Involvement of amygdalar protein kinase A, but not calcium/calmodulin-dependent protein kinase II, in the reconsolidation of cocaine-related contextual memories in rats

Abstract

Rationale Contextual control over drug relapse depends on the successful reconsolidation and retention of context-response-cocaine associations in long-term memory stores. The basolateral amygdala (BLA) plays a critical role in cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior; however, less is known about the cellular mechanisms of this phenomenon. Objectives The present study evaluated the hypothesis that protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII) activation in the BLA is necessary for the reconsolidation of context-response-cocaine memories that promote subsequent drug context-induced cocaine-seeking behavior. Methods Rats were trained to lever-press for cocaine infusions in a distinct context, followed by extinction training in a different context. Rats were then briefly re-exposed to the previously cocaine-paired context or an unpaired context in order to reactivate cocaine-related contextual memories and initiate their reconsolidation or to provide a similar behavioral experience without explicit cocaine-related memory reactivation, respectively. Immediately after this session, rats received bilateral microinfusions of vehicle, the PKA inhibitor, Rp-Adenosine 3′,5′-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS), or the CaMKII inhibitor, KN-93, into the BLA or the posterior caudate putamen (anatomical control region). Rats were then tested for cocaine-seeking behavior (responses on the previously cocaine-paired lever) in the cocaine-paired context and the extinction context. Results Intra-BLA infusion of Rp-cAMPS, but not KN-93, following cocaine memory reconsolidation impaired subsequent cocaine-seeking behavior in a dose-dependent, site-specific, and memory reactivation-dependent fashion. Conclusions PKA, but not CaMKII, activation in the BLA is critical for cocaine memory re-stabilization processes that facilitate subsequent drug context-induced instrumental cocaine-seeking behavior.

CaMKII regulates proteasome phosphorylation and activity and promotes memory destabilization following retrieval

“…Consistent with this revised theory, in the present study we found that CaMKII activity was critical for retrieval-induced increases in proteasome activity in the amygdala and pharmacological manipulation of CaMKII activity rescued memory impairments that resulted from local infusions of a protein synthesis inhibitor, mirroring the effect we have previously observed with a proteasome inhibitor (Jarome et al, 2011). This result strongly suggests a critical role for CaMKII signaling in the reconsolidation process and may explain findings from other studies where CaMKII inhibitors have not impaired memory when administered following retrieval (Arguello et al, 2014). …”

“…Several studies have demonstrated that CaMKII is a critical regulator of memory consolidation (e.g., Chen, Bambah-Mukku, Pollonini, and Alberini, 2012; Halt et al, 2012; Naskar, Wan, and Kemenes, 2014; Ota, Monsey, Wu, and Schafe, 2010; Wan, Mackay, Iqbal, Naskar, and Kemenes, 2010), but despite this evidence, little is known about how CaMKII regulates memory reconsolidation following retrieval (Arguello et al, 2014; Da Silva et al, 2013; Sakurai et al, 2007). One theory is that CaMKII is involved in transcriptional and subsequent translational regulation in neurons following retrieval (Tronson and Taylor, 2007), as well as AMPA receptor trafficking (Johansen et al, 2011).…”

“…Interestingly, the role of CaMKII in the reconsolidation of fear memories has never been examined. Additionally, studies examining the role of CaMKII in the reconsolidation of memory for other behavioral tasks have found mixed results, with some indicating normal memory retention following post-retrieval inhibition of CaMKII signaling (Arguello et al, 2014; Da Silva, Cardoso, Bonini, Benetti, and Izquierdo, 2013; Sakurai, Yu, and Tan, 2007). One intriguing explanation for these mixed results is that CaMKII regulates protein degradation upstream of its potential (but not proven) regulation of protein synthesis during the reconsolidation process (Jarome and Helmstetter, 2013).…”

Epigenetic mechanisms of memory formation and reconsolidation

“…PKA is also a critical component of the reconsolidation process (Arguello et al, 2014; Kemenes, Kemenes, Michel, Papp, and Muller, 2006; Sanchez, Quinn, Torregrossa, and Taylor, 2010; Tronson et al, 2006) and can bidirectionally regulate H3K9 dimethylation and H3 acteylation in striatal tissue (Li et al, 2004). Considering that PKA activators and HDAC inhibitors can both enhance memory reconsolidation, this suggests that PKA could regulate histone acetylation during the reconsolidation process.…”

Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement

“…Within the BLA, inhibition of protein synthesis or of elements of the mitogen activated protein kinase signaling pathway, including protein kinase A and extracellular signal-regulated kinase (ERK), disrupts contextual cocaine-memory reconsolidation and subsequent drug context-induced reinstatement of extinguished cocaine-seeking (Arguello et al, 2014; Fuchs et al, 2009; Wells et al, 2013). Evidence suggests that ERK-induced phosphorylation requires interaction between ERK and activated GRs at least in the hippocampus (Reul, 2014).…”