The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform
Bertha K Madras - One of the best experts on this subject based on the ideXlab platform.
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cannabinoid receptor agonist and antagonist effects on motor function in normal and 1 methyl 4 phenyl 1 2 5 6 tetrahydropyridine mptp treated non human primates
Psychopharmacology, 2001Co-Authors: Justin P Meschler, Allyn C. Howlett, Bertha K MadrasAbstract:Rationale: Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. Objectives: We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Methods: Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. Results: The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist Levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, Levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Conclusions: Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
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d 2 but not d 1 dopamine receptor agonists potentiate cannabinoid induced sedation in nonhuman primates
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Justin P Meschler, Allyn C. Howlett, Francis A Clarkson, Patricia J Mathews, Bertha K MadrasAbstract:In primates, CB1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D1 or D2 dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys ( Macaca fasicularis ) alone and after administration of a low dose of the CB1 agonist Levonantradol. Alone, the CB1cannabinoid receptor agonist Levonantradol (0.01–0.3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D2-type dopamine agonists quinelorane (0.001–1.0 mg/kg; n = 4) or pergolide (0.01–1.0 mg/kg) or a D1 dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3–3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after administration of a threshold dose of Levonantradol (0.03 mg/kg), D2-type agonists, but not the D1 agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D2, but not D1 dopamine agonists, potentiate sedation in monkeys treated with a CB1cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D2 agonists, but not by a D1dopamine agonist, differentiating D1 and D2dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D2 dopamine receptor activity by a nonsedating dose of a cannabinoid agonist has implications for the pathophysiology and treatment of dopamine-related neuropsychiatric disorders and drug addiction. Cannabinoid agonists and D2 dopamine agonists should be combined with caution.
Justin P Meschler - One of the best experts on this subject based on the ideXlab platform.
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cannabinoid receptor agonist and antagonist effects on motor function in normal and 1 methyl 4 phenyl 1 2 5 6 tetrahydropyridine mptp treated non human primates
Psychopharmacology, 2001Co-Authors: Justin P Meschler, Allyn C. Howlett, Bertha K MadrasAbstract:Rationale: Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. Objectives: We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Methods: Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. Results: The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist Levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, Levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Conclusions: Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
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d 2 but not d 1 dopamine receptor agonists potentiate cannabinoid induced sedation in nonhuman primates
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Justin P Meschler, Allyn C. Howlett, Francis A Clarkson, Patricia J Mathews, Bertha K MadrasAbstract:In primates, CB1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D1 or D2 dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys ( Macaca fasicularis ) alone and after administration of a low dose of the CB1 agonist Levonantradol. Alone, the CB1cannabinoid receptor agonist Levonantradol (0.01–0.3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D2-type dopamine agonists quinelorane (0.001–1.0 mg/kg; n = 4) or pergolide (0.01–1.0 mg/kg) or a D1 dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3–3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after administration of a threshold dose of Levonantradol (0.03 mg/kg), D2-type agonists, but not the D1 agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D2, but not D1 dopamine agonists, potentiate sedation in monkeys treated with a CB1cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D2 agonists, but not by a D1dopamine agonist, differentiating D1 and D2dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D2 dopamine receptor activity by a nonsedating dose of a cannabinoid agonist has implications for the pathophysiology and treatment of dopamine-related neuropsychiatric disorders and drug addiction. Cannabinoid agonists and D2 dopamine agonists should be combined with caution.
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thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses
Pharmacology Biochemistry and Behavior, 1999Co-Authors: Justin P Meschler, Allyn C. HowlettAbstract:Abstract Absinthe, an abused drug in the early 1900s, has been speculated to activate the receptors responsible for marijuana intoxication (the CB 1 cannabinoid receptor) (Nature 253:365–356; 1975). To test this hypothesis, we investigated oil of wormwood ( Artemisia absinthium ) the active plant product found in absinthe, and thujone, the active compound found in oil of wormwood. Radioligand receptor binding assays employing membrane preparations from rat brains containing CB 1 cannabinoid receptors, and human tonsils containing CB 2 receptors, demonstrated that thujone displaced [ 3 H]CP55940, a cannabinoid agonist, only at concentrations above 10 μM. HPLC analysis of oil of wormwood revealed that only the fractions having mobility close to thujone displaced [ 3 H]CP55940 from the CB 1 cannabinoid receptor. [ 35 S]GTPγS binding assays revealed that thujone failed to stimulate G-proteins even at 0.1 mM. Thujone failed to inhibit forskolin-stimulated adenylate cyclase activity in N18TG2 membranes at 1 mM. Rats administered thujone exhibited different behavioral characteristics compared with rats administered a potent cannabinoid agonist, Levonantradol. Therefore, the hypothesis that activation of cannabinoid receptors is responsible for the intoxicating effects of thujone is not supported by the present data.
