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Journal ArticleDOI

The central neuropharmacology of psychotropic cannabinoids.

01 Jan 1988-Pharmacology & Therapeutics (Pharmacol Ther)-Vol. 36, pp 189-261
About: This article is published in Pharmacology & Therapeutics.The article was published on 1988-01-01. It has received 167 citations till now. The article focuses on the topics: Neuropharmacology.
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18 Dec 1992-Science
TL;DR: In this article, an arachidonylethanthanolamide (anandamide) was identified in a screen for endogenous ligands for the cannabinoid receptor and its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and confirmed by synthesis.
Abstract: Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.

5,283 citations

Journal ArticleDOI
TL;DR: Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature.

2,764 citations

Journal ArticleDOI
TL;DR: 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.
Abstract: 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.

2,070 citations


Cites background from "The central neuropharmacology of ps..."

  • ..., 1990) most of the biochemical studies employed concentrations of A”-THC that were in excess of physiologically meaningful concentrations that might be found in the brain (for review, see Martin, 1986; Pertwee, 1988)....

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  • ...Without evidence that cannabinoids act through a specific receptor coupled to a functional effector system, researchers were prone to study the effects of cannabinoids on membrane properties, membrane-bound enzymes, eicosanoid production, metabolism, and other neurotransmitter systems in vitro (Hilhard et al., 1985; Martin, 1986; Pertwee, 1988; Reichman et al., 1988)....

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Journal ArticleDOI
TL;DR: This review focuses on the manner with which three of these compounds, (−)‐trans‐Δ 9‐tetrahydrocannabinol (Δ9‐THC), (−]‐cannabidiol (CBD) and (−)-trans‐ Δ9‐TetrahYDrocannabivarin (Γ‐THCV), interact with cannabinoid CB1 and CB2 receptors.
Abstract: Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

1,492 citations


Cites background from "The central neuropharmacology of ps..."

  • ...…TRPV1, transient receptor potential vanilloid receptor 1; A, activation; P, potentiation; (þ ), increase induced; ( ), decrease induced. aSee review by Oz (2006) for references and further details. bSee review by Pertwee (1988) for references, further details and additional actions of D9-THC....

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Journal ArticleDOI
TL;DR: This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors, and describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.

1,456 citations

References
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Journal Article
TL;DR: A diagrammatic summary of the membrane actions of anesthetics and tran-quilizers is shown, and the membrane fluidization may explain the enhanced neurosecretion of membrane-bound materials, by a mechanism of membranes-membrane fusion.
Abstract: A diagrammatic summary of the membrane actions of anesthetics and tran-quilizers is shown in figure 15. According to the definition of an anesthetic as a drug which directly blocks the membrane action potential, without appreciably affecting the resting potential, a wide variety of lipid-soluble compounds may be considered as anesthetics. Under conditions of general anesthesia the membrane concentration of an anesthetic is 0.003 moles/kg dry membrane, the anesthetic occupying a volume of 0.02% in the membrane phase. Under conditions of local anesthesia the membrane concentration is 0.04 moles/kg membrane, with an occupying volume of 0.3% in the membrane. The partitioning into the membrane is about 1/10 that of olive oil and about ⅕ that of octanol. These figures hold for many nerve-blocking drugs, and in order to explain differences in the in vivo action of these drugs, other factors must be considered, such as anesthetic sensitization etc. The biomembranes expand or swell about 10 times more than the anesthetic volume of occupation in the membrane, 0.4% expansion occuring under conditions of general anesthesia, and 2 to 3% expansion occuring under conditions of local anesthesia. Although the anesthetics electrically stabilize the membrane, they fluidize and disorder the components within the membrane, probably including membrane water. As a consequence of membrane expansion, membrane-associated enzymes and proteins can be either stimulated or inhibited. The pathways for facilitated fluxes of solutes across membranes are invariably depressed, presumably because of the conformation changes brought about by the membrane-expanding anesthetics; the Na+-conductance channel of the action potential appears to be one of these facilitated pathways. The anesthetic amines displace membrane-bound Ca++ and generally depress passive fluxes of cations. The neutral anesthetics generally increase membrane-bound Ca++ and generally increase the passive fluxes. The membrane fluidization may explain the enhanced neurosecretion of membrane-bound materials, by a mechanism of membrane-membrane fusion.

