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Alexandros Makriyannis - One of the best experts on this subject based on the ideXlab platform.
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Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates.
Journal of Pharmacology and Experimental Therapeutics, 2020Co-Authors: Lisa M. Wooldridge, Yingpeng Liu, Spyros P. Nikas, Alexandros Makriyannis, Jack Bergman, Brian D. KangasAbstract:Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, Food and Drug Administration-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their prescription. Previous studies have shown that a metabolically stable analog of the endocannabinoid anandamide, Methanandamide (mAEA), may produce lesser cognitive disruption than that associated with the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), raising the possibility that endocannabinoids may offer a therapeutic advantage over currently used medications. The present studies were conducted to evaluate this possibility by comparing the antiemetic effects of Δ9-THC (0.032-0.1 mg/kg) and mAEA (3.2-10.0 mg/kg) against nicotine- and lithium chloride (LiCl)-induced emesis and prodromal hypersalivation in squirrel monkeys. Pretreatment with 0.1 mg/kg Δ9-THC blocked nicotine-induced emesis and reduced hypersalivation in all subjects and blocked LiCl-induced emesis and reduced hypersalivation in three of four subjects. Pretreatment with 10 mg/kg mAEA blocked nicotine-induced emesis in three of four subjects and LiCl-induced emesis in one of four subjects and reduced both nicotine- and LiCl-induced hypersalivation. Antiemetic effects of Δ9-THC and mAEA were reversed by rimonabant pretreatment, providing verification of cannabinoid receptor type 1 mediation. These studies systematically demonstrate for the first time the antiemetic effects of cannabinoid agonists in nonhuman primates. Importantly, although Δ9-THC produced superior antiemetic effects, the milder cognitive effects of mAEA demonstrated in previous studies suggest that it may provide a favorable treatment option under clinical circumstances in which antiemetic efficacy must be balanced against side effect liability. SIGNIFICANCE STATEMENT: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a paucity of animal models. The present studies systematically demonstrate for the first time the antiemetic effects of the phytocannabinoid Δ9-tetrahydrocannabinol and endocannabinoid analog Methanandamide in nonhuman primates.
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analysis of tolerance and behavioral physical dependence during chronic cb1 agonist treatment effects of cb1 agonists antagonists and noncannabinoid drugs
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Rajeev I. Desai, Alexandros Makriyannis, Ganesh A. Thakur, Kiran V. Vemuri, Shama Bajaj, Jack BergmanAbstract:Behavioral studies of chronic CB 1 receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB 1 ligands as well as mechanistic commonalities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB 1 agonists [(6 aR ,10 aR )-3-(1-adamantyl)-6,6,9-trimethyl-6 a ,7,10,10 a -tetrahydrobenzo[ c ]chromen-1-ol (AM411), 9 β -(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R -(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3- de ]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), (R)-(+)-arachidonyl-19-hydroxy-29-propylamide (Methanandamide)], CB 1 antagonists [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide (SR141716A), 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide (AM4113)], and dopamine (DA)–related [methamphetamine, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine hydrobromide (SKF82958), ( R )-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine hydrochloride (SCH23390), (6 aR )-5,6,6 a ,7-tetrahydro-6-propyl-4 H -dibenzo[ de,g ]quinoline-10,11-diol ( R -(−)-NPA), haloperidol] and opioid (morphine, naltrexone) drugs on scheduled-controlled responding under a 30-response fixed ratio schedule of stimulus-shock termination in squirrel monkeys were compared before and during chronic treatment with the long-acting CB 1 agonist AM411 (1.0 mg/kg per day, i.m.). Prechronic treatment with all drugs except naltrexone (1–10 mg/kg) produced dose-related decreases in responses rates. Dose-response re-determinations during chronic treatment revealed the following: 1) >250-fold (AM411, Methanandamide) and >45-fold (AM4054, WIN55,212.2, Δ 9 -THC) rightward shifts in the ED 50 values for CB 1 agonists; 2) >100-fold and >20-fold leftward shifts in the ED 50 values for SR141716A and AM4113, respectively; and 3) approximately 4.8-fold and 10-fold rightward shifts in the ED 50 values for methamphetamine and the DA D 2 agonist R- (−)-NPA, respectively. Dose-response relationships for other DA-related and opioid drugs were unchanged by chronic CB 1 agonist treatment. Differences in the magnitude of tolerance among CB 1 agonists during chronic treatment may be indicative of differences in their pharmacological efficacy, whereas the enhanced sensitivity to behaviorally disruptive effects of CB 1 antagonists may provide evidence for CB 1 -related behavioral and/or physical dependence. Finally, the development of cross-tolerance to methamphetamine and R- (−)-NPA bolsters previous evidence of interplay between CB 1 and DA D 2 signaling mechanisms.
