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Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse.

ABSTRACT: BACKGROUND:Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms. METHODS:In the first series of experiments, we trained rats for nicotine-induced conditioned place preference (CPP) or nicotine self-administration and ventricularly microinjected them with the protein synthesis inhibitor anisomycin immediately after UCS-induced memory retrieval. In the second series of experiments, we used tyramide-amplified immunohistochemistry-fluorescence in situ hybridization to examine neural ensembles in the basolateral amygdala (BLA) reactivated by nicotine conditioned stimulus- or UCS-induced memory retrieval. We then used the Daun02 chemogenetic inactivation procedure to selectively inhibit the nicotine UCS-reactivated BLA neuronal ensembles. RESULTS:Ventricular injections of the anisomycin immediately after nicotine UCS memory retrieval inhibited subsequent nicotine CPP and relapse to operant nicotine seeking after short or prolonged abstinence. More important, within BLA, distinct neuronal ensembles encoded pavlovian CPP and operant self-administration reward memories and nicotine (the UCS) injections in the home cage reactivated both neuronal ensembles. Daun02 chemogenetic inactivation of the nicotine-reactivated ensembles inhibited both nicotine CPP and relapse to nicotine seeking. CONCLUSIONS:Results demonstrate that the nicotine UCS-induced memory retrieval manipulation reactivates multiple nicotine reward memories that are encoded by distinct BLA neuronal ensembles that play a role in nicotine preference and relapse.

SUBMITTER: Xue YX

PROVIDER: S-EPMC6192421 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse.

Xue Yan-Xue YX Chen Ya-Yun YY Zhang Li-Bo LB Zhang Li-Qun LQ Huang Geng-Di GD Sun Shi-Chao SC Deng Jia-Hui JH Luo Yi-Xiao YX Bao Yan-Ping YP Wu Ping P Han Ying Y Hope Bruce T BT Shaham Yavin Y Shi Jie J Lu Lin L

Biological psychiatry 20170511 11

<h4>Background</h4>Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivating nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus [UCS]) and then pharmacologically interfering with memory reconsolidation decreased relapse to nicotine seeking in rats and nicotine craving in smokers. Here, we investigated underlying mechanisms.<h4>Metho ...[more]

PMID: 28648649

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Project description:ImportanceA relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results.ObjectiveTo develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke.Design, setting, and participantsA translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke.InterventionThe study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma).Main outcomes and measuresNicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke.ResultsSixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76).Conclusions and relevanceIn rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.

Project description:The dynorphin (DYN)/kappa-opioid receptor (KOR) system plays a conserved role in stress-induced reinstatement of drug seeking for prototypical substances of abuse. Due to nicotine's high propensity for stress-induced relapse, we hypothesized that stress would induce reinstatement of nicotine seeking-like behavior in a KOR-dependent manner. Using a conditioned place preference (CPP) reinstatement procedure in mice, we show that both foot-shock stress and the pharmacological stressor yohimbine (2 mg/kg, i.p.) induce reinstatement of nicotine CPP in a norbinaltorphimine (norBNI, a KOR antagonist)-sensitive manner, indicating that KOR activity is necessary for stress-induced nicotine CPP reinstatement. After reinstatement testing, we visualized robust c-fos expression in the basolateral amygdala (BLA), which was reduced in mice pretreated with norBNI. We then used several distinct but complementary approaches of locally disrupting BLA KOR activity to assess the role of KORs and KOR-coupled intracellular signaling cascades on reinstatement of nicotine CPP. norBNI injected locally into the BLA prevented yohimbine-induced nicotine CPP reinstatement without affecting CPP acquisition. Similarly, selective deletion of BLA KORs in KOR conditional knock-out mice prevented foot-shock-induced CPP reinstatement. Together, these findings strongly implicate BLA KORs in stress-induced nicotine seeking-like behavior. In addition, we found that chemogenetic activation of G?i signaling within CaMKII? BLA neurons was sufficient to induce nicotine CPP reinstatement, identifying an anatomically specific intracellular mechanism by which stress leads to reinstatement. Considered together, our findings suggest that activation of the DYN/KOR system and G?i signaling within the BLA is both necessary and sufficient to produce reinstatement of nicotine preference.Considering the major impact of nicotine use on human health, understanding the mechanisms by which stress triggers reinstatement of drug-seeking behaviors is particularly pertinent to nicotine. The dynorphin (DYN)/kappa-opioid receptor (KOR) system has been implicated in stress-induced reinstatement of drug seeking for other commonly abused drugs. However, the specific role, brain region, and mechanisms that this system plays in reinstatement of nicotine seeking has not been characterized. Here, we report region-specific engagement of the DYN/KOR system and subsequent activation of inhibitory (Gi-linked) intracellular signaling pathways within the basolateral amygdala during stress-induced reinstatement of nicotine preference. We show that the DYN/KOR system is necessary to produce this behavioral state. This work may provide novel insight for the development of therapeutic approaches to prevent stress-related nicotine relapse.

Project description:Through Pavlovian appetitive conditioning, environmental cues can become predictors of food availability. Over time, however, the food, and thus the value of the associated cues, can change based on environmental variations. This change in outcome necessitates updating of the value of the cue to appropriately alter behavioral responses to these cues. The basolateral amygdala (BLA) is critical in updating the outcomes of learned cues. However, it is unknown if the same BLA neuronal ensembles that are recruited in the initial associative memory are required when the new cue-outcome association is formed during reversal learning. The current study used the Daun02 inactivation method that enables selective targeting and disruption of activated neuronal ensembles in Fos-lacZ transgenic rats. Rats were implanted with bilateral cannulas that target the BLA and underwent appetitive discriminative conditioning in which rats had to discriminate between two auditory stimuli. One stimulus (CS+) co-terminated with food delivery, and the other stimulus was unrewarded (CS-; counterbalanced). Rats were then tested for CS+ or CS- memory retrieval and infused with either Daun02 or a vehicle solution into the BLA to inactivate either CS+ or CS- neuronal ensembles that were activated during that test. To assess if the same neuronal ensembles are necessary to update the value of the new association when the outcomes are changed, rats underwent reversal learning: the CS+ was no longer followed by food (reversal CS-, rCS-), and the CS- was now followed by food (reversal CS+; rCS+). The group that received Daun02 following CS+ session showed a decrease in conditioned responding and increased latency to the rCS- (previously CS+) during the first session of reversal learning, specifically during the first trial. This indicates that the neuronal ensemble that was activated during the recall of the CS+ memory was the same neuronal ensemble needed for learning the new outcome of the same CS, now rCS-. Additionally, the group that received Daun02 following CS- session was slower to respond to the rCS+ (previously CS-) during reversal learning. This indicates that the neuronal ensemble that was activated during the recall of the CS- memory was the same neuronal ensemble needed for learning the new outcome of the same CS. These results demonstrate that different neuronal ensembles within the BLA mediate memory recall of CS+ and CS- cues and reactivation of each cue-specific neuronal ensemble is necessary to update the value of that specific cue to respond appropriately during reversal learning. These results also indicate substantial plasticity within the BLA for behavioral flexibility as both groups eventually showed similar terminal levels of reversal learning.

Dataset Information

Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse.

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Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse.

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