Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuronal distribution of cannabinoid receptor in the adult rat brain is reported, combining receptor binding radioautography using the synthetic psychoactive cannabinoid ligand CP55,940 with in situ hybridization histochemistry using oligonucleotide probes complementary to rat cannabinoid receptor cDNA. In the cerebral cortex, especially in the frontal and cingulate cortex, dense binding was found in layers I and VI together with slight mRNA levels in a majority of both pyramidal and non-pyramidal-shaped neurons and of high mRNA levels in a moderate number of non-pyramidal-shaped neurons especially in layers II-III and V-VI. In the hippocampal dentate gyrus, very dense staining was found in the molecular layer together with high mRNA levels in a moderate number of hilar neurons close to the granular layer. In Ammon's horn, especially in the CA3 sector, very dense binding was found in the dendritic layers together with slight mRNA levels in the majority of the pyramidal cells and high mRNA levels in a moderate number of interneurons. In the basal ganglia, binding was very dense in the lateral putamen, substantia nigra pars reticulata, globus pallidus and entopeduncular nucleus, moderate in the medial putamen and caudate; and slight in the accumbens, together with slight to moderate mRNA levels in the striatal medium-sized neurons. Together with slight binding, slight to moderate mRNA levels were found in the majority of the neurons in the subthalamic nucleus. No binding and mRNA were found in the substantia nigra pars compacta and ventral tegmental area. Slight to moderate binding was found together with slight to moderate mRNA levels in the majority of neurons in the anterior olfactory nucleus; septum, especially medial septum and diagonal band of Broca; amygdala, especially basolateral amygdala; lateral habenula; ventromedial hypothalamic nucleus; lateral interpeduncular nucleus; central gray, dorsal cochlear nucleus; parabrachial nucleus; dorsal pontine tegmentum; pontine nuclei; commissural part of the nucleus tractus solitarius; inferior olive and dorsal horn of the spinal cord. In the cerebellum, very dense binding was found in the molecular layer together with slight mRNA levels in the majority of the granule cells and moderate mRNA levels in the basket and stellate cells. In conclusion, this study provides, for the first time, indirect assessment of the neurons containing cannabinoid receptor in the entire adult rat brain and will serve as a basis for future direct morphological confirmation using receptor immunohistochemistry and for functional studies.
 ...
PMID:Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. 137 55

A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
 ...
PMID:Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. 199 16

We have recently found that cannabinoid receptor binding and gene expression markedly decreased in extrapyramidal structures of aged rats. The present study was designed to analyze the possible existence of similar aging-induced changes in cannabinoid receptor binding and gene expression in brain regions other than extrapyramidal areas, but that also contain a significant population of cannabinoid receptors, such as the cerebellum, hippocampal structures, limbic and hypothalamic nuclei, the cerebral cortex and others. To this end, we analyzed cannabinoid receptor binding, using autoradiography, and cannabinoid receptor mRNA levels, using in situ hybridization, in slide-mounted brain sections obtained from young (3 month old) and aged (> 2 year old) rats. Results were as follows. In the cerebellum, aged rats exhibited a marked decrease in cannabinoid receptor binding in the molecular layer (-33.3%), although accompanied by no changes in mRNA levels in the granular layer. In the cerebral cortex, a small, although statistically significant, decrease in binding was found in the deep layer (VI) (-18.3%) of aged rats, whereas no changes were found in the superficial layer (I). As in the case of the cerebellum, mRNA levels did not change in the cerebral cortex layers (II-III and V-VI). The different regions of the Ammon's horn of the hippocampus exhibited similar cannabinoid receptor binding levels in aged and young rats. Interestingly, mRNA levels decreased in aged rats to a small, but statistically significant, extent (CA1: -26.1%; CA2: -21.6%; CA3: -14.4%). This was also seen in another hippocampal structure, the dentate gyrus (-14.6%), although in this region binding levels increased in aged rats (+28.4%). Two hypothalamic structures, the arcuate nucleus and the ventromedial hypothalamic nucleus, exhibited decreased cannabinoid receptor binding in aged rats (-31.1% and -30.3%, respectively), but this was not seen in the medial preoptic area. This was accompanied by no changes in mRNA levels in the ventromedial hypothalamic nucleus. In the limbic structures, aged rats exhibited similar binding levels to young rats. This was seen in the nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus. However, mRNA levels slightly decreased in the basolateral amygdaloid nucleus (-13.4%), whereas they were not altered in the septum nuclei. Finally, other brain structures, such as the central gray substance and the brainstem, exhibited similar binding levels in aged and young rats. However, it is important to note that mRNA levels increased significantly (+211.2%) in the brainstem of aged rats, an area where the levels of binding and mRNA were very low in young rats. This marked increase may be related to an increase in the presence of glial elements in this region, as revealed by the increase in the immunoreactivity for glial fibrillary acidic protein observed in the brainstem of aged rats as compared to young animals. In summary, senescence was associated with changes in cannabinoid receptors in the cerebellum, the cerebral cortex, limbic and hypothalamic structures, the hippocampus and other brain regions. However, the changes observed (i) were not as marked and relevant as those early reported in extrapyramidal areas, and (ii) exhibited regional differences that might be attributed to the different roles played by these receptors in each region. Of particular relevance by their magnitude were the aging-induced decrease in binding found in the cerebellum and the hypothalamus, and the increase in mRNA levels observed in the brainstem. The latter might be related to an increase in the presence of glial cells which might contain cannabinoid receptor mRNA.
 ...
PMID:Changes in cannabinoid receptor binding and mRNA levels in several brain regions of aged rats. 974 81