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Discriminative stimulus functions of Methanandamide and ∆9-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol
Psychopharmacology, 2009Co-Authors: Torbjörn U. C. Järbe, Subramanian K. Vadivel, Alexandros MakriyannisAbstract:Objective The aim of the study was to characterize in vivo the aminoalkylindoles WIN55,212-2 (WIN) and AM678 (naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone) as cannabinoid receptor (CB1R) ligands using drug discrimination. Tests also involved ∆9-tetrahydrocannabinol (THC) and R-(+)-Methanandamide (mAEA), a metabolically stable analog of the endogenous ligand anandamide, as well as the CB1R selective antagonist/inverse agonist rimonabant; tests with ethanol assessed pharmacological specificity. We used two different drug discriminations (mAEA and THC) allowing us to explore potential differences in CB1R activation which could be attributed to variations in their respective CB1R signaling mechanisms.
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effects of am1346 a high affinity cb1 receptor selective anandamide analog on open field behavior in rats
Behavioural Pharmacology, 2007Co-Authors: Torbjörn U. C. Järbe, Nicholas V Dipatrizio, Alexandros MakriyannisAbstract:AM1346 is a cannabinoid receptor type 1 (CB1R) anandamide analog [alkoxyacid amide of N-eicosa-(5Z, 8Z, 11Z, 14Z)-tetraenylamine] with high affinity and selectivity for the CB1 vs. CB2 receptor [Ki (CB1)=1.5 nmol/l; Ki (CB2)=152 nmol/l]. The present study characterized the effects of AM1346 (5.6-18 mg/kg) and its interaction with the CB1R antagonist/inverse agonist SR141716 (1-5.6 mg/kg) on open-field behaviors of rats. AM1346 reduced ambulation (horizontal activity), rearing (vertical activity) and increased the degree of circling and the latency to leave the central area of the open-field arena. AM1346 also tended to reduce defecation and to increase vocalization in a dose-dependent manner. In pretreatment studies, SR141716 completely blocked the effects of AM1346 on circling and latency and partially antagonized the effects of 18 mg/kg AM1346 on ambulation and rearing. SR141716 also tended to decrease AM1346-induced vocalization in a dose-dependent manner. Earlier studies have shown that SR141716, given alone, can increase grooming behavior and, as well, produces dose-related increases in scratching. In the present studies, these effects were attenuated in a dose-related manner by AM1346. The present profile of behavioral effects for AM1346 is consistent with its designation as a CB1R agonist. When combined with drug discrimination data (surmountable antagonism of effects of SR141716 by Delta(9)-THC and AM1346 but not by Methanandamide, i.e. AM356), these data indicate that the anandamide analog AM1346 may be more behaviorally similar to cannabinoids like Delta(9)-THC than to other anandamide-based molecules such as Methanandamide.