Allyn C. Howlett - One of the best experts on this subject based on the ideXlab platform.
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cannabinoid receptor agonist and antagonist effects on motor function in normal and 1 methyl 4 phenyl 1 2 5 6 tetrahydropyridine mptp treated non human primates
Psychopharmacology, 2001Co-Authors: Justin P Meschler, Allyn C. Howlett, Bertha K MadrasAbstract:Rationale: Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. Objectives: We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Methods: Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. Results: The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist Levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, Levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Conclusions: Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
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d 2 but not d 1 dopamine receptor agonists potentiate cannabinoid induced sedation in nonhuman primates
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Justin P Meschler, Allyn C. Howlett, Francis A Clarkson, Patricia J Mathews, Bertha K MadrasAbstract:In primates, CB1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D1 or D2 dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys ( Macaca fasicularis ) alone and after administration of a low dose of the CB1 agonist Levonantradol. Alone, the CB1cannabinoid receptor agonist Levonantradol (0.01–0.3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D2-type dopamine agonists quinelorane (0.001–1.0 mg/kg; n = 4) or pergolide (0.01–1.0 mg/kg) or a D1 dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3–3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after administration of a threshold dose of Levonantradol (0.03 mg/kg), D2-type agonists, but not the D1 agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D2, but not D1 dopamine agonists, potentiate sedation in monkeys treated with a CB1cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D2 agonists, but not by a D1dopamine agonist, differentiating D1 and D2dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D2 dopamine receptor activity by a nonsedating dose of a cannabinoid agonist has implications for the pathophysiology and treatment of dopamine-related neuropsychiatric disorders and drug addiction. Cannabinoid agonists and D2 dopamine agonists should be combined with caution.
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thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses
Pharmacology Biochemistry and Behavior, 1999Co-Authors: Justin P Meschler, Allyn C. HowlettAbstract:Abstract Absinthe, an abused drug in the early 1900s, has been speculated to activate the receptors responsible for marijuana intoxication (the CB 1 cannabinoid receptor) (Nature 253:365–356; 1975). To test this hypothesis, we investigated oil of wormwood ( Artemisia absinthium ) the active plant product found in absinthe, and thujone, the active compound found in oil of wormwood. Radioligand receptor binding assays employing membrane preparations from rat brains containing CB 1 cannabinoid receptors, and human tonsils containing CB 2 receptors, demonstrated that thujone displaced [ 3 H]CP55940, a cannabinoid agonist, only at concentrations above 10 μM. HPLC analysis of oil of wormwood revealed that only the fractions having mobility close to thujone displaced [ 3 H]CP55940 from the CB 1 cannabinoid receptor. [ 35 S]GTPγS binding assays revealed that thujone failed to stimulate G-proteins even at 0.1 mM. Thujone failed to inhibit forskolin-stimulated adenylate cyclase activity in N18TG2 membranes at 1 mM. Rats administered thujone exhibited different behavioral characteristics compared with rats administered a potent cannabinoid agonist, Levonantradol. Therefore, the hypothesis that activation of cannabinoid receptors is responsible for the intoxicating effects of thujone is not supported by the present data.
D X Da Silveira - One of the best experts on this subject based on the ideXlab platform.
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therapeutic use of cannabis sativa on chemotherapy induced nausea and vomiting among cancer patients systematic review and meta analysis
European Journal of Cancer Care, 2008Co-Authors: F Machado C Rocha, Sergio Carlos Stefano, R De Cassia Haiek, L Rosa M Q Oliveira, D X Da SilveiraAbstract:This paper aims to evaluate the anti-emetic efficacy of cannabinoids in cancer patients receiving chemotherapy using a systematic review of literature searched within electronic databases such as PUBMED, EMBASE, PSYCINFO, LILACS, and ‘The Cochrane Collaboration Controlled Trials Register’. Studies chosen were randomized clinical trials comprising all publications of each database until December 2006. From 12 749 initially identified papers, 30 fulfilled the inclusion criteria for this review, with demonstration of superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs and placebo. The adverse effects were more intense and occurred more often among patients who used cannabinoids. Five meta-analyses were carried out: (1) dronabinol versus placebo [n = 185; relative risk (RR) = 0.47; confidence interval (CI) = 0.19– 1.16]; (2) Dronabinol versus neuroleptics [n = 325; RR = 0.67; CI = 0.47–0.96; number needed to treat (NNT) = 3.4]; (3) nabilone versus neuroleptics (n = 277; RR = 0.88; CI = 0.72–1.08); (4) Levonantradol versus neuroleptics (n = 194; RR = 0.94; CI = 0.75–1.18); and (5) patients’ preference for cannabis or other drugs (n = 1138; RR = 0.33; CI = 0.24–0.44; NNT = 1.8). The superiority of the anti-emetic efficacy of cannabinoids was demonstrated through meta-analysis.
