SR141716A is an inverse agonist at the human cannabinoid CB1 receptor

Landsman, Robert S.; Burkey, Thomas H.; Consroe, Paul; Roeske, William R.; Yamamura, Henry I.

doi:10.1016/s0014-2999(97)01160-6

Cited by 245 publications

(157 citation statements)

References 4 publications

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“…1A). Thus, CB1R exerts a constitutive inhibitory effect on cAMP accumulation in HEK-293 cells, consistent with previous data obtained in CHO cells (7) or rat brain membrane preparations (17). This effect is similar for CB1-WT and CB1-EGFP, showing that CB1-EGFP is functional.…”

Section: Cb1-egfp Is Functional and Displays A Predominantly Intracelsupporting

confidence: 91%

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Leterrier

Bonnard

Carrel

et al. 2004

Journal of Biological Chemistry

216

234

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The CB1 cannabinoid receptor (CB1R) displays a significant level of ligand-independent (i.e. constitutive) activity, either when heterologously expressed in nonneuronal cells or in neurons where CB1Rs are endogenous. The present study investigates the consequences of constitutive activity on the intracellular trafficking of CB1R. When transfected in HEK-293 cells, CB1R is present at the plasma membrane, but a substantial proportion (ϳ85%) of receptors is localized in intracellular vesicles. Detailed analysis of CB1-EGFP expressed in HEK-293 cells shows that the intracellular CB1R population is mostly of endocytic origin and that treatment with inverse agonist AM281 traps CB1R at the plasma membrane through a monensin-sensitive recycling pathway. Co-transfection with dominant positive or dominant negative mutants of the small GTPases Rab5 and Rab4, but not Rab11, profoundly modifies the steady-state and ligand-induced intracellular distribution of CB1R, indicating that constitutive endocytosis is Rab5-dependent, whereas constitutive recycling is mediated by Rab4. In conclusion, our results indicate that, due to its natural constitutive activity, CB1R permanently and constitutively cycles between plasma membrane and endosomes, leading to a predominantly intracellular localization at steady state.

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Section: Cb1-egfp Is Functional and Displays A Predominantly Intracelsupporting

confidence: 91%

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Leterrier

Bonnard

Carrel

et al. 2004

Journal of Biological Chemistry

216

234

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“…Although it is clear that drugs that interfere with CB1 transmission can suppress food intake, the mechanisms by which they accomplish this are less well understood. Biochemical studies indicate that many of these drugs, including SR141716, AM251, and AM1387, act as inverse agonists and exert actions on signal transduction mechanisms when administered in the absence of CB1 receptor stimulation (ie they inhibit GTPgS and increase cAMP production; Landsman et al, 1997;Mato et al, 2002;McLaughlin et al, 2006). In one recent study, CB1-knockout and wild-type mice responded comparably on a progressive ratio schedule reinforced with corn oil, while wild-type mice treated with SR141716 decreased responding, suggesting that SR141716 may exert inverse agonist effects in addition to simply blocking CB1 receptors (Ward and Dykstra, 2005).…”

Section: Introductionmentioning

confidence: 99%

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Sink

McLaughlin

Wood

et al. 2007

Neuropsychopharmacol

143

193

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Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dosedependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists. Neuropsychopharmacology (2008) 33, 946-955;

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“…CB1 receptor antagonist also facilitates short-term olfactory memory in a social recognition test that requires hippocampal processing (Terranova et al 1996). Although these results are consistent with a role for chronic activation of CB1 receptors in learning and memory, this interpretation is still unconfirmed because SR141716A, the CB1 receptor antagonist used for these studies, may also act as an inverse agonist at these receptors (Landsman et al 1997). If SR141716A is indeed serving not only to inhibit binding and activation by CB1 receptor ligands but also to suppress tonic constitutive activity of the unoccupied receptor, then identification of the function of endogenous cannabinoid receptors may have to await the development of pharmacological reagents with more selective actions.…”

Section: Evidence For a Role For Endogenous Cannabinoid Receptor Ligamentioning

confidence: 80%

Cellular and Molecular Mechanisms Underlying Learning and Memory Impairments Produced by Cannabinoids: Figure 1.

Sullivan

2000

Learn. Mem.

163

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Why does smoking marijuana impair learning and memory? Behavioral studies suggest that a disruption of normal hippocampal function contributes to these deficits. In vitro experiments find that cannabinoid receptor activation reduces neurotransmitter release below the levels required to trigger long-term changes in synaptic strength in the hippocampus. Cannabinoids reduce glutamate release through a G-protein-mediated inhibition of the calcium channels responsible for neurotransmitter release from hippocampal neurons. These mechanisms likely play a role in the learning and memory impairments produced by cannabinoids and by endogenous cannabinoid receptor ligands.

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SR141716A is an inverse agonist at the human cannabinoid CB1 receptor

Cited by 245 publications

References 4 publications

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

Constitutive Endocytic Cycle of the CB1 Cannabinoid Receptor

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Cellular and Molecular Mechanisms Underlying Learning and Memory Impairments Produced by Cannabinoids: Figure 1.

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