Cannabinoids, such as marijuana, are known to impair learning and memory perhaps through their actions in the hippocampus where cannabinoid receptors are expressed at high density. Although cannabinoid receptor activation decreases glutamatergic synaptic transmission in cultured hippocampal neurons, the mechanisms of this action are not known. Cannabinoid receptor activation also inhibits calcium channels that support neurotransmitter release in these cells, making modulation of these channels a candidate for cannabinoid-receptor-mediated effects on synaptic transmission. Whole cell patch-clamp recordings of glutamatergic neurons cultured from the CA1 and CA3 regions of the hippocampus were used to identify the mechanisms of the effects of cannabinoids on synaptic transmission. Cannabinoid receptor activation reduced excitatory postsynaptic current (EPSC) size by approximately 50% but had no effect on the amplitude of spontaneous miniature EPSCs (mEPSCs). This reduction in EPSC size was accompanied by an increase in paired-pulse facilitation measured in low (1 mM) extracellular calcium and by a decrease in paired-pulse depression measured in normal (2.5 mM) extracellular calcium. Together, these results strongly support the hypothesis that cannabinoid receptor activation decreases EPSC size by reducing release of neurotransmitter presynaptically while having no effect on postsynaptic sensitivity to glutamate. Further experiments were done to identify the molecular mechanisms underlying this cannabinoid-receptor-mediated decrease in neurotransmitter release. Cannabinoid receptor activation had no effect on the size of the presynaptic pool of readily releasable neurotransmitter-filled vesicles, eliminating reduction in pool size as a mechanism for cannabinoid-receptor-mediated effects. After blockade of Q- and N-type calcium channels with omega-agatoxin TK and omega-conotoxin GVIA; however, activation of cannabinoid receptors reduced EPSC size by only 14%. These results indicate that cannabinoid receptor activation reduces the probability that neurotransmitter will be released in response to an action potential via an inhibition of presynaptic Q- and N-type calcium channels. This molecular mechanism most likely contributes to the impairment of learning and memory produced by cannabinoids and may participate in the analgesic, antiemetic, and anticonvulsive effects of these drugs as well.
 ...
PMID:Mechanisms of cannabinoid-receptor-mediated inhibition of synaptic transmission in cultured hippocampal pyramidal neurons. 1048 47

Using a new antibody developed against the C-terminus of the cannabinoid receptor (CB1), the immunostaining in the hippocampus revealed additional axon terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) synapses were also strongly immunoreactive for CB1 receptors, as were axon terminals of perisomatic inhibitory cells containing cholecystokinin. Asymmetrical (glutamatergic) synapses, however, were always negative for CB1. To investigate the effect of presynaptic CB1 receptor activation on hippocampal inhibition, we recorded inhibitory postsynaptic currents (IPSCs) from principal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55,940) suppressed IPSCs evoked by local electrical stimulation, which could be prevented or reversed by the CB1 receptor antagonist SR141716A. Action potential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also examined the effects of CB1 receptor agonists on Ca2+-independent miniature IPSCs (mIPSC). Both agonists were without significant effect on the frequency or amplitude of mIPSCs. Synchronous gamma oscillations induced by kainic acid in the CA3 region of hippocampal slices were reversibly reduced in amplitude by the CB1 receptor agonist CP 55,940, which is consistent with an action on IPSCs. We used CB1-/- knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that activation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations.
 ...
PMID:Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. 1099 7