Steven R Childers - One of the best experts on this subject based on the ideXlab platform.
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Cannabinoid Agonist Signal Transduction in Rat Brain: Comparison of Cannabinoid Agonists in Receptor Binding,
2015Co-Authors: G-protein Activation, Adenylyl Cyclase Inhibition, Christopher S. Breivogel, Steven R ChildersAbstract:To investigate differences in agonist affinity, potency, and effi-cacy across rat brain regions, five representative cannabinoid compounds were investigated in membranes from three differ-ent rat brain regions for their ability to maximally stimulate [35S]guanosine-59-O-(3-thio)triphosphate (GTPgS) binding and bind to cannabinoid receptors (measured by inhibition of [3H]antagonist binding) under identical assay conditions. In all three brain regions, the rank order of potency for the stimulation of [35S]GTPgS binding and the inhibition of [3H]SR141716A binding for these compounds were identical, with CP55940 ’ Levonantradol. WIN55212-2 $ D9-tetrahydrocannabinol (D9-THC). methanandamide. The rank order of efficacy was not related to potency, and relative maximal agonist effects varied across regions. Receptor binding fit to a three-site model fo
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Activation of G-proteins in brain by endogenous and exogenous cannabinoids
The AAPS Journal, 2006Co-Authors: Steven R ChildersAbstract:The biological response to cannabinoid agonist begins when the agonist-bound receptor activates G-protein G_α subunits, thus initiating a cascade of signal transduction pathways. For this reason, information about cannabinoid receptors/G-protein coupling is critical to understand both the acute and chronic actions of cannabinoids. This review focuses on these mechanisms, predominantly examining the ability of cannabinoid agonists to activate G-proteins in brain with agonist-stimulated [^35S]guanylyl-5′-O-(γ-thio)-triphosphate ([^35S]GTPγS) binding. Acute efficacies of cannabinoid agonists at the level of G-protein activation depend not only on the ability of the agonist to induce a high affinity state in G_α for GTP, but also to induce a low affinity for GDP. When several agonists are compared, it is clear that cannabinoid agonists differ considerably in their efficacy. Both WIN 55212-2 and Levonantradol are full agonists, while Δ^9 is a weak partial agonist. Of interest, anandamide and its stable analog methanand amide are partial agonists. Chronic treatment in vivo with cannabinoids produces significant tolerance to the physiological and behavioral effects of these drugs, and several studies have shown that this is accompanied by a significant loss in the ability of cannabinoid receptors to couple to G-proteins in brain. These effects vary across different brain regions and are usually (but not always) accompanied by loss of cannabinoid receptor binding. Although the relationship between cannabinoid receptor desensitization and tolerance has not yet been established, these mechanisms may represent events that lead to a loss of cannabinoid agonist response and development of tolerance.
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cannabinoids modulate potassium current in cultured hippocampal neurons
Receptors & Channels, 1993Co-Authors: Sam A Deadwyler, Robert E Hampson, B A Bennett, Thomas A Edwards, M A Pacheco, Susan J Ward, Steven R ChildersAbstract:Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significance. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, Levonantradol and WIN 55,212-2) on cultured neurons from hippocampus, a brain region that exhibits high cannabinoid receptor density. The electrophysiological effects of cannabinoids were determined by whole-cell patch clamp recordings of voltage-dependent potassium currents. The voltage dependence of the rapidly inactivating potassium A current (IA), characteristic of hippocampal neurons, was significantly altered in a concentration-dependent manner by cannabinoid analogs. Decreased inactivation, which led to an increased activation of IA near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on IA while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid analogs was similar to that observed with respect to binding at cannabinoid receptors in brain membranes. The concentration-related effectiveness of cannabinoid analogs in modulating IA was similar to their potency in stimulating low Km GTPase in cell membranes isolated from the cannabinoid receptor-rich dentate gyrus. These data support the conclusion that cannabinoid effects on IA are mediated through G-protein-coupled receptors. This cannabinoid-induced shift in the voltage dependence of IA could serve to counteract fast, transient, depolarizing events such as action potentials and synaptic currents in hippocampal neurons.