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Nociceptin, or orphanin FQ (N/OFQ), the endogenous ligand of NOP receptors, is known to regulate learning and memory processes. To verify the role of N/OFQ in the acquisition of contextual (CFC) and tone fear conditioning (TFC), Wistar male rats received intracerebroventricular injections of N/OFQ (0.1-5.0 nmol) before training, and were tested 24 and 48 hr later to access the freezing response to context and tone, respectively. The intermediate doses (1.0 and 2.5 nmol) impaired the CFC test, sparing TFC. The highest dose (5.0 nmol) reduced freezing during both tests, a result that may be due to nonspecific effects. The posttraining injection of N/OFQ (1 or 5 nmol) did not interfere with CFC and TFC, suggesting a specific effect of the peptide in acquisition processes. Moreover, the impairment observed with N/OFQ (1 nmol) in CFC cannot be attributed to a state-dependent learning because it was not reversed by its pretest administration. The data support the negative role of N/OFQ in the acquisition of aversively motivated tasks, which encompass a spatial component and depend on the hippocampus.

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

In contextual fear conditioning (CFC), hippocampus is thought to process environmental stimuli into a configural representation of the context and send it to amygdala nuclei, which current evidences point to be the site of CS-US association and fear memory storage. If it is true, hippocampus should influence learning-induced plasticity in the amygdala nuclei after CFC acquisition. To test this, we infused wistar rats with saline or AP5, a NMDA receptor antagonist, in the dorsal hippocampus just before a CFC session, in which they were conditioned to a single shock, exposed to the context with no shocks or received an immediate shock. The rats were perfused, their brains harvested and immunohistochemically stained for cAMP element binding protein (CREB) phosphorylation ratio (pCREB/CREB) in lateral (LA), basal (B) and central (CeA) amygdala nuclei. CFC showed a learning-specific increase in pCREB ratio in B and CeA, in conditioned-saline rats compared to context and immediate shocked ones. Further, conditioned rats that received AP5 showed a decrease in pCREB ratio in LA, B and CeA. Our results support the current ideas that the role of hippocampus in contextual fear conditioning occurs by sending contextual information to amygdala to serve as conditioned stimulus.