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effects of delta 9 tetrahydrocannabinol and r Methanandamide on open field behavior in rats
Behavioural Pharmacology, 1998Co-Authors: Torbjörn U. C. Järbe, Alexandros Makriyannis, R Sheppard, Richard J Lamb, Sonyuan Lin, Andreas GoutopoulosAbstract:This study compared the effects of (R)-Methanandamide, an analog of the mammalian brain constituent anandamide, and delta-9-tetrahydrocannabinol on the open-field behavior of male Sprague-Dawley rats. Rats were individually housed with free access to food and water. Animals were treated with 0, 1, 3, and 5.6 mg/kg delta-9-tetrahydrocannabinol given i.p. 30 min pre-session; and 0, 3, 10, and 18 mg/kg (R)-Methanandamide, 15 min pre-session. The behavioral categories recorded were ambulation (the number of squares crossed), rearing (the number of times the rat stood erect on its hind-legs), latency (the time in seconds to leave the starting area, the circle in the center of the field), circling (the number of times the animal turned around its vertical axis, 0.5 point given for each 180 degrees turn), grooming (the number of cleaning bouts), urination and defecation (the number of urination spots and fecal boli deposited during the 5 min observation period). Delta-9-tetrahydrocannabinol was more potent than (R)-Methanandamide, but otherwise the effects of delta-9-tetrahydrocannabinol and (R)-Methanandamide were similar, with one exception; whereas delta-9-tetrahydrocannabinol produced dose-related increases in circling, (R)-Methanandamide did not increase circling over the doses examined. The delta-9-tetrahydrocannabinol-induced increase in circling was blocked by the central cannabinoid receptor CB1 antagonist SR 141716. The differential effects with regard to circling may indicate that there are qualitative behavioral differences in the effects of delta-9-tetrahydrocannabinol and (R)-Methanandamide.
Ryszard Brus - One of the best experts on this subject based on the ideXlab platform.
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neonatal dsp 4 treatment modifies antinociceptive effects of the cb1 receptor agonist Methanandamide in adult rats
Neurotoxicity Research, 2012Co-Authors: Eva Korossymruk, Katarzyna Kuter, Ryszard Szkilnik, Monika Rykaczewskaczerwinska, Przemyslaw Nowak, Richard M Kostrzewa, Ryszard BrusAbstract:To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB1-receptor agonist Methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg sc × 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after Methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB1 receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of Methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB1 receptor density in the brain.
Jack Bergman - One of the best experts on this subject based on the ideXlab platform.
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Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates.
Journal of Pharmacology and Experimental Therapeutics, 2020Co-Authors: Lisa M. Wooldridge, Yingpeng Liu, Spyros P. Nikas, Alexandros Makriyannis, Jack Bergman, Brian D. KangasAbstract:Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, Food and Drug Administration-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their prescription. Previous studies have shown that a metabolically stable analog of the endocannabinoid anandamide, Methanandamide (mAEA), may produce lesser cognitive disruption than that associated with the primary psychoactive constituent in cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), raising the possibility that endocannabinoids may offer a therapeutic advantage over currently used medications. The present studies were conducted to evaluate this possibility by comparing the antiemetic effects of Δ9-THC (0.032-0.1 mg/kg) and mAEA (3.2-10.0 mg/kg) against nicotine- and lithium chloride (LiCl)-induced emesis and prodromal hypersalivation in squirrel monkeys. Pretreatment with 0.1 mg/kg Δ9-THC blocked nicotine-induced emesis and reduced hypersalivation in all subjects and blocked LiCl-induced emesis and reduced hypersalivation in three of four subjects. Pretreatment with 10 mg/kg mAEA blocked nicotine-induced emesis in three of four subjects and LiCl-induced emesis in one of four subjects and reduced both nicotine- and LiCl-induced hypersalivation. Antiemetic effects of Δ9-THC and mAEA were reversed by rimonabant pretreatment, providing verification of cannabinoid receptor type 1 mediation. These studies systematically demonstrate for the first time the antiemetic effects of cannabinoid agonists in nonhuman primates. Importantly, although Δ9-THC produced superior antiemetic effects, the milder cognitive effects of mAEA demonstrated in previous studies suggest that it may provide a favorable treatment option under clinical circumstances in which antiemetic efficacy must be balanced against side effect liability. SIGNIFICANCE STATEMENT: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a paucity of animal models. The present studies systematically demonstrate for the first time the antiemetic effects of the phytocannabinoid Δ9-tetrahydrocannabinol and endocannabinoid analog Methanandamide in nonhuman primates.
