Hippocampus muscarinic M4 receptor mRNA expression may influence central cholinergic activity, causing fear memory strengthening by peripheral adrenaline

Adrenaline (Ad) strengthens contextual fear memory by increasing blood glucose, possibly enhancing hippocampus acetylcholine synthesis. Nevertheless, it is unclear if peripheral Ad influences the cholinergic system, contributing to contextual fear memory strengthening. We aimed to evaluate whether peripheral Ad alters muscarinic receptor expression and if the cholinergic system is involved in peripheral Ad contextual fear memory strengthening effect. Wild-type (WT) and Ad-deficient male mice (129 × 1/SvJ) underwent a fear conditioning procedure followed by intraperitoneal pre-training and pre-context administration of Ad (0.1 mg/kg), atropine (10 mg/kg), methylatropine (0.5 mg/kg), Ad (0.1 mg/kg) plus atropine (10 mg/kg) or vehicle (NaCl, 0.9%). Shock responsiveness and freezing behaviour were accessed. Hippocampal M₁, M₂, and M₄