Research ArticleNeuroscience

β-Arrestin–biased β-adrenergic signaling promotes extinction learning of cocaine reward memory

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Sci. Signal.  09 Jan 2018:
Vol. 11, Issue 512, eaam5402
DOI: 10.1126/scisignal.aam5402

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Extinguishing memories to fight addiction

Relapse in cocaine addicts can be prevented by training addicts not to respond to drug-associated cues. This process is called extinction learning in animal models of drug addiction. Activation of the β-adrenergic receptor, which can preferentially stimulate signaling mediated by β-arrestins or G proteins, is implicated in extinction learning. Huang et al. determined that the β-arrestin–dependent pathway was required downstream of β-adrenergic receptor activation to promote extinction learning in two different models, including a self-administration paradigm. Specifically, β-arrestin signaling was required in excitatory neurons in the infralimbic prefrontal cortex, a region of the brain involved in attenuating the association between drugs and cues. Thus, enhancing β-arrestin signaling in the infralimbic prefrontal cortex may augment the effect of cognitive therapy in preventing drug-seeking behavior and relapse in cocaine addicts.


Extinction learning of cocaine-associated contextual cues can help prevent cocaine addicts from relapsing. Pharmacological manipulation of β-adrenergic receptor (β-AR) during extinction learning is being developed as a potential strategy to treat drug addiction. We demonstrated that the extinction learning of cocaine-associated memory was mediated by β-arrestin2–biased but not heterotrimeric guanine nucleotide–binding protein (G protein)–dependent β-adrenergic signaling. We found that administration of the nonbiased β-AR antagonist propranolol, but not the G protein–biased β-AR antagonist carvedilol, blocked extinction learning of cocaine-conditioned place preference and the associated ERK activation in the infralimbic prefrontal cortex. Overexpression of β-arrestin2 in the infralimbic prefrontal cortex promoted extinction learning, which was blocked by propranolol. Knockout of β-arrestin2 in the infralimbic prefrontal cortex, specifically in excitatory neurons, impaired extinction learning of cocaine-conditioned place preference, which was not rescued by carvedilol. β-Arrestin2 signaling in infralimbic excitatory neurons was also required for the extinction learning in the cocaine self-administration model. Our results suggest that β-arrestin–biased β-adrenergic signaling in the infralimbic prefrontal cortex regulates extinction learning of cocaine-associated memories and could be therapeutically targeted to treat addiction.

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