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analysis of tolerance and behavioral physical dependence during chronic cb1 agonist treatment effects of cb1 agonists antagonists and noncannabinoid drugs
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Rajeev I. Desai, Alexandros Makriyannis, Ganesh A. Thakur, Kiran V. Vemuri, Shama Bajaj, Jack BergmanAbstract:Behavioral studies of chronic CB 1 receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB 1 ligands as well as mechanistic commonalities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB 1 agonists [(6 aR ,10 aR )-3-(1-adamantyl)-6,6,9-trimethyl-6 a ,7,10,10 a -tetrahydrobenzo[ c ]chromen-1-ol (AM411), 9 β -(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R -(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3- de ]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), Δ 9 -tetrahydrocannabinol (Δ 9 -THC), (R)-(+)-arachidonyl-19-hydroxy-29-propylamide (Methanandamide)], CB 1 antagonists [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide (SR141716A), 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl- N -(piperidin-1-yl)-1 H -pyrazole-3-carboxamide (AM4113)], and dopamine (DA)–related [methamphetamine, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine hydrobromide (SKF82958), ( R )-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benzazepine hydrochloride (SCH23390), (6 aR )-5,6,6 a ,7-tetrahydro-6-propyl-4 H -dibenzo[ de,g ]quinoline-10,11-diol ( R -(−)-NPA), haloperidol] and opioid (morphine, naltrexone) drugs on scheduled-controlled responding under a 30-response fixed ratio schedule of stimulus-shock termination in squirrel monkeys were compared before and during chronic treatment with the long-acting CB 1 agonist AM411 (1.0 mg/kg per day, i.m.). Prechronic treatment with all drugs except naltrexone (1–10 mg/kg) produced dose-related decreases in responses rates. Dose-response re-determinations during chronic treatment revealed the following: 1) >250-fold (AM411, Methanandamide) and >45-fold (AM4054, WIN55,212.2, Δ 9 -THC) rightward shifts in the ED 50 values for CB 1 agonists; 2) >100-fold and >20-fold leftward shifts in the ED 50 values for SR141716A and AM4113, respectively; and 3) approximately 4.8-fold and 10-fold rightward shifts in the ED 50 values for methamphetamine and the DA D 2 agonist R- (−)-NPA, respectively. Dose-response relationships for other DA-related and opioid drugs were unchanged by chronic CB 1 agonist treatment. Differences in the magnitude of tolerance among CB 1 agonists during chronic treatment may be indicative of differences in their pharmacological efficacy, whereas the enhanced sensitivity to behaviorally disruptive effects of CB 1 antagonists may provide evidence for CB 1 -related behavioral and/or physical dependence. Finally, the development of cross-tolerance to methamphetamine and R- (−)-NPA bolsters previous evidence of interplay between CB 1 and DA D 2 signaling mechanisms.
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Analysis of Tolerance and Behavioral/Physical Dependence during Chronic CB1 Agonist Treatment: Effects of CB1 Agonists, Antagonists, and Noncannabinoid Drugs
2012Co-Authors: Rajeev I. Desai, Ros Makriyannis, Ganesh A. Thakur, Kiran V. Vemuri, Shama Bajaj, Jack BergmanAbstract:Behavioral studies of chronic CB1 receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB1 ligands as well as mechanistic common-alities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB1 agonists [(6aR,10aR)-3-(1-adamantyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c] chromen-1-ol (AM411), 9b-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), D9-tetra-hydrocannabinol (D9-THC), (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (Methanandamide)], CB1 antagonists [5-(4-chlor-ophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)
Marcello Solinas - One of the best experts on this subject based on the ideXlab platform.
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the endogenous cannabinoid anandamide produces δ 9 tetrahydrocannabinol like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Marcello Solinas, Subramanian K. Vadivel, Daniele Piomelli, Sevil Yasar, Gianluigi Tanda, Zuzana Justinova, Carrie E Wertheim, Steven R GoldbergAbstract:Anandamide is an endogenous ligand for brain cannabinoid CB(1) receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., Methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and Methanandamide were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.
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The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport.
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Marcello Solinas, Subramanian K. Vadivel, Daniele Piomelli, Sevil Yasar, Gianluigi Tanda, Zuzana Justinova, Carrie E Wertheim, Steven R GoldbergAbstract:Anandamide is an endogenous ligand for brain cannabinoid CB(1) receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., Methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and Methanandamide were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.
