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)

Operant delayed non-matching-to-position (delayed non-matching-to-position) tasks have been widely used as tests of working memory in rats, but have suffered some loss in sensitivity to differentiating selective mnemonic from non-mnemonic deficits due to floor and ceiling effects. To circumvent this problem, a novel delayed non-matching-to-position was developed in which the retention interval was adjusted on a trial-by-trial basis to hold performance accuracy at an intermediate value. The present study assessed the effects of three amnestic drugs in this delayed non-matching-to-position. Rats were administered (i.p.) NMDA receptor antagonist ((5R,10S)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d,] cyclohepten-5,10-imine (Dizocilpine or MK-801), muscarinic receptor antagonist (-)-scopolamine hydrobromide (scopolamine), or cannabinoid receptor agonist ((R)-(+)-[2, 3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenylmethanone) (WIN 55, 212-2). At high doses, both MK-801 (0.12-0.25 mg/kg) and scopolamine (0.25 mg/kg) produced deficits not selective to working memory. At low doses, scopolamine (0.06-0.12 mg/kg) and MK-801 (0.06 mg/kg) produced no deficits in any mnemonic or secondary measures. WIN 55, 212-2 produced deficits at 2.0 mg/kg that were consistent with a specific impairment of working memory. Using this particular delayed non-matching-to-position revealed that consistent changes in performance accuracy at the short retention interval were evident for scopolamine and MK-801, at times in the absence of changes in response tendency, which are consistent with an interpretation that these drugs produce general deficits in reference or procedural memory. In contrast, cannabinoid-induced deficits in choice accuracy support previous reports of delay-dependent deficits. Together, these data suggest that this delayed non-matching-to-position task is able to differentiate deficit patterns of amnestic drugs, and isolate the effects of motivational side effects of drugs from working memory measurement.
Eur J Pharmacol 2000 Sep 01
PMID:A performance-dependent adjustment of the retention interval in a delayed non-matching-to-position paradigm differentiates effects of amnestic drugs in rats. 1096 48

The effect of the endogenous cannabinoid, anandamide on Ca(2+) flux responses mediated by voltage-dependent Ca(2+) channels was studied in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with 45Ca(2+) and membrane potentials were generated by establishing K(+) gradients across the vesicle using the ionophore, valinomycin. Anandamide, in the range of 1-100 microM, inhibited depolarization-induced efflux responses. Anandamide also functionally modulated the effects of nifedipine (1-10 microM) and Bay K 8644 (1 microM) on Ca(2+) flux responses. Pretreatment with the specific cannabinoid receptor antagonist, SR141716A (1 microM), pertussis toxin (5 microg/ml), the amidohydrolase inhibitor, phenylmethylsulfonyl fluoride (0.2 mM) or the cyclooxygenase inhibitor, indomethacin (5 microM) did not alter the inhibition of efflux responses by anandamide. Arachidonic acid (10-100 microM) also effectively inhibited 45Ca(2+) efflux from membrane vesicles. In radioligand binding studies, it was found that both anandamide and arachidonic acid inhibited the specific binding of [3H]PN 200-110 to transverse tubule membranes with IC(50) values of 4.4+/-0. 7 and 13.4+/-3.5 microM, respectively. These results indicate that anandamide, independent of cannabinoid receptor activation, directly inhibits the function of voltage-dependent calcium channels and modulates the specific binding of calcium channel ligands of the dihydropyridine class.
Eur J Pharmacol 2000 Sep 15
PMID:Endogenous cannabinoid anandamide directly inhibits voltage-dependent Ca(2+) fluxes in rabbit T-tubule membranes. 1098 Feb 58

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.
Eur J Neurosci 2000 Sep
PMID:Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. 1099 7

Large-scale cDNA microarrays were employed to assess transient changes in gene expression levels following acute and chronic exposure to cannabinoids in rats. A total of 24,456 cDNA clones were randomly selected from a rat brain cDNA library, amplified by PCR, and arrayed at high density to investigate differential gene expression profiles following acute (24 h), intermediate (7 days), and chronic (21 days) exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient of marijuana. Hippocampal mRNA probes labeled with (33)P obtained from both vehicle and Delta(9)-THC-treated animals were hybridized with identical cDNA microarrays. Results revealed a total of 49 different genes altered by Delta(9)-THC exposure; of these, 28 were identified, 10 had homologies to expressed sequence tags (ESTs), and 11 had no homology to known sequences in the GenBank database. Chronic or acute cannabinoid receptor activation altered expression of several genes (i.e., prostaglandin D synthase, calmodulin) involved in biochemical cascades of cannabinoid synthesis or cannabinoid effector systems. Other genes [i.e., neural cell adhesion molecule (NCAM), myelin basic protein], whose relation to cannabinoid system function was not immediately obvious, were also significantly altered. Verification of the changes obtained with the large-scale screen was determined by RNA dot blots in different groups of animals treated the same as those in the large-scale screen. Results are discussed in terms of the different types of genes affected at different times during chronic Delta(9)-THC exposure.
Physiol Genomics 2000 Sep 08
PMID:Large-scale analysis of gene expression changes during acute and chronic exposure to [Delta]9-THC in rats. 1101 13

