Sequential administration of D-cycloserine and MK801 reduces pERK-expressing neurons in the lateral amygdala and disrupts threat memory reconsolidation.

Post-traumatic stress disorder (PTSD) is characterized by persistent threat-related memories for which there are limited effective treatment options. The N-methyl-D-aspartate (NMDA) receptor-dependent extracellular signal-regulated kinase (ERK) pathway in the lateral amygdala (LA) is necessary for synaptic plasticity, threat memory consolidation and reconsolidation. Disruption of these memories during the reconsolidation window has been proposed as a therapeutic strategy for PTSD, however, no current therapies using this strategy are available. To disrupt reconsolidation, memories must first be brought into a labile state. We investigated the effect of the NMDA receptor partial agonist D-cycloserine (DCS) and the ketamine-like non-competitive antagonist MK801 on threat memory reconsolidation in mice. Using auditory threat conditioning, DCS, or saline vehicle, was administered one hour before memory reactivation to facilitate labilization of a recalled threat memory, followed by MK801 or a saline vehicle after reactivation. Experimental groups included vehicle, DCS 15 mg/kg, MK801 0.06 mg/kg, and MK801 0.12 mg/kg alone and in combination. The effect of behavioural and drug interventions on phospho-ERK-expressing neurons in the LA was analysed using neuron counting and topographical mapping in the LA. MK801 alone and in combination with DCS reduced the number of pERK neurons in the LA across all doses. Freezing behaviour was reduced by high-dose MK801 when combined with DCS. These findings suggest that DCS and MK801 together effectively disrupt threat memory reconsolidation in the LA and offer an NMDA-based combined drug and behavioural treatment strategy for PTSD.