Adenosine A2A receptors control generalization of contextual fear in rats.

Fear learning is essential to survival, but traumatic events may lead to abnormal fear consolidation and overgeneralization, triggering fear responses in safe environments, as occurs in post-traumatic stress disorder (PTSD). Adenosine A2A receptors (A2AR) control emotional memory and fear conditioning, but it is not known if they affect the consolidation and generalization of fear, which was now investigated. We now report that A2AR blockade through systemic administration of the A2AR antagonist SCH58261 immediately after contextual fear conditioning (within the consolidation window), accelerated fear generalization. Conversely, A2AR activation with CGS21680 decreased fear generalization. Ex vivo electrophysiological recordings of field excitatory post-synaptic potentials (fEPSPs) in CA3-CA1 synapses and of population spikes in the lateral amygdala (LA), showed that the effect of SCH58261 is associated with a reversion of fear conditioning-induced decrease of long-term potentiation (LTP) in the dorsal hippocampus (DH) and with increased amplitude of LA LTP in conditioned animals. These data suggest that A2AR are engaged during contextual fear consolidation, controlling long-term potentiation mechanisms in both DH and LA during fear consolidation, impacting on fear generalization; this supports targeting A2AR during fear consolidation to control aberrant fear processing in PTSD and other fear-related disorders.

Newly acquired and reactivated contextual fear memories are more intense and prone to generalize after activation of prelimbic cortex NMDA receptors.

Activity in the rodent prelimbic (PL) cortex contributes to consolidation, retrieval and reconsolidation of learned fear. The PL cortex is considered homologous to the primate dorsal anterior cingulate cortex (dACC). In patients with post-traumatic stress disorder (PTSD), the dACC is often reported to be hyperactive after acquisition and/or around the retrieval of the traumatic memory. It is still unknown, however, whether there is a relationship between altered dACC functioning at these time points and PTSD-associated behavioral outcomes, such as fear overgeneralization. The present study sought to investigate this matter by associating contextual fear conditioning with bilateral and selective activation of PL cortex N-methyl-D-aspartate (NMDA) glutamate receptors with NMDA (0.03-0.3nmol) while the learned fear was being consolidated, retrieved or reconsolidated. We report that this pharmacological intervention induced generalized fear expression and/or extinction deficits in animals subjected to a strong contextual fear conditioning protocol when conducted post-acquisition, pre-retrieval or post-retrieval. These results suggest that newly acquired and reactivated fear memories undergo abnormal consolidation or reconsolidation after PL cortex NMDA receptor activation. The consolidation or reconsolidation of a contextual fear memory trace induced by a weak fear training protocol was also potentiated by PL cortex NMDA receptor activation. Altogether, the present findings connect altered PL cortex activity with changes in specificity and/or intensity of a contextual fear memory, which might shed light on the PTSD neurobiology and related behavioral outcomes.