Enhanced Rewarding Properties of Morphine, but not Cocaine, in βarrestin-2 Knock-Out Mice

Bohn, Laura M.; Gainetdinov, Raul R.; Sotnikova, Tatyana D.; Medvedev, Ivan O.; Lefkowitz, Robert J.; Dykstra, Linda; Caron, Marc G.

doi:10.1523/jneurosci.23-32-10265.2003

Cited by 206 publications

(263 citation statements)

References 51 publications

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“…Although others have found that sensitization to morphine is not b-arrestin 2-dependent (Bohn et al, 2003), we have found that this context-specific response to multiple doses of morphine is reduced in mice lacking b-arrestin 2. However, our assay differed in several important ways; we examined the first 30 min after morphine (30 vs 120 min), after 3 rather than 9 days of repeated morphine, and our sensitization protocol was context-associated.…”

Section: Discussioncontrasting

confidence: 94%

“…This response requires D1 receptors, the phosphoprotein DARPP32 (Becker et al, 2001;Borgkvist et al, 2007;Urs et al, 2011) and ERK (Borgkvist et al, 2008;Urs et al, 2011). We, and others, have shown that the locomotor effect of morphine is blunted in mice lacking b-arrestin 2 (Bohn et al, 2003;Urs et al, 2011). As morphine induces the formation of a b-arrestin 2/ERK complex in D1 neurons, it has been suggested that this complex mediates the hyperlocomotor effect of morphine (Urs et al, 2011).…”

Section: Discussionmentioning

confidence: 83%

“…Psychomotor effects of morphine Acute locomotion: Another of the behavioral phenotypes of b-arr2À/À mice is the reduced locomotor effect of morphine (Bohn et al, 2003;Urs et al, 2011). We hypothesized that, similar to the analgesic effect of morphine, this may also be due to altered JNK activity.…”

Section: Jnk Inhibition Reverses Behavioral Phenotypes Of Morphine Inmentioning

confidence: 99%

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Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Mittal

Tan

Egbuta

et al. 2012

Neuropsychopharmacol

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The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking b-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by b-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with b-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking b-arrestin 2 (b-arr2À/À) to examine this interaction, we found that b-arr2À/À neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting b-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking b-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of b-arr2À/À mice, to + / + levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in b-arr2À/À mice were also returned to + / + levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in b-arr2À/À mice to + / + levels. In summary, removing b-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of b-arr2À/À mice.

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Section: Discussioncontrasting

confidence: 94%

Section: Discussionmentioning

confidence: 83%

Section: Jnk Inhibition Reverses Behavioral Phenotypes Of Morphine Inmentioning

confidence: 99%

See 1 more Smart Citation

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Mittal

Tan

Egbuta

et al. 2012

Neuropsychopharmacol

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“…MEF trafficking. MEF cells were transiently transfected with 2-2.5 g of 5-HT2AR-YFP cDNA by using the Gene Pulser Xcell electroporation system as described previously (Bio-Rad) (36). Images presented are representative of at least four separate transfections and drug treatments.…”

Section: Discussionmentioning

confidence: 99%

Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

Schmid

Raehal

Bohn

2008

Proc. Natl. Acad. Sci. U.S.A.

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212

224

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Visual and auditory hallucinations accompany certain neuropsychiatric disorders, such as schizophrenia, and they also can be induced by the use or abuse of certain drugs. The heptahelical serotonin 2A receptors (5-HT2ARs) are molecular targets for druginduced hallucinations. However, the cellular mechanisms by which the 5-HT2AR mediates these effects are not well understood. Drugs acting at the 5-HT2AR can trigger diverse signaling pathways that may be directed by the chemical properties of the drug. ␤-arrestins are intracellular proteins that bind to heptahelical receptors and represent a point where such divergences in liganddirected functional signaling could occur. Here we compare the endogenous agonist, serotonin, to a synthetic 5-HT2AR hallucinogenic agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), in mice lacking ␤-arrestin-2, as well as in cells lacking ␤-arrestins. In mice, we find that serotonin induces a head twitch response by a ␤-arrestin-2-dependent mechanism. However, DOI invokes the behavior independent of ␤-arrestin-2. The two structurally distinct agonists elicit different signal transduction and trafficking patterns upon activation of 5-HT2AR, which hinge on the presence of ␤-arrestins. Our study suggests that the 5-HT2AR-␤-arrestin interaction may be particularly important in receptor function in response to endogenous serotonin levels, which could have major implications in drug development for treating neuropsychiatric disorders such as depression and schizophrenia.5-HT2A receptor ͉ G protein-coupled receptor ͉ internalization ͉ MAP kinase ͉ schizophrenia

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“…20 Briefly, the CPP procedure consisted of day 1 of preconditioning (pretest), where the mice were allowed to freely move between all chambers of the CPP apparatus and the time spent (basal preference) in each chamber was recorded for 30 min. In the conditioning phase, the mice were injected with morphine (3 or 6 mg kg À1 ) on days 2, 4 and 6 and Sal on days 3, 5 and 7, and the drug was randomly paired with alternating compartments, such that half of the mice received drug in the black compartment and the other half in the white compartment.…”

Section: Conditioned Place Preferencementioning

confidence: 99%

The physiological relevance of functional selectivity in dopamine signalling

Urs

Caron

2014

Int J Obes Supp

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We sought to determine the role of functionally selective dopamine (DA) signalling pathways (G protein or b-arrestin) in DA-dependent behaviours. Mice that were globally deficient for b-arrestins or mice deficient in GSK3b in D2 receptor (D2R)-expressing neurons were used to investigate the role of functional selectivity in DA-dependent behaviours such as locomotor activity and conditioned place preference (CPP). Wild-type or knockout mice were injected with drugs such as morphine and amphetamine, which are known to increase DA levels in the brain and to induce a hyper-locomotor response and CPP. Unlike b-arrestin1 (barr1)-deficient mice, mice globally deficient for b-arrestin2 (barr2) mount a reduced hyperlocomotor response to either morphine or amphetamine. However, mice deficient in GSK3b in D2R-expressing neurons show a significantly reduced locomotor response to only amphetamine but not morphine. Interestingly, all mice tested show a normal CPP response to either morphine or amphetamine. b-arrestin-mediated DA receptor signalling has an important role in the locomotor response, but not CPP, to drugs such as morphine and amphetamine, demonstrating a functional selectivity of DA-dependent behaviours in mice. It is likely that G-protein-dependent signalling through DA receptors mediates the CPP response.

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Enhanced Rewarding Properties of Morphine, but not Cocaine, in βarrestin-2 Knock-Out Mice

Cited by 206 publications

References 51 publications

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Agonist-directed signaling of the serotonin 2A receptor depends on β-arrestin-2 interactions in vivo

The physiological relevance of functional selectivity in dopamine signalling

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