to the dorsal and ventral medulla and olfactory bulb. GLP-1R mRNA was detected in numerous brain regions, including the mitral cell layer of the olfactory bulb; temporal cortex; caudal hippocampus; lateral septum; amygdala; nucleus accumbens; ventral pallium; nucleus basalis Meynert; bed nucleus of the stria terminalis; preoptic area; paraventricular, supraoptic, arcuate, and dorsomedial nuclei of the hypothalamus; lateral habenula; zona incerta; substantia innominata; posterior thalamic nuclei; ventral tegmental area; dorsal tegmental, posterodorsal tegmental, and interpeduncular nuclei; substantia nigra, central gray; raphe nuclei; parabrachial nuclei; locus ceruleus, nucleus of the solitary tract; area postrema; dorsal nucleus of the vagus; lateral reticular nucleus; and spinal cord. These studies, in addition to describing the sites of GLP-1 and GLP-1R synthesis, suggest that the efferent connections from the nucleus of the solitary tract are more widespread than previously reported. Although the current role of GLP-1 in regulating neuronal physiology is not known, these studies provide detailed information about the sites of GLP-1 synthesis and potential sites of action, an important first step in evaluating the function of GLP-1 in the brain. The widespread distribution of GLP-1R mRNA-containing cells strongly suggests that GLP-1 not only functions as a satiety factor but also acts as a neurotransmitter or neuromodulator in anatomically and functionally distinct areas of the central nervous system.

Animals↗
PubMed1999

DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation.

The homeobox genes in the Dlx family are required for differentiation of basal forebrain neurons and craniofacial morphogenesis. Herein, we studied the expression of Dlx-1, Dlx-2, and Dlx-5 RNA and protein in the mouse forebrain from embryonic day 10.5 (E10.5) to E12.5. We provide evidence that Dlx-2 is expressed before Dlx-1, which is expressed before Dlx-5. We also demonstrate that these genes are expressed in the same cells, which may explain why single mutants of the Dlx genes have mild phenotypes. The DLX proteins are localized primarily to the nucleus, although DLX-5 also can be found in the cytoplasm. During development, the fraction of Dlx-positive cells increases in the ventricular zone. Analysis of the distribution of DLX-1 and DLX-2 in M-phase cells suggests that these proteins are distributed symmetrically to daughter cells during mitosis. We propose that DLX-negative cells in the ventricular zone are specified progressively to become DLX-2-expressing cells during neurogenesis; as these cells differentiate, they go on to express DLX-1, DLX-5, and DLX-6. This process appears to be largely the same in all regions of the forebrain that express the Dlx genes. In the basal telencephalon, these DLX-positive cells differentiate into projection neurons of the striatum and pallidum as well as interneurons, some of which migrate to the cerebral cortex and the olfactory bulb.

3T3 Cells↗
PubMed1998

Immunohistochemical localization of the neural cannabinoid receptor in rat brain.

The cannabinoid receptor family consists of two inhibitory G-protein-coupled receptors, CB1 and CB2. CB1 is distributed primarily in neural tissue, whereas CB2 is distributed predominantly in immune cells. The distribution of cannabinoid receptors in neural tissue has been demonstrated by using ligand binding autoradiography with CP55,940, a high-affinity cannabinoid receptor ligand, and in situ hybridization. However, the localization of CB1 within individual cells in the brain remains to be defined. In the present study, domain-specific polyclonal antibody to amino acids 83-98 of CB1 was used to define the expression of the neural cannabinoid receptor at the histochemical level. The use of CB1-specific antiserum is advantageous in view of recent reports that CB2 also is expressed in the brain and binds CP55,940. Thus, utilization of anti-CB1 antiserum would allow for the specific detection of CB1 protein expression. The regional staining pattern for CB1 in rat brain was consistent with that reported for CB1 using ligand binding autoradiography and in situ hybridization. Intense immunoreactivity was present in the hippocampal formation, the basal ganglia, and the molecular layer of the cerebellum. Moderate immunohistochemical staining was observed in the olfactory bulb, piriform cortex, cerebral cortex, and the granular layer of the cerebellum. In addition, immunoreactive staining was concentrated on afferent projections and dendritic processes of neuronal cells and was present within cell bodies and on cell surfaces. These data indicate that the anti-CB1 antibody is a sensitive probe for the unequivocal histological discrimination of CB1 protein expression.

Animals↗
PubMed1998

Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor.

Stimulation of the epidermal growth factor receptor (EGF-R) produces numerous effects on central nervous system (CNS) cells in vitro including neuronal survival and differentiation, astrocyte proliferation and the proliferation of multipotent progenitors. However, the in vivo role of EGF-R is less well understood. In the present study, we demonstrate that EGF-R null mice generated on a 129Sv/J Swiss Black background undergo focal but massive degeneration the olfactory bulb, piriform cortex, neocortex, and thalamus between postnatal days 5 and 8 which is due, at least in part, to apoptosis. Some of the neuronal populations that degenerate do not normally express EGF-R, indicating an indirect mechanism of neuronal death. There were also delays in GFAP expression within the glia limitans and within structures outside the germinal zones in early postnatal ages. At or just prior to the onset of the degeneration, however, there was an increase in GFAP expression in these areas. The brains of EGF-R (-/-) animals were smaller but cytoarchitecturally normal at birth and neuronal populations appeared to be intact, including striatal GABAergic and midbrain dopaminergic neurons which have previously been shown to express EGF-R. Multipotent progenitors and astrocytes derived from EGF-R (-/-) mice were capable of proliferating in response to FGF-2. These data demonstrate that EGF-R expression is critical for the maintenance of large portions of the postnatal mouse forebrain as well as the normal development of astrocytes.

Animals↗
PubMed1993

Characterization and regulation of corticotropin-releasing factor receptors in the central nervous, endocrine and immune systems.

Corticotropin-releasing factor (CRF) plays a major role in coordinating the endocrine, autonomic, behavioural and immune responses to stress through actions in the brain and in the periphery. CRF receptors identified in brain, pituitary and spleen have comparable kinetic and pharmacological characteristics, guanine nucleotide sensitivity and adenylate cyclase-stimulating activity. Differences were observed in the molecular mass of the CRF receptor complex between brain (58,000 Da) and pituitary and spleen (75,000 Da), which appeared to be due to differential glycosylation of the receptor proteins. In autoradiographic studies, CRF receptors were localized in highest densities in anterior and intermediate lobes of the pituitary, olfactory bulb, cerebral cortex, amygdala, cerebellum and the macrophage-rich marginal zones and red pulp regions of the spleen. CRF can modulate the number of CRF receptors in both the brain and pituitary in a reciprocal manner. The demonstration of functional CRF receptors in brain, pituitary and spleen suggests the importance of this neuropeptide in integrating the responses of the CNS, endocrine and immune systems to physiological, psychological and immunological stimuli.

Animals↗