Jessica A Higginbotham - US grants

PROJECT SUMMARY/ABSTRACT Environmentally induced craving and drug relapse are major impediments to the treatment of cocaine addiction. This form of craving and relapse is dependent on the retrieval of context-drug associative memories. Remarkably, these memories become unstable when reactivated by memory retrieval, and they must be re- stabilized through the protein synthesis-dependent process of memory reconsolidation in order to be maintained over time. The goal of this NRSA research proposal is to elucidate neural mechanisms that inhibit or facilitate context-cocaine memory reconsolidation in the basolateral amygdala (BLA), a requisite brain region for this phenomenon. This is important from a treatment perspective, since manipulations that either disrupt facilitative or potentiate inhibitory mechanisms of memory reconsolidation may impair the maintenance of context-drug memories and thus the ability of drug-associated contexts to precipitate relapse. Specific aim 1 will test the hypothesis that the stimulation of cannabinoid type 1 receptors (CB1R) in the BLA inhibits cocaine memory reconsolidation by suppressing known cellular/molecular mechanisms of memory reconsolidation. This aim rests on our preliminary data that intra-BLA CB1R antagonism enhances context-cocaine memory reconsolidation and promotes subsequent contextual control over drug-seeking behavior. The experiments will characterize changes in the activation or expression of extracellular signal-regulated kinase (ERK), mechanistic target of rapamycin complex 1 (mTOR), and zinc finger 268 (zif268) that are produced by memory retrieval and CB1R antagonism. Specific aim 2 will test the hypothesis that noradrenergic signaling in the BLA facilitates cocaine-memory reconsolidation and will aim to establish the neuroanatomical source of critical norepinephrine. This aim expands upon our preliminary data that ?-adrenergic receptor (?-AR) antagonism in the BLA, following explicit context- cocaine memory reactivation, disrupts subsequent cocaine-seeking behavior in a dose-dependent fashion. To determine whether this is a true memory reconsolidation deficit, control experiments will examine whether the effect depends on memory retrieval and destabilization. Additional experiments will assess whether monosynaptic adrenergic input from the locus coeruleus (LC) and/or the nucleus tractus solitaricus (NTS) is required for cocaine-memory reconsolidation through the stimulation of ?-adrenergic receptors in the BLA. The proposed research will target novel scientific questions using a sophisticated instrumental model of drug memory reconsolidation in combination with quantitative Western blotting, pharmacological manipulations, in vivo and ex vivo optogenetics in genetically modified tyrosine hydroxylase-cre recombinase (TH-Cre) rats. This research endeavor has the potential to identify neural targets for the development of therapeutic interventions that prevent cue-induced craving and relapse. Furthermore, the NRSA will provide opportunities for a talented predoctoral diversity scholar to hone her research, analytical, and communication skills and promote her career development through continuing education and interactions with a mentoring team of experts.