2,146 citations

Journal Article
TL;DR: The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult as discussed by the authors, however, it is difficult to prove.
Abstract: Marijuana seems firmly established as another social drug in Western countries, regardless of its current legal status. Patterns of use vary widely. As with other social drugs, the pattern of use is critical in determining adverse effects on health. Perhaps the major area of concern about marijuana use is among the very young. Using any drug on a regular basis that alters reality may be detrimental to the psychosocial maturation of young persons. Chronic use of marijuana may stunt the emotional growth of youngsters. Evidence for an amotivational syndrome is largely based on clinical reports; whether marijuana use is a cause or effect is uncertain. A marijuana psychosis, long rumored, has been difficult to prove. No one doubts that marijuana use may aggravate existing psychoses or other severe emotional disorders. Brain damage has not been proved. Physical dependence is rarely encountered in the usual patterns of social use, despite some degree of tolerance that may develop. The endocrine effects of the drug might be expected to delay puberty in prepubertal boys, but actual instances have been rare. As with any material that is smoked, chronic smoking of marijuana will produce bronchitis; emphysema or lung cancer have not yet been documented. Cardiovascular effects of the drug are harmful to those with preexisting heart disease; fortunately the number of users with such conditions is minimal. Fears that the drug might accumulate in the body to the point of toxicity have been groundless. The potential deleterious effects of marijuana use on driving ability seem to be self-evident; proof of such impairment has been more difficult. The drug is probably harmful when taken during pregnancy, but the risk is uncertain. One would be prudent to avoid marijuana during pregnancy, just as one would do with most other drugs not essential to life or well-being. No clinical consequences have been noted from the effects of the drug on immune response, chromosomes, or cell metabolites. Contamination of marijuana by spraying with defoliants has created the clearest danger to health; such attempts to control production should be abandoned. Therapeutic uses for marijuana, THC, or cannabinoid homologs are being actively explored. Only the synthetic homolog, nabilone, has been approved for use to control nausea and vomiting associated with cancer chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

530 citations

Journal Article
TL;DR: It is demonstrated that pertussis toxin treatment of cells abolished the cannabimimetic response in intact cells and in membranes derived therefrom, demonstrating the requirement for a functional Gi in the action of cannabIMimetic drugs.
Abstract: The cellular mechanism of action of the cannabimimetic drugs is examined using cultured cells. In membranes from N18TG2 neuroblastoma cells and the neuroblastoma X glioma hybrid cells, NG108-15, the psychoactive cannabinoid drugs and their nantradol analogs could inhibit adenylate cyclase activity. This response was not observed in either the soluble adenylate cyclase from rat sperm or membrane-bound adenylate cyclases from C6 glioma or S49 lymphoma cells. This cellular selectivity provides further evidence for the existence of specific receptors for the cannabimimetic compounds. Receptor-mediated inhibition of adenylate cyclase requires the presence of a guanine nucleotide-binding protein complex, Gi. Gi can be functionally inactivated as a result of an ADP-ribosylation modification catalyzed by pertussis toxin. The present study demonstrates that pertussis toxin treatment of cells abolished the cannabimimetic response in intact cells and in membranes derived therefrom. The action of pertussis toxin required NAD+ as substrate for in vitro modification of neuroblastoma membranes. Furthermore, pertussis toxin was able to catalyze the labeling of a neuroblastoma membrane protein in vitro using [32P] NAD+ under conditions similar to those by which attenuation of the cannabimimetic inhibition of adenylate cyclase could be demonstrated. This evidence demonstrates the requirement for a functional Gi in the action of cannabimimetic drugs.

469 citations