Contextual fear expression engages a complex set of interactions between ventromedial prefrontal cortex cholinergic, glutamatergic, nitrergic and cannabinergic signaling

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Rats re-exposed to an environment previously associated with the onset of shocks evoke a set of conditioned defensive responses in preparation to an eventual flight or fight reaction. Ventromedial prefrontal cortex (vmPFC) is mutually important for controlling the behavioral/physiological consequences of stress exposure and the one's ability to satisfactorily undergo spatial navigation. While cholinergic, cannabinergic and glutamatergic/nitrergic neurotransmissions within the vmPFC are shown as important for modulating both behavioral and autonomic defensive responses, there is a gap on how these systems would interact to ultimately coordinate such conditioned reactions. Then, males Wistar rats had guide cannulas bilaterally implanted to allow drugs to be administered in vmPFC 10 min before their re-exposure to the conditioning chamber where three shocks were delivered at the intensity of 0.85 mA for 2 s two days ago. A femoral catheter was implanted for cardiovascular recordings the day before fear retrieval test. It was found that the increment of freezing behavior and autonomic responses induced by vmPFC infusion of neostigmine (acetylcholinesterase inhibitor) were prevented by prior infusion of a transient receptor potential vanilloid type 1 (TRPV1) antagonist, N-methyl-d-aspartate receptor antagonist, neuronal nitric oxide synthase inhibitor, nitric oxide scavenger and soluble guanylate cyclase inhibitor. A type 3 muscarinic receptor antagonist was unable to prevent the boosting in conditioned responses triggered by a TRPV1 agonist and a cannabinoid receptors type 1 antagonist. Altogether, our results suggest that expression of contextual conditioned responses involves a complex set of signaling steps comprising different but complementary neurotransmitter pathways.