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

Abstract

The amygdala has long been considered a primary locus in mediating the effects of previously drug-associated stimuli on subsequent drug-seeking behavior, and the NMDA subtype of glutamate receptor within the amygdala is important for the consolidation of associations between environmental conditioned stimuli and the effects of addictive drugs. Here we demonstrate that amygdala NMDA receptors are also necessary for the reconsolidation of drug-associated memories. Using a behavioral task that specifically measures the conditioned reinforcing properties of a previously drug-paired stimulus, we show that infusion of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-APV) into the basolateral amygdala before a memory reactivation session disrupted the drugassociated memory and abolished subsequent instrumental responding for conditioned reinforcement. This effect was memory reactivation dependent, and the memory deficit persisted for at least 4 weeks. In contrast, infusion of D-APV immediately after the memory reactivation session had no effect on subsequent responding for conditioned reinforcement, indicating that NMDA receptors have a temporally limited role in the reconsolidation process. Furthermore, in molecular studies, we show that the reconsolidation-impairing effect of D-APV is correlated with downstream reductions in expression of the plasticity-related immediate early gene, zif268. We also demonstrate that systemic antagonism of NMDA receptors with MK-801 [(ϩ)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate] before memory reactivation subsequently reduced previously acquired instrumental drug-seeking behavior that depends on drug-associated cues acting as conditioned reinforcers. These data suggest that drugs modulating glutamatergic transmission at the NMDA receptor may be useful in the future treatment of relapse prevention in drug addiction through memory reconsolidation blockade.

d-cycloserine in the basolateral amygdala prevents extinction and enhances reconsolidation of odor-reward associative learning in rats

“…Consistent with our interpretation that a positive modulation of NMDA transmission may help to stabilize the original odor-reward memory trace when reactivated, a previous study showed that intracerebroventricular blockade of NMDARs immediately after reactivation induced amnesia for the stimuli association (Torras-Garcia et al, 2005). Similarly, the administration of the NMDARs antagonist APV within the BLA prior to (but not after) a reactivation session, prevented reconsolidation of drug-associated memory, indicating that NMDARs have a temporally limited role in the reconsolidation process (Milton, Lee, Butler, Gardner & Everitt, 2008).…”

Reconsolidation and the Dynamic Nature of Memory

“…Currently, there are several studies that have examined the mechanisms involved in transforming a consolidated memory to a labile state. Although the NR2B subunit is critical for memories to return to a labile state within the LBA for fear conditioning (Ben , NMDA receptors in the hippocampus and within the amygdala for appetitive memories are thought to play a direct role in the restabilization process following the reactivation of the memory (Milton et al 2008;Suzuki et al 2008). In the hippocampus, voltage-gated calcium channels (VGCCs) (Suzuki et al 2008) and protein degradation ) are critical for a memory to return to a labile state.…”

Differential Role of Muscarinic Transmission within the Entorhinal Cortex and Basolateral Amygdala in the Processing of Irrelevant Stimuli

“…Importantly, these doses were lower than the doses shown before to impair classical conditioning when infused to BLA (See et al, 2003), because impairment of conditioning per se (impaired conditioning in the NPE groups) masks the effects of experimental manipulations on LI. Infusion volume was based on a routinely used volume in similar behavioral studies ( (Barros et al, 2001;Lewis and Gould, 2007a, b;Roesler et al, 2002;Seillier et al, 2007) for EC; (Barros et al, 2001;Chhatwal et al, 2009;Milton et al, 2008;See et al, 2001See et al, , 2003Zhao et al, 2009) for BLA). Infusions were given in a different room from the behavioral testing area.…”