Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ<sup>9</sup>-Tetrahydrocannabinol

McKinney, Diana L.; Cassidy, Michael P.; Collier, Lauren; Martin, Billy R.; Wiley, Jenny L.; Selley, Dana E.; Sim‐Selley, Laura J.

doi:10.1124/jpet.107.130328

Cited by 80 publications

(78 citation statements)

References 44 publications

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“…These data, coupled with the 50% decrease in binding sites, are consistent with results of previous findings on cannabinoid tolerance in mice and extend them to include diuretic effects (Fan et al, 1994;McKinney et al, 2008;Singh et al, 2011;Nguyen et al, 2012). Of note, earlier studies typically used doses of THC ranging from 20 to 60 mg/kg daily to investigate the development of tolerance, with dosing regimens lasting from 2 to 13 days (Fan et al, 1994;Bass and Martin, 2000;McKinney et al, 2008). The present studies demonstrate that a 1-week exposure to a lower daily dosage of THC suffices to reveal substantial tolerance to cannabinoid effects, comparable to that reported using higher daily dosages.…”

Section: Discussionsupporting

confidence: 81%

“…Moreover, the magnitude of the rightward shifts of the THC and AM4054 dose-response curves for diuresis approximate those observed for the antinociceptive effects of both drugs. These data, coupled with the 50% decrease in binding sites, are consistent with results of previous findings on cannabinoid tolerance in mice and extend them to include diuretic effects (Fan et al, 1994;McKinney et al, 2008;Singh et al, 2011;Nguyen et al, 2012). Of note, earlier studies typically used doses of THC ranging from 20 to 60 mg/kg daily to investigate the development of tolerance, with dosing regimens lasting from 2 to 13 days (Fan et al, 1994;Bass and Martin, 2000;McKinney et al, 2008).…”

Section: Discussionsupporting

confidence: 77%

“…5). Mouse cerebellum has previously been shown to have a high density of CB1 receptors sites (Herkenham et al, 1991) that are sensitive to downregulation (McKinney et al, 2008). The B max for CB1 receptors in vehiclemice was 170 6 30 pmol/mg.…”

Section: Tablementioning

confidence: 99%

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Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Chopda

Parge

Thakur

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of D 9-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the k-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to .90% of maximal possible effect. Treatment with THC produced 9-and 7-fold rightward shifts of the diuresis and antinociception doseresponse curves for THC and, respectively, 7-and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to .35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the B max value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis doseeffect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 77%

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Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Chopda

Parge

Thakur

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Indeed, repeated administration of JZL184 (40 mg/kg) causes region-specific downregulation and desensitization of CB 1 receptors in the hippocampus, cingulate cortex, somatosensory cortex, and periaqueductal gray of mouse brain, but no significant alterations in the caudate putamen, globus pallidus, hypothalamus, substantia nigra, or cerebellum . Similarly, repeated THC administration causes regionally dependent reductions in CB 1 receptor agoniststimulated [ 35 S]GTPgS binding, including large decreases in the hippocampus, cingulate cortex, periaqueductal gray, and cerebellum, while the striatum is resistant to these adaptive changes (McKinney et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

Kinsey

Wise

Ramesh

et al. 2013

J Pharmacol Exp Ther

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157

148

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The monoacylglycerol lipase (MAGL) inhibitor 4-nitrophenyl 4-(dibenzo [d] [1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) produces antinociceptive and anti-inflammatory effects. However, repeated administration of high-dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, crosstolerance to the pharmacological effects of cannabinoid receptor agonists, and cannabinoid receptor type 1 (CB 1 ) downregulation and desensitization. This functional CB 1 receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low-dose JZL184 maintains its antinociceptive actions in the chronic constriction injury of the sciatic nerve neuropathic pain model and protective effects in a model of nonsteroidal anti-inflammatory drug-induced gastric hemorrhages. Mice given daily injections of high-dose JZL184 ($16 mg/kg) for 6 days displayed decreased CB 1 receptor density and function in the brain, as assessed in 35 S]thio)triphosphate binding assays, respectively. In contrast, normal CB 1 receptor expression and function were maintained following repeated administration of low-dose JZL184 (#8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high-dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low-dose JZL184 treatment. Consistent with these observations, repeated high-dose JZL184, but not repeated low-dose JZL184, elicited cross-tolerance to the common pharmacological effects of D 9-tetrahydrocannabinol. This same pattern of effects was found in a rimonabant [(5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)]-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB 1 receptor tachyphylaxis/tolerance or cannabinoid dependence.

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“…Previous studies have extensively characterized the desensitization and downregulation of CB1 in response to THC in rodent models (SimSelley, 2003;McKinney et al, 2008). CB1 is phosphorylated by G protein-coupled receptor kinase, desensitized by association with ␤-arrestin, and internalized.…”

Section: Discussionmentioning

confidence: 99%

Role of Cannabinoid Receptor Type 1 Desensitization in Greater Tetrahydrocannabinol Impairment of Memory in Adolescent Rats

Moore

Greenleaf²,

Acheson³

et al. 2010

J Pharmacol Exp Ther

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Adolescence is a well defined developmental period during which marijuana use is common. However, little is known about the response to marijuana in adolescents compared with adults. We have shown previously that adolescent rats are more impaired than adults by ⌬ 9 -tetrahydrocannabinol (THC), the main psychoactive compound in marijuana, in a spatial learning task, but the mechanism responsible for this differential impairment is not understood. We determined the role of THC tolerance and cannabinoid receptor type 1 (CB1) regulation in THC-induced spatial learning impairment in adolescent and adult rats. We measured the development of tolerance to THC-induced learning impairment in adolescent (postnatal days 30 -35) and adult (postnatal days 70 -75) rats. We pretreated them for 5 days with 10 mg/kg THC, and then evaluated the effects of vehicle or THC treatment on learning during training in the Morris water maze. We also determined CB1 number and functional coupling in the hippocampus of adolescents and adults. Finally, we measured the time course of hippocampal CB1 desensitization in adolescents and adults during treatment with 10 mg/kg THC or vehicle. Our results indicate that adults, but not adolescents, become tolerant to the effects of THC during water maze training after 5 days of pretreatment. CB1s in adolescent hippocampus are less functionally coupled to G proteins and desensitize more slowly in response to THC treatment than those of adults. THC may impair learning in adolescents more than in adults because of delayed activation of cellular homeostatic adaptive mechanisms underlying cannabinoid tolerance in the hippocampus.

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Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol

Cited by 80 publications

References 44 publications

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

Role of Cannabinoid Receptor Type 1 Desensitization in Greater Tetrahydrocannabinol Impairment of Memory in Adolescent Rats

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Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

Cited by 80 publications

References 44 publications

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

Role of Cannabinoid Receptor Type 1 Desensitization in Greater Tetrahydrocannabinol Impairment of Memory in Adolescent Rats

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Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ⁹-Tetrahydrocannabinol