Environmentally-induced drug relapse is a major obstacle in the rehabilitation of cocaine users. Cocaine- associated environments maintain stimulus control over cocaine-induced behavior via context-response- cocaine associations that must be maintained in long-term memory. Thus, treatments that selectively weaken or eliminate such cocaine memories may reduce the propensity to relapse in former drug addicts. Remarkably, cocaine-related long-term memories become labile following retrieval (i.e., memory reactivation), and these memories need to be re-stabilized, or reconsolidated, into long-term storage in order to be maintained. Furthermore, evidence suggests that the basolateral amygdala (BLA) is required for the reconsolidation of cocaine memories that promote drug context-induced cocaine seeking (non-reinforced active lever presses, which provided an index of motivation for cocaine;Fuchs et al., 2009). The proposed NRSA research plan will extend this line of inquiry by exploring the intracellular mechanisms of cocaine-memory reconsolidation in the BLA with a focus on two signaling molecules: extracellular signal-related kinase (ERK) and cyclin-dependent protein kinase 5 (Cdk5).
Specific aim 1 will be to test the hypothesis that ERK-mediated signaling in the BLA facilitates the reconsolidation of cocaine memories that are critical for contextual control over instrumental cocaine seeking and will explore possible downstream mechanisms of this phenomenon. Preliminary data show that intra-BLA U0126 (MEK/ERK inhibitor) treatment impairs cocaine-memory reconsolidation in a memory reactivation-dependent manner and disrupts subsequent drug context-induced cocaine seeking (Exp. 1a, in progress). These data provide sound rationale for Exp. 1b, which will utilize quantitative Western blotting to characterize changes in the activation of Elk-1, CREB, and zif268, the transcription factors that are likely activated by ERK in the BLA during memory reconsolidation (Aim 1b). As follow-up, antisense oligonucleotide or small interfering RNA manipulation will be used to assess whether the activation of Elk-1, CREB, or zif268 is required for cocaine-memory reconsolidation and subsequent contextual control over cocaine seeking.
Specific aim 2 will be to test the hypothesis that Cdk5 in the BLA interferes with the reconsolidation of cocaine memories that are critical for contextual control over instrumental cocaine seeking. Based on evidence that Cdk5 negatively regulates ERK in vitro, Exp. 2 will assess whether intra-BLA ?-butyrolactone (Cdk5 inhibitor) treatment will enhance cocaine-memory reconsolidation in a memory reactivation-dependent manner and increase subsequent drug context-induced cocaine seeking. In summary, a combination of sophisticated behavioral procedures and cutting edge molecular techniques will be used to explore the intracellular mechanisms of cocaine-memory reconsolidation, a cognitive process that maintains maladaptive addictive memories and thus stimulates environmentally-induced drug craving and relapse. This research endeavor has the potential to provide novel insights for addiction treatment development.
Cocaine addiction is a serious public health, social, and economic problem in the United States, in part because cocaine addicts are highly susceptible to environmentally-triggered relapse even after extended periods of drug abstinence. The experiments outlined in this predoctoral NRSA proposal will utilize a rodent model of drug relapse in order to identify novel molecular brain mechanisms that underlie the reconsolidation of cocaine-associated memories into long-term memory storage and thus the ability of these memories to drive relapse behaviors. A better understanding of such mechanisms may contribute to the development of treatments designed to weaken or abolish these memories in order to prevent drug relapse in former cocaine users.
|Xie, Xiaohu; Wells, Audrey M; Fuchs, Rita A (2014) Cocaine seeking and taking: role of hippocampal dopamine D1-like receptors. Int J Neuropsychopharmacol 17:1533-8|
|Lasseter, Heather C; Xie, Xiaohu; Arguello, Amy A et al. (2014) Contribution of a mesocorticolimbic subcircuit to drug context-induced reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 39:660-9|