The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U0126 was administered after exposure to an unpaired context), suggesting that ERK in the BLA plays a critical role in restabilizing contextual cocaine-related memories. Next, Experiment 2 evaluated the hypothesis that the transcription factor (TF) nuclear factor-&kappab (NF-&kappaB) would also critically mediate instrumental cocaine-memory reconsolidation in the BLA. Remarkably, the NF-&kappab inhibitor, sulfasalazine (SSZ), administered bilaterally into the BLA following cocaine-memory reactivation, did not significantly alter subsequent cocaine-seeking behavior, relative to VEH, despite producing an observable trend for an enhancement in this behavior. Future studies will be needed to further examine this relationship, but the present findings may suggest that NF-&kappaB TFs acts as negative regulators of cocaine-memory reconsolidation. Finally, Experiment 3 tested the hypothesis that members of the Src family of tyrosine kinases (SFKs) are obligatory for instrumental cocaine-memory reconsolidation. Consistent with our hypothesis, PP2, a nonspecific inhibitor of SFKs, administered bilaterally into the DH after cocaine-memory reactivation, attenuated subsequent drug-context induced motivation for cocaine, relative to VEH, in a memory reactivation-dependent manner. This effect was associated with a preferential disruption of SFK-mediated phosphorylation of the NR2a N-methyl-D-aspartate receptor (NMDAR) subunit. Together, these findings begin to illuminate how the BLA and DH may subserve the long-term stability of maladaptive cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior.Doctor of Philosoph