Data, initially anecdotal, but recently supported on more solid experimental evidence, suggest that cannabinoids might be beneficial in the treatment of some of the symptoms of multiple sclerosis (MS). Despite this evidence, there are no data on the possible changes in cannabinoid CB(1) or CB(2) receptors, the main molecular targets for the action of cannabinoids, either in the postmortem brain of patients with MS or in animal models of this disease. The present study addressed this question using the model of experimental allergic encephalomyelitis (EAE) in Lewis rats generated by inoculation of guinea pig myelin basic protein in Freund's adjuvant. After inoculation, animals were examined daily to detect the appearance of neurological signs. The first signs appeared around day 10 after inoculation, reaching the highest degree by day 13, when animals were sacrificed and their brains removed and used for analysis of CB(1) receptor binding, mRNA levels, and activation of GTP-binding proteins. CB(1) receptor binding and mRNA levels were not affected in EAE rats in brain areas such as the hippocampus, limbic structures, and cerebellum. However, there was a marked decrease in both parameters in the caudate-putamen, both in the lateral and medial parts, although this decrease did not correspond with decreases in binding in the nuclei recipient of striatal output neurons, which suggests that changes in CB(1) receptors are exclusively located in the cell bodies of striatal neurons. In addition, CB(1) receptor binding, but not mRNA levels, also decreased in the cerebral cortex, both in the deep and the superficial layers. The analysis of [(35)S]GTPgammaS binding after activation of CB(1) receptors with WIN55,212-2, a synthetic agonist, revealed that, despite the decrease in the number of CB(1) receptors in EAE rats, these were more efficiently coupled to GTP-binding protein-mediated signaling mechanisms in both the caudate-putamen and the cerebral cortex of these animals. In summary, these data suggest that the generation of EAE in Lewis rats would be associated with changes in CB(1) receptors in striatal and cortical neurons, which might be related to the alleviation of some motor signs observed after the treatment with cannabinoid receptor agonists in similar models of MS in rodents.
Synapse 2001 Sep 01
PMID:Changes in cannabinoid CB(1) receptors in striatal and cortical regions of rats with experimental allergic encephalomyelitis, an animal model of multiple sclerosis. 1139 80

The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB(1) cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). SR 141716A-precipitated Delta(9)-THC withdrawal was ameliorated in mu-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB(1) cannabinoid receptors. An acute injection of morphine in Delta(9)-THC-dependent mice undergoing SR 1417161A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist dose 50 (AD(50)) (95% CL) = 0.035 (0.03--0.04), and head shakes, AD(50) (95% CL) = 0.07 (0.04--0.12). In morphine-dependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipitated morphine withdrawal failed to occur in mu-opioid knockout mice and was significantly decreased in CB(1) cannabinoid receptor knockout mice. Acute treatment of Delta(9)-THC in morphine-dependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD(50) (95% CL) = 0.5 (0.3--1.0), and head shakes AD(50) (95% CL) = 0.6 (0.57--0.74) in dose-dependent manners, but failed to diminish the occurrence of diarrhea or jumping. Finally, naloxone and SR 141716A failed to elicit any overt effects in Delta(9)-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the mu-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence.
J Pharmacol Exp Ther 2001 Sep
PMID:Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice. 1150 97

Previous studies in our laboratory have demonstrated that cannabinoids administered intravenously attenuate the duration of nocifensive behavior and block the development of hyperalgesia produced by intraplantar injection of capsaicin. In the present study, we extended these observations and determined whether cannabinoids attenuate capsaicin-evoked pain and hyperalgesia through spinal and peripheral mechanisms, and whether the antihyperalgesia was receptor mediated. Separate groups of rats were pretreated 7 min before capsaicin with an intrathecal injection of vehicle or the cannabinoid receptor agonist WIN 55,212-2 at doses of 0.1, 1.0 or 10 microg in 10 microl. Although the intrathecal application of WIN 55,212-2 did not alter nocifensive behavior following capsaicin, it produced a dose-dependent decrease in hyperalgesia to heat and mechanical stimuli. Intrathecal pretreatment with the CB1 receptor antagonist SR141716A (10 microg) blocked the antihyperalgesia produced by WIN 55,212-2. The ability of intrathecal administration of WIN 55,212-2 to attenuate hyperalgesia was not due to motor deficits since the highest dose of WIN 55,212-2 did not alter performance on the rota-rod test. To investigate whether cannabinoids attenuated capsaicin-evoked hyperalgesia through peripheral mechanisms, separate groups of rats were pretreated with an intraplantar injection of WIN 55,212-2 at doses of 0.1, 1.0, 10 or 30 microg in 100 microl 5 min before capsaicin. Intraplantar pretreatment with WIN 55,212-2 produced a dose-dependent attenuation of hyperalgesia to heat, but did not attenuate mechanical hyperalgesia or the duration of nocifensive behavior. The inactive enantiomer WIN 55,212-3 did not alter the development of hyperalgesia. SR141716A (100 microg) co-injected with WIN 55,212-2 (30 microg) partially attenuated the effects of WIN 55,212-2 on hyperalgesia to heat. Intraplantar injection of the highest dose of WIN 55,212-2 did not interfere with the development of hyperalgesia following capsaicin injection into the contralateral paw. These data show that cannabinoids possess antihyperalgesic properties at doses that alone do not produce antinociception, and are capable of acting at both spinal and peripheral sites.
Pain 2001 Sep
PMID:Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms. 1151 89

Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Delta(9)-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB(1) cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Delta(9)-THC, indicating that Delta(9)-THC afforded protection to neurons via the CB(1) receptor. In Delta(9)-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB(1) receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration.
J Neurosci 2001 Sep 01
PMID:Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. 1151 36

We studied the effects of nociceptin, the endogenous ligand of the opioid OP4 receptor, and of two cannabinoid receptor agonists WIN 55,212-2 and CP-55,940 (0.001-1 micromol/kg each) on the neurogenic tachycardia and bradycardia in pithed rats. Electrical stimulation (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibres and injection of nicotine 2 micromol/kg or isoprenaline 0.5 nmol/kg increased heart rate by about 70 beats/min (bpm) in pithed rats pretreated with atropine 1.5-2 micromol/kg. The electrically induced tachycardia was reduced dose dependently by nociceptin, WIN 55,212-2 and CP-55,940 (by 60, 30 and 20% at the highest dose, respectively). The OP4 and cannabinoid receptor agonists diminished the nicotine- but not the isoprenaline-stimulated increase in heart rate. In pithed rats pretreated with propranolol 3 micromol/kg, vagal stimulation (5 Hz, 1 ms, 15 V for 10 s) or injection of methacholine (5-10 nmol/kg) decreased heart rate by about 30 bpm. Nociceptin, but not WIN 55,212-2 or CP-55,940 decreased the vagal bradycardia dose dependently (the inhibitory effect of 1 micromol/kg was about 40%). Nociceptin failed to modify the methacholine-induced decrease in heart rate. The OP4 receptor antagonists naloxone benzoylhydrazone 5 micromol/kg and/or [Phe1Psi(CH2-NH)Gly2]-nociceptin(1-13)NH2 0.7 micromol/kg, but not the OP(1-3) receptor antagonist naloxone 10 micromol/kg, diminished the inhibitory action of nociceptin on the neurogenic tachycardia and bradycardia. The inhibitory effect of both cannabinoid receptor agonists on the neurogenic tachycardia was abolished by the CB1 receptor antagonist SR 141716 0.1 micromol/kg. The present data suggest that the postganglionic sympathetic nerve fibres innervating the rat heart are endowed with presynaptic opioid OP4 and cannabinoid CB1 receptors, activation of which inhibits the neurogenic tachycardia. The parasympathetic nerve fibres innervating the heart and causing bradycardia are endowed with presynaptic opioid OP4 but not cannabinoid receptors.
Naunyn Schmiedebergs Arch Pharmacol 2001 Sep
PMID:Modulation of the cardiac autonomic transmission of pithed rats by presynaptic opioid OP4 and cannabinoid CB1 receptors. 1152 Nov 66

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient of cannabis sativa, reduces both extracellular hippocampal acetylcholine concentration and correct alternation tasks in the T-maze. The principal aim of this study was to determine whether a chronic Delta(9)-THC treatment would induce tolerance both to the reduction of extracellular hippocampal acetylcholine concentration and memory deficit produced by the drug. Our results show that a chronic Delta(9)-THC treatment (5mg/kg, i.p., twice daily for two weeks) did not produce tolerance to the inhibitory effects induced by the drug. Moreover, no strict temporal correlation between the two Delta(9)-THC effects was observed: the inhibition in extracellular acetylcholine concentration appeared only 80 min after treatment, while the reduction of correct alternation tasks in the T-maze began after 20 min. The cognitive and cholinergic effects induced by a chronic Delta(9)-THC treatment were completely blocked by the CB(1) cannabinoid receptor antagonist SR 141716A, indicating an involvement of CB(1) cannabinoid receptors in the persistent negative effects induced by the drug. These findings confirm the proposition that CB(1) cannabinoid receptors mediate the negative effects induced by Delta(9)-THC both on hippocampal extracellular acetylcholine concentration and correct alternation tasks in the T-maze, and they indicate that these effects may be differentiated. However, the major outcome of this work is the demonstration that no tolerance to the two inhibitory effects develops after a chronic Delta(9)-THC treatment.
Neuropharmacology 2001 Sep
PMID:Effects of chronic Delta(9)-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze. 1152 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>