PKCɛ Regulates Behavioral Sensitivity, Binding and Tolerance to the CB1 Receptor Agonist WIN55,212-2

Wallace, Mary; Newton, Philip M.; McMahon, Thomas; Connolly, Jacklyn; Huibers, Anne; Whistler, Jennifer L.; Messing, Robert O.

doi:10.1038/npp.2008.230

Cited by 12 publications

(8 citation statements)

References 48 publications

(57 reference statements)

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“…We recently determined that a PKCε signaling pathway is activated by ethanol to augment GABA release in CeA (Bajo et al, 2008). PKCε reportedly negatively regulates the affinity of WIN2 at CB1 (Wallace et al, 2009), although a possible modulation of eCB activity at CB1 by PKCε is uncertain. Nonetheless, these two kinases appear as interesting candidates to participate in the opposite regulation of GABA release by ethanol and eCBs, and a combined crosstalk between PKA and PKCε to regulate ethanol and eCB effects also is possible (Kelm et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

Roberto

Cruz

Bajo

et al. 2010

Neuropsychopharmacol

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The central amygdala (CeA) plays a major role in alcohol dependence and reinforcement, and behavioral and neurochemical evidence suggest a role for the endocannabinoid (eCB) system in ethanol binging and dependence. We used the slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. SR1 or AM251 applied alone augmented IPSPs, revealing a tonic eCB activity that decreased inhibitory transmission in CeA. Paired-pulse analysis suggested a presynaptic CB1 mechanism. Intracellular BAPTA abolished the ability of AM251 to augment IPSPs, demonstrating the eCB-driven nature and postsynaptic origin of the tonic CB1-dependent control of GABA release. Superfusion of ethanol increased IPSPs and addition of WIN2 reversed the ethanol effect. Similarly, prior superfusion of WIN2 prevented subsequent ethanol effects on GABAergic transmission. The ethanol-induced augmentation of IPSPs was additive to CB1 blockade, ruling out a participation of CB1 in the action of acute ethanol. Our study points to an important role of CB1 in CeA where the eCBs tonically regulate neuronal activity, and suggests a potent mechanism for modulating CeA tone during challenge with ethanol.

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Section: Discussionmentioning

confidence: 99%

The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

Roberto

Cruz

Bajo

et al. 2010

Neuropsychopharmacol

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“…Alternatively, CB 1 R and CB 2 R agonists, especially those that are structurally related to AEA, may also interact with other GPCRs such as the vanilloid type-1 receptor (TRPV1) or the recently deorphanized GPR55 (Brown 2007; Howlett 2004; Pacher et al 2006; Oz 2006 for reviews). Identifying these differences in receptor activation and subsequent downstream signaling might provide clues for more rational drug (D) design through the development of novel ligands with enhanced pharmacological selectivity and specificity (for further discussion(s) on ligand/receptor interaction(s) and signaling pathways, see, e.g., Wallace et al 2009 and Glass and Northup (1999) concerning cannabinoids and Saidak et al 2006 regarding opioids).…”

Section: Introductionmentioning

confidence: 99%

Discriminative stimulus functions of methanandamide and ∆9-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol

Järbe

Vadivel

et al. 2009

Psychopharmacology

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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 Δ9-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. Methods There were two concurrently trained groups of rats. One group discriminated between i.p. injected vehicle and 10 mg/kg mAEA. The other group was trained to discriminate between vehicle and 1.8 mg/kg THC. Results Dose generalization curves for AM678, WIN55,212-2, THC, and mAEA suggested the following rank order of potency: AM678>WIN55,212-2≥THC>mAEA in both drug discrimination groups. Challenge by 1 mg/kg rimonabant resulted in shifts to the right of the generalization curves for the two aminoalkylindoles (4.4-fold for AM678 and 11.3-fold for WIN in the mAEA group, whereas for the THC group, the corresponding values were 13 and 2.6, respectively), suggesting surmountable antagonism. Ethanol did not generalize in either of the two groups, suggesting pharmacological specificity. Conclusion Data are congruent with the general observation that there is substantial overlap in the discriminative stimulus effects of CB1R ligands across different chemical classes. However, the quantitative differences in the interactions between the two aminoalkylindoles and rimonabant in the two discrimination groups suggest subtle variations in the ligand–receptor activation(s).

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“…Twenty four hrs after the final injection, mice were sacrificed to isolate tissue for binding analysis. Behavioral tests for antinociception, hypothermia and locomotor activity were conducted essentially as described previously (Wallace et al, 2009). Briefly, antinociception was assessed by tail flick withdrawal response latencies by placing the mice on a tail flick analgesia meter (Columbus Instruments, Columbus, OH).…”

Section: Methodsmentioning

confidence: 99%

Differential Regulation of Behavioral Tolerance to WIN55,212-2 by GASP1

Martini

Thompson

Kharazia

et al. 2010

Neuropsychopharmacol

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Cannabinoid agonists have shown some promise clinically as analgesics, in particular for cancer pain where they have the additional benefit of decreasing nausea. However, as for most other drugs, the long-term use of cannabinoids is limited by the development of tolerance. Several molecular mechanisms have been proposed to explain drug tolerance including receptor downregulation. Cannabinoid CB1 receptors can be downregulated in vitro through an interaction with the G protein-coupled receptor associated sorting protein1, GASP1, which targets CB1 receptors for degradation after their agonist-mediated endocytosis. To investigate whether GASP1-mediated post-endocytic sorting of the CB1 receptor contributes to tolerance to cannabinoid drugs in vivo, we generated a mouse with a disruption of GASP1. In wild-type mice, repeated administration of the cannabinoid agonist WIN55,212-2 promoted downregulation of CB1 receptor levels and concomitant tolerance to the effects of drug on antinociception, motor incoordination, and locomotor hypoactivity. In contrast, GASP1 knock-out mice did not develop tolerance to any of these effects and showed no significant receptor down-regulation. Taken together, this study provides evidence that GASP1 regulates CB1 receptor downregulation in vivo, and that post-endocytic receptor trafficking plays a key role in development of tolerance to WIN55,212-2.

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PKCɛ Regulates Behavioral Sensitivity, Binding and Tolerance to the CB1 Receptor Agonist WIN55,212-2

Cited by 12 publications

References 48 publications

The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

The Endocannabinoid System Tonically Regulates Inhibitory Transmission and Depresses the Effect of Ethanol in Central Amygdala

Discriminative stimulus functions of methanandamide and ∆9-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol

Differential Regulation of Behavioral Tolerance to WIN55,212-2 by GASP1

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