Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala

Abstract

Data derived from in vitro preparations indicate that NMDA receptors play a critical role in synaptic plasticity in the CNS. More recently, in viva pharmacological manipulations have suggested that an NMDA-dependent process may be involved in specific forms of behavioral plasticity. All of the work thus far has focused on the possible role of NMDA receptors in the acquisition of responses.However, there are many examples in the behavioral literature of learninginduced changes that involve the reduction or elimination of a previously acquired response. Experimental extinction is a primary example of the elimination of a learned response. Experimental extinction is well described in the behavioral literature, but has not received the same attention in the neurobiological literature. As a result, the neural mechanisms that underlie this important form of learning are not at all understood. In the present experiments, the fear-potentiated startle paradigm was employed to begin to investigate neural mechanisms of extinction. The results show that infusion of the NMDA antagonist D,L-2-amino-5phOS-phonovaleric acid (AP5) into the amygdala, a limbic structure known to be important for fear conditioning, dose-dependently blocked extinction of conditioned fear. Control experiments showed that the blockade of extinction was neither the result of the permanent disruption of amygdaloid function nor the result of decreased sensitivity of the animals to the conditioned stimulus. Infusion of AP5 into the interpositus nucleus of the cerebellum, a control site, did not block extinction. Finally, intra-amygdala infusion of a selected dose of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione did not block extinction of conditioned fear. These results, together with a previous report from our laboratory (Miserendino et al., 1990), demonstrate the importance of the amygdala in the elaboration of conditioned fear and suggest that an NMDA-dependent process might underlie the extinction of conditioned fear.

Systemic administration of the benzodiazepine receptor partial inverse agonist FG‐7142 disrupts corticolimbic network interactions

“…These results suggest that both descending corticoamygdaloid and ascending amygdalocortical pathways play a critical role in forming affectively significant associations during aversive learning (Laviolette et al, 2005). Interestingly, prior acute or chronic stress interferes with the subsequent extinction of fear conditioning or the recall of extinction learning (Izquierdo et al, 2006;Miracle et al, 2006), processes mediated by both mPFC (Milad and Quirk, 2002;Morgan and LeDoux, 1995;Quirk et al, 2000) and BLA (Chhatwal et al, 2005;Falls et al, 1992;Walker et al, 2002). Thus, the FG-7142-induced disruption of synchronized activity within and between mPFC and BLA reported in the present study may provide a useful model for examining the effects of stressors on corticolimbic interactions.…”

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

“…The extinction of conditioned fear involves the amygdala (Falls et al, 1992;Lu et al, 2001;Barad, 2006), as well as a loop between the amygdala and the medial prefrontal cortex (Sotres -Bayon et al, 2004, 2006). The prefrontal cortex gains Fear in the VPA rat model of autism K Markram et al increasing importance during the extinction process by inhibiting amygdaloid responses to fear conditioned stimuli (Rosenkranz et al, 2003), presumably through excitatory projections on inhibitory neurons in the amygdala (Quirk et al, 2003).…”

Glutamate NMDA Receptors within the Amygdala Participate in the Modulatory Effect of Glucocorticoids on Extinction of Conditioned Fear in Rats

“…Group one to group four animals received vehicle + saline, vehicle + DEX (1.0 mg/kg), AP5 (2.0 ng/side) + DEX (1.0 mg/kg), AP5 (2.0 ng/side) + saline, respectively. The particular doses of AP5 and DEX we used here were followed the studies of Falls et al (1992) and Yang et al (2006). AP5 was given 10 min prior to DEX injection.…”