D1/5 dopamine receptors are necessary for learning a novel context.

Dopamine participates in encoding memories and could either encode rewarding/aversive value of unconditioned stimuli or act as a novelty signal triggering contextual learning. Here we show that intraperitoneal injection of the dopamine D1/5R antagonist SCH23390 impairs contextual fear conditioning and tone-shock association, while intrahippocampal injection only impairs contextual fear conditioning. By using the context pre-exposure facilitation effect test, we show that SCH23390 is able to block the encoding of the context during the pre-exposure phase. Thus, we provide additional evidence that dopamine is involved in encoding conjunctive representations of new contexts.

Activation of nociceptin/orphanin FQ receptors inhibits contextual fear memory reconsolidation.

Several neuropeptidergic systems act as modulators of cognitive performances. Among them, nociceptin, an opioid-like peptide also known as orphanin FQ (N/OFQ), has recently gained attention. Stimulation of its receptor, the N/OFQ opioid receptor (NOP), which is expressed in brain regions involved in emotion, memory and stress response, has inhibitory effects on the acquisition and/or consolidation of spatial and emotional memory in rodents. Recently, N/OFQ was also proposed to be linked to the pathogenesis of Post-Traumatic Stress Disorder in humans. However, until now the effect of the activation of the N/OFQ-NOP system on already consolidated memory, such as during retrieval and reconsolidation phases, has never been explored. In the present study, we investigated the consequences of systemic injection of NOP agonists or i.c.v. injection of the N/OFQ peptide on the retrieval and the reconsolidation of contextual fear memory in mice. We demonstrate that the activation of the N/OFQ system impairs the reconsolidation of context-dependent but not cue-dependent aversive memories. We also show that this amnestic effect is associated with decreased c-Fos expression in the hippocampus and amygdala. Our data thus provide the first evidence that the NOP receptor could be targeted during the reconsolidation process to weaken maladaptive memories. The N/OFQ-NOP system might constitute in the future an interesting pharmacological target for interfering with so-called "pathological memories", in particular those involving maladaptive contextual memories.