The effects of chronic exposure to cannabinoids on short-term memory in rats were assessed during repeated daily injections of an initially debilitating dose (3.75 mg/kg) of the potent CB1 cannabinoid receptor ligand, WIN 55,212-2. Delayed nonmatch to sample (DNMS) performance was assessed over a 35-day exposure period in which performance was initially disrupted during the first 21 days of exposure but recovered by day 30 and was stable at pre-drug levels for 5 days thereafter. Withdrawal was precipitated by injections of the CB1 receptor antagonist SR141716A and transiently reduced performance for 2 days but was restabilized to pre-drug levels within 3-4 days. Concomitant recording from identified CA1 and CA3 hippocampal neurons demonstrated a marked correspondence in the time course of suppression of peak firing in the sample and delay phases of the task to the drug-induced performance deficits over the same days of exposure. Hippocampal encoding of task-relevant events and performance levels "tracked" each other on a daily basis throughout the chronic cannabinoid treatment and withdrawal regimen. However, hippocampal neuronal activity in the nonmatch phase of the task was unaffected by the chronic cannabinoid treatment or withdrawal, suggesting that only a select population of hippocampal neurons and synapses are involved in cannabinoid-sensitive short-term memory processes.
 ...
PMID:Tolerance to the memory disruptive effects of cannabinoids involves adaptation by hippocampal neurons. 1292 45

Cortical information processing requires an orchestrated interaction between a large number of pyramidal cells and albeit fewer, but highly diverse GABAergic interneurons (INs). The diversity of INs is thought to reflect functional and structural specializations evolved to control distinct network operations. Consequently, specific cortical functions may be selectively modified by altering the input-output relationship of unique IN populations. Here, we report that persistently active cannabinoid receptors, the site of action of endocannabinoids, and the psychostimulants marijuana and hashish, switch off the output (mute) of a unique class of hippocampal INs. In paired recordings between cholecystokinin-immunopositive, mossy fiber-associated INs, and their target CA3 pyramidal cells, no postsynaptic currents could be evoked with single presynaptic action potentials or with repetitive stimulations at frequencies <25 Hz. Cannabinoid receptor antagonists converted these "mute" synapses into high-fidelity ones. The selective muting of specific GABAergic INs, achieved by persistent presynaptic cannabinoid receptor activation, provides a state-dependent switch in cortical networks.
 ...
PMID:Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. 1473 12

Transgenic mice are overtaking the role of model animals in neuroscience. They are used in developmental, anatomical, and physiological as well as experimental neurology. However, most results on the organization of the nervous system derive from the rat. The rat hippocampus and its neuronal elements have been thoroughly investigated, revealing remarkable functional and morphological diversity and specificity among hippocampal interneurons. Our aim was to examine the properties of distinct hippocampal interneuron populations, i.e., those immunoreactive for calcium-binding proteins (parvalbumin, calbindin, and calretinin), neuropeptides (cholecystokinin, neuropeptide Y, somatostatin, vasoactive intestinal polypeptide), and certain receptors (metabotropic glutamate receptor 1alpha, cannabinoid receptor type 1) in four strains of mice widely used in transgenic technology, and to compare their properties to those in the rat. Our data indicate that the distribution as well as the dendritic and axonal arborization of mouse interneurons immunoreactive for the different markers was identical in the examined mouse strains, and in most respects are similar to the features found in the rat. The postsynaptic targets of neurons terminating in the perisomatic (parvalbumin), proximal (calbindin), and distal (somatostatin) dendritic region, as well as on other interneurons (calretinin), also matched those found in the rat. However, a few significant differences could also be observed between the two species in addition to the already described immunoreactivity of mossy cells for calretinin: the absence of spiny calretinin-immunoreactive interneurons in the CA3 region, sparse contacts between calretinin-immunoreactive interneurons, and the axon staining for somatostatin and neuropil labeling for cholecystokinin. We can conclude that the morphofunctional classification of interneurons established in the rat is largely valid for mouse strains used in transgenic procedures.
 ...
PMID:Immunocytochemically defined interneuron populations in the hippocampus of mouse strains used in transgenic technology. 1522 83

