Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

Abstract

Recent data from our laboratory have demonstrated that appetitive drug memories undergo protein synthesis-dependent reconsolidation in the basolateral amygdala (BLA), an area important in the formation of emotional memories. We here investigated the importance of the BLA in the reconsolidation of opiate conditioned withdrawal memories. Rats with bilateral cannulas implanted in the BLA were trained to respond for heroin (0.12 mg/kg, i.v.) under a seeking-taking schedule, which required responding on a seeking lever to gain the opportunity to self-administer heroin by a single response on a taking lever. After induction of opiate dependence with subcutaneously implanted, heroin-filled osmotic minipumps (3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 heroin), rats received five consecutive pairings of a conditioned stimulus (CS) (tone, light, and odor compound) paired with naloxone (0.10 mg/kg, s.c.)-precipitated withdrawal. We replicated our previous findings that heroin seeking is suppressed in the presence of the withdrawal-associated CS. However, infusion of Zif268 antisense oligodeoxynucleotide into the BLA before reactivation of the CS-withdrawal association abolished this conditioned suppression in a reactivation-dependent manner. We also report that reconsolidation of CS-withdrawal memories upregulates Zif268 protein in the basolateral but not central nucleus of the amygdala and that Zif268 knockdown occurs selectively in the BLA. These results demonstrate that drug withdrawal memories undergo protein synthesis-dependent reconsolidation in the BLA and suggest a common mechanism for the reconsolidation of both appetitive and aversive drug memories.

Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates κ-Opioid-Dependent Dysphoria

“…The KOR-dependent activation of the IEG zif268 (also called Egr-1) after stress is consistent with previous studies showing zif268 is a direct downstream target of p38 (Rolli et al, 1999) and suggests that swim stress-induced immobility and aversion could be partly mediated by genes induced by zif268. Recent reports have also demonstrated that zif268 is critical in conditioned withdrawal, another aversive behavioral model (Hellemans et al, 2006). Collectively, these studies suggest that zif268 may be one mediator of the aversive response underlying dysphoria.…”

Modelos animales de adicción a las drogas

“…En estos estudios, tras conseguir una adquisición estable de la AA, se reactiva la memoria (exponiendo a los animales a la caja de AA durante un breve intervalo de tiempo) y poco tiempo después (de minutos a un par de horas), los animales realizan sesiones de extinción o reciben una inyección de un fármaco amnésico. Ambos tratamientos reducen de forma rápida y efectiva la búsqueda de drogas (acelerando la extinción de la respuesta de AA) y bloquean la reinstauración (Hellemans, Everitt y Lee, 2006;Lee, Milton y Everitt, 2006;Lee, Platt, Rowlett, Adewale y Spealman, 2005;Sánchez, Quinn, Torregrossa y Taylor, 2010;Yan et al, 2014;Yan, Kong, Wu, Newman y Xu, 2013).…”

Intra-Amygdala and Systemic Antagonism of NMDA Receptors Prevents the Reconsolidation of Drug-Associated Memory and Impairs Subsequently Both Novel and Previously Acquired Drug-Seeking Behaviors

“…Rats were trained in operant chambers (Med Associates) as described previously (Hellemans et al, 2006). Selfadministration training took place over nine daily sessions, controlled by the Whisker control system.…”