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anandamide administration alone and after inhibition of fatty acid amide hydrolase faah increases dopamine levels in the nucleus accumbens shell in rats
Journal of Neurochemistry, 2006Co-Authors: Zuzana Justinova, Marcello Solinas, Steven R Goldberg, Gianluigi TandaAbstract:Although endogenous cannabinoid systems have been implicated in the modulation of the rewarding effects of abused drugs and food, little is known about the direct effects of endogenous ligands for cannabinoid receptors on brain reward processes. Here we show for the first time that the intravenous administration of anandamide, an endogenous ligand for cannabinoid receptors, and its longer-lasting synthetic analog Methanandamide, increase the extracellular dopamine levels in the nucleus accumbens shell of awake, freely moving rats, an effect characteristic of most drugs abused by humans. Anandamide produced two distinctly different effects on dopamine levels: (1) a rapid, transient increase that was blocked by the cannabinoid CB1 receptor antagonist rimonabant, but not by the vanilloid VR1 receptor antagonist capsazepine, and was magnified and prolonged by the fatty acid amide hydrolase (FAAH) enzyme inhibitor, URB597; (2) a smaller delayed and long-lasting increase, not sensitive to CB1, VR1 or FAAH blockade. Both effects were blocked by infusing either tetrodotoxin (TTX, 1 µm) or calcium-free Ringer's solution through the microdialysis probe, demonstrating that they were dependent on the physiologic activation of dopaminergic neurotransmission. Thus, these results indicate that anandamide, through the activation of the mesolimbic dopaminergic system, participates in the signaling of brain reward processes.
Steven R Goldberg - One of the best experts on this subject based on the ideXlab platform.
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the endogenous cannabinoid anandamide produces δ 9 tetrahydrocannabinol like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Marcello Solinas, Subramanian K. Vadivel, Daniele Piomelli, Sevil Yasar, Gianluigi Tanda, Zuzana Justinova, Carrie E Wertheim, Steven R GoldbergAbstract:Anandamide is an endogenous ligand for brain cannabinoid CB(1) receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., Methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and Methanandamide were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.
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The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport.
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Marcello Solinas, Subramanian K. Vadivel, Daniele Piomelli, Sevil Yasar, Gianluigi Tanda, Zuzana Justinova, Carrie E Wertheim, Steven R GoldbergAbstract:Anandamide is an endogenous ligand for brain cannabinoid CB(1) receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., Methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and Methanandamide were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.
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anandamide administration alone and after inhibition of fatty acid amide hydrolase faah increases dopamine levels in the nucleus accumbens shell in rats
Journal of Neurochemistry, 2006Co-Authors: Zuzana Justinova, Marcello Solinas, Steven R Goldberg, Gianluigi TandaAbstract:Although endogenous cannabinoid systems have been implicated in the modulation of the rewarding effects of abused drugs and food, little is known about the direct effects of endogenous ligands for cannabinoid receptors on brain reward processes. Here we show for the first time that the intravenous administration of anandamide, an endogenous ligand for cannabinoid receptors, and its longer-lasting synthetic analog Methanandamide, increase the extracellular dopamine levels in the nucleus accumbens shell of awake, freely moving rats, an effect characteristic of most drugs abused by humans. Anandamide produced two distinctly different effects on dopamine levels: (1) a rapid, transient increase that was blocked by the cannabinoid CB1 receptor antagonist rimonabant, but not by the vanilloid VR1 receptor antagonist capsazepine, and was magnified and prolonged by the fatty acid amide hydrolase (FAAH) enzyme inhibitor, URB597; (2) a smaller delayed and long-lasting increase, not sensitive to CB1, VR1 or FAAH blockade. Both effects were blocked by infusing either tetrodotoxin (TTX, 1 µm) or calcium-free Ringer's solution through the microdialysis probe, demonstrating that they were dependent on the physiologic activation of dopaminergic neurotransmission. Thus, these results indicate that anandamide, through the activation of the mesolimbic dopaminergic system, participates in the signaling of brain reward processes.