β1-Adrenoceptor in the Central Amygdala Is Required for Unconditioned Stimulus-Induced Drug Memory Reconsolidation
Advance Access Publication: December
β1-Adrenoceptor in the Central Amygdala Is Required for Unconditioned Stimulus-Induced Drug Memory Reconsolidation
Huiwen Zhu 0
Yiming Zhou 0
Zhiyuan Liu 0
Xi Chen 0
Yanqing Li 0
Xing Liu 0
Lan Ma 0
0 and the Collaborative Innovation Center for Brain Science , 138 Yixueyuan Road, Shanghai, China; Xing Liu, MD , Pharmacology Research Center, Fudan University , 220 Handan Road, Shanghai , China
Background: Drug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus) or drugs (unconditioned stimulus). Whether conditioned stimulus and unconditioned stimulus retrieval trigger different memory reconsolidation processes is not clear. Methods: Protein synthesis inhibitor or β-adrenergic receptor (β-AR) antagonist was systemically administrated or intra-central amygdala infused immediately after cocaine reexposure in cocaine-conditioned place preference or self-administration mice models. β-ARs were selectively knocked out in the central amygdala to further confirm the role of β-adrenergic receptor in cocaine reexposure-induced memory reconsolidation of cocaine-conditioned place preference. Results: Cocaine reexposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-conditioned place preference. Cocaine-priming-induced reinstatement was also impaired with post cocaine retrieval manipulation, in contrast to the relapse behavior with post context retrieval manipulation. Cocaine retrieval, but not context retrieval, induced central amygdala activation. Protein synthesis inhibitor or β1-adrenergic receptor antagonist infused in the central amygdala after cocaine retrieval, but not context retrieval, inhibited memory reconsolidation and reinstatem1e-andtr.eβnergic receptor knockout in the central amygdala suppressed cocaine retrieval-triggered memory reconsolidation and reinstatement of cocaine conditioned place preference. 1β-adrenergic receptor antagonism after cocaine retrieval also impaired reconsolidation and reinstatement of cocaine self-administration. Conclusions: Cocaine reward memory triggered by unconditioned stimulus retrieval is distinct from conditioned stimulus retrieval. Unconditioned stimulus retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. Post unconditioned stimulus retrieval manipulation can prevent drug memory reconsolidation and relapse to cocaine, thus providing a potential strategy for the prevention of substance addiction.
β-AR; unconditioned stimulus; conditioned stimulus; memory reconsolidation; cocaine
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The State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and the Institutes of Brain
Science, and the Collaborative Innovation Center for Brain Science, and Pharmacology Research Center, Fudan
University, Shanghai, China.
H.Z., Y.Z., and Z.L. contributed equally to this work.
It is well known that drug memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus
(CS) or unconditioned stimulus (US). Whether CS and US retrieval trigger different memory reconsolidation processes is unknown.
In this study, we found that US retrieval, but not CS retrieval, triggered memory reconsolidation of cocaine-conditioned place
preference dependent on β1-AR and de novo protein synthesis in the central amygdala. Furthermore, cocaine priming-induced
reinstatement was impaired with post US retrieval manipulation in contrast to the relapse behavior with post CS retrieval
manipulation. In cocaine self-administration1,β-AR antagonism after US retrieval also impaired reconsolidation and reinstatement. Our
study indicates that reconsolidation of cocaine reward memory triggered by US retrieval is distinct from CS retrieval. US retrieval
induced reconsolidation of cocaine reward memory depends on1β-adrenergic signaling in the central amygdala.
Introduction
Drug addiction is commonly considered a learning and memory whether US retrieval and CS retrieval are different in the
inducdisorder (Boening, 2001;Hyman, 2005). The reinforcing effects of tion of the memory reconsolidation process.
a drug (known as unconditioned stimulus [US]), such as drug- Many studies have demonstrated that β-AR is involved in
elicited euphoria, are strongly associated with environmental reconsolidation, because systemic or intra-basolateral
amygcues (known as conditioned stimulus [CS]) (Hyman and Malenka, dala (BLA) injection of a β-AR antagonist immediately after CS
2001; Shalev et al., 2002;Koob and Volkow, 2016). Consequently, retrieval prevents memory reconsolidation of cocaine-SA or
exposure to drug-associated environmental cues can evoke v-ar conditioned place preference (CPP)
(Milton et al., 200O8;tis et al.,
ious degrees of psychological dependence or compulsive drug 2013)
. In the signaling cascades downstream of β-AR, amygdala
taking (Cadet et al., 2014W;ise and Ko (...truncated)