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) catalyse the hydrolysis of the endocannabinoids anandamide and 2-arachidonoyl glycerol. We investigated their ultrastructural distribution in brain areas where the localization and effects of cannabinoid receptor activation are known. In the hippocampus, FAAH was present in somata and dendrites of principal cells, but not in interneurons. It was located mostly on the membrane surface of intracellular organelles known to store Ca(2+) (e.g. mitochondria, smooth endoplasmic reticulum), less frequently on the somatic or dendritic plasma membrane. MGL immunoreactivity was found in axon terminals of granule cells, CA3 pyramidal cells and some interneurons. In the cerebellum, Purkinje cells and their dendrites are intensively immunoreactive for FAAH, together with a sparse axon plexus at the border of the Purkinje cell/granule cell layers. Immunostaining for MGL was complementary, the axons in the molecular layer were intensively labelled leaving the Purkinje cell dendrites blank. FAAH distribution in the amygdala was similar to that of the CB(1) cannabinoid receptor: evident signal in neuronal somata and proximal dendrites in the basolateral nucleus, and hardly any labelling in the central nucleus. MGL staining was restricted to axons in the neuropil, with similar relative signal intensities seen for FAAH in different nuclei. Thus, FAAH is primarily a postsynaptic enzyme, whereas MGL is presynaptic. FAAH is associated with membranes of cytoplasmic organelles. The differential compartmentalization of the two enzymes suggests that anandamide and 2-AG signalling may subserve functional roles that are spatially segregated at least at the stage of metabolism.
 ...
PMID:Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. 1523 53

Endocannabinoid signaling, mediated by presynaptic CB1 cannabinoid receptors on neurons, is fundamental for the maintenance of synaptic plasticity by modulating neurotransmitter release from axon terminals. In the rodent basal forebrain, CB1 cannabinoid receptor-like immunoreactivity is only harbored by a subpopulation of cholinergic projection neurons. However, endocannabinoid control of cholinergic output from the substantia innominata, coincident target innervation of cholinergic and CB1 cannabinoid receptor-containing afferents, and cholinergic regulation of endocannabinoid synthesis in the hippocampus suggest a significant cholinergic-endocannabinergic interplay. Given the functional importance of the cholinergic modulation of endocannabinoid signaling, here we studied CB1 cannabinoid receptor distribution in cholinergic basal forebrain territories and their cortical projection areas in a prosimian primate, the gray mouse lemur. Perisomatic CB1 cannabinoid receptor immunoreactivity was unequivocally present in non-cholinergic neurons of the olfactory tubercule, and in cholecystokinin-containing interneurons in layers 2/3 of the neocortex. Significantly, CB1 cannabinoid receptor-like immunoreactivity was localized to cholinergic perikarya in the magnocellular basal nucleus. However, cortical cholinergic terminals lacked detectable CB1 cannabinoid receptor levels. A dichotomy of CB1 cannabinoid receptor distribution in frontal (suprasylvian) and parietotemporal (subsylvian) cortices was apparent. In the frontal cortex, CB1 cannabinoid receptor-containing axons concentrated in layers 2/3 and layer 6, while layer 4 and layer 5 were essentially devoid of CB1 cannabinoid receptor immunoreactivity. In contrast, CB1 cannabinoid receptors decorated axons in all layers of the parietotemporal cortex with peak densities in layer 2 and layer 4. In the hippocampus, CB1 cannabinoid receptor-containing terminals concentrated around pyramidal cell somata and proximal dendrites in the CA1-CA3 areas, and granule cell dendrites in the molecular layer of the dentate gyrus. CB1 cannabinoid receptors frequently localized to inhibitory GABAergic terminals while leaving glutamatergic boutons unlabeled. Aging did not affect either the density or layer-specific distribution of CB1 cannabinoid receptor-immunoreactive processes. We concluded that organizing principles of CB1 cannabinoid receptor-containing neurons and their terminal fields within the basal forebrain are evolutionarily conserved between rodents and prosimian primates. In contrast, the areal expansion and cytoarchitectonic differentiation of neocortical subfields in primates is associated with differential cortical patterning of CB1 cannabinoid receptor-containing subcortical and intracortical afferents.
 ...
PMID:Redistribution of CB1 cannabinoid receptors during evolution of cholinergic basal forebrain territories and their cortical projection areas: a comparison between the gray mouse lemur (Microcebus murinus, primates) and rat. 1612 64


1 2 3 4 Next >>