Complex Effects of NMDA Receptor Antagonist APV in the Basolateral Amygdala on Acquisition of Two-Way Avoidance Reaction and Long-Term Fear Memory

Abstract

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about an involvement of this structure in more complex aversive learning, such as acquisition of an active avoidance reaction. In the present study, rats with a pretraining injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), into the basolateral amygdala (BLA) were found to be impaired in two-way active avoidance learning. During multitrial training in a shuttle box, the APV-injected rats were not different from the controls in sensitivity to shock or in acquisition of freezing to contextual cues. However, APV injection led to impaired retention of contextual fear when tested 48 h later, along with an attenuation of c-Fos expression in the amygdala. These results are consistent with the role of NMDA receptors of the BLA in long-term memory of fear, previously documented in Pavlovian conditioning paradigms. The APV-induced impairment in the active avoidance learning coincided with deficits in directionality of the escape reaction and in attention to conditioned stimuli. These data indicate that normal functioning of NMDA receptors in the basolateral amygdala is required during acquisition of adaptive instrumental responses in a shuttle box but is not necessary for acquisition of short-term contextual fear in this situation.Pavlovian fear conditioning has become a widely used model system to study neural substrates underlying aversive learning (LeDoux 1998;Fanselow and LeDoux 1999). Using this approach, a considerable body of data has been accumulated that indicates the essential role of the nuclei of the amygdala, especially the lateral and basolateral nuclei, in associative changes during fear conditioning (Quirk et al. 1995;Maren and Fanselow 1996;Maren et al. 1996a;Schafe et al. 2000). However, the data based on inhibitory avoidance learning support the argument that the amygdala mainly modulates the consolidation of fear memories in other brain structures (McGaugh et al. 1995;Roozendaal et al. 1997;Cahill and McGaugh 1998). One of the possible resolutions of this dispute is that the amygdala may play a dual role in these paradigms; namely, that in classical fear conditioning, the amygdala serves as the site of plasticity underlying fear learning, whereas in inhibitory avoidance learning, the amygdala modulates the strength of aversive memory located elsewhere (Wilensky et al. 2000).Notably, both the fear conditioning and the inhibitory avoidance paradigms consist of a very low number of trials, thus limiting an opportunity to assess the role of the amygdala in a complex relation between fear processing and an acquisition of the instrumental reaction. One of the approaches to address this question involves more complex models of aversive learning, such as the active avoidance paradigm, which includes fear conditioning and demands dozens of trials to learn the instrumental response (for review, see Bolles 1979; Mineka 1979).The process of...

Nicotine ameliorates NMDA receptor antagonist-induced deficits in contextual fear conditioning through high-affinity nicotinic acetylcholine receptors in the hippocampus

“…The amygdala is critically involved in both cued and contextual fear conditioning (Phillips and LeDoux, 1992) and contains NMDARs (Maren et al, 1996). In support, direct infusion of APV into the amygdala disrupted acoustic fear potentiated startle and fear conditioning (Fanselow and Kim, 1994; Fanselow et al, 1994; Kim et al, 1991; Laurent and Westbrook, 2009; Maren et al, 1996; Miserendino et al, 1990; Savonenko et al, 2003). It is also possible that the observed deficit in cued fear conditioning was due to the effects of MK-801 in other brain regions, including the hippocampus.…”

Cognitive Deficit in Amyloid-β–Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-γ Activation

“…Moreover, in this study, we used the Morris water maze test to evaluate cognitive function instead of the shuttle avoidance test so that we could focus on hippocampus function. The shuttle avoidance test (also called the 2-way active avoidance test) is considered to measure nondeclarative memory and relies on both classic fear conditioning and instrumental conditioning 21 and is often thought to be primarily striatum dependent. 22 On the other hand, a spatial working memory task, such as the Morris water maze test, depends on hippocampus function, [23][24][25] and we hypothesized that an even lower dose of telmisartan treatment would moderate hippocampal activity.…”

ERK2 and CREB activation in the amygdala when an event is remembered as “Fearful” and not when it is remembered as “Instructive”

“…It has been suggested that active shuttle avoidance task measures nondeclarative memory (Savonenko et al, 2003) and is hippocampus independent. Another possible explanation for the results is that, while the amygdala becomes less involved, other brain areas such as the caudate nucleus (Packard et al, 1994) but not the hippocampus become involved.…”