Extracellular Signal-Regulated Kinase in the Basolateral Amygdala, but not the Nucleus Accumbens Core, is Critical for Context-Response-Cocaine Memory Reconsolidation in Rats

Abstract

The reconsolidation of cocaine memories following retrieval is necessary for the sustained ability of a cocaine-paired environmental context to elicit cocaine seeking. Extracellular signal-regulated kinase (ERK) is an intracellular signaling molecule involved in nucleus accumbens core (NACc)-mediated reconsolidation of Pavlovian cocaine memories. Here, we used a rodent model of drug context-elicited relapse to test the hypothesis that ERK would be similarly required for the reconsolidation of context-response-cocaine memories that underlie drug context-induced reinstatement of instrumental cocaine-seeking behavior, with a focus on the NACc and on the basolateral amygdala (BLA), another important locus for the reconsolidation of cocaine memories. We show that the mitogen-activated protein kinase (MEK)/ERK1/2 inhibitor, U0126 (1.0 μg/0.5 μl/hemisphere), microinfused bilaterally into the BLA--but not the NACc--immediately after brief re-exposure to a previously cocaine-paired context (that is, cocaine-memory reactivation), significantly attenuated subsequent drug context-induced cocaine seeking relative to vehicle (VEH). This effect in the BLA was associated with a transient inhibition of ERK1/2 phosphorylation, and it depended on memory reactivation given that U0126 administered following exposure to a novel context did not alter subsequent cocaine seeking. Furthermore, similar to U0126, baclofen+muscimol-induced (B+M; 106.8/5.7 ng/0.5 μl/hemisphere) neural inactivation of the NACc, following cocaine-memory reactivation, failed to alter subsequent cocaine seeking. These findings demonstrate that ERK activation in the BLA, but not the NACc, is required for the reconsolidation of context-response-cocaine associative memories. Together with prior research, these results suggest that contextual drug-memory reconsolidation in Pavlovian and instrumental settings involves distinct neuroanatomical mechanisms.

Selective, Retrieval-Independent Disruption of Methamphetamine-Associated Memory by Actin Depolymerization

“…Continuing to explore the question of memory strength, as well as the type of memory and translational potential, we next assessed the ability of LatA to disrupt the maintenance of context-induced reinstatement of METH seeking, an animal model of drug seeking/relapse that relies on instrumental learning of a contextual memory (44, 57) (Fig. 4C).…”

“…We and others have taken the approach of post-consolidation manipulations focused on the time of retrieval (e.g. blockade of reconsolidation and accelerated extinction) (44-48). In the current study we hypothesized that the actin cytoskeleton supporting structural plasticity may be a target for manipulating the strength of METH-dependent associations after the typical consolidation period.…”

Dopamine D3 receptor alterations in cocaine-dependent humans imaged with [11C](+)PHNO

“…In chronic cocaine users, decreased amygdalar volume and changes in functional connectivity involving the amygdala have been described (Gu et al, 2010; Makris et al, 2004) In rodents, D 3 R antagonists injected into the amygdala have decreased cocaine self-administration under second-order schedules of reinforcement (Di Ciano, 2008), anxiety-like behaviors (Diaz et al, 2011) and more recently cocaine seeking (Xi et al, 2012). In addition, the amygdala has been implicated in cocaine-induced behavioral inflexibility (Stalnaker et al, 2007), cocaine memory reconsolidation (Wells et al, 2012) and stress-induced relapse (Smith and Aston-Jones, 2008). Despite not knowing the attributable D 3 R percentage in the amygdala of humans, these findings suggest that the D 3 R receptors represent an attractive pharmacologic target in this region.…”

Effects of Conditional Central Expression of HIV-1 Tat Protein to Potentiate Cocaine-Mediated Psychostimulation and Reward Among Male Mice

“…Although the mechanistic basis of this interaction is beyond the scope of this initial study, Tat protein modulates a number of intracellular pathways in vitro (Gibellini et al, 1998), which could feasibly contribute to this behavioral result, most notably extracellular-signal regulatory kinase mitogenactivated protein (ERK1/2 MAP) kinase (Rusnati et al, 2001). ERK1/2 MAP kinases have been implicated in both the reinforcing properties of cocaine (Valjent et al, 2000) and the reinstatement of cocaine self-administration (Lu et al, 2005;Wells et al, 2013). The host of interactions between Tat and the brain highlight many avenues by which Tat may influence drug reward, and which will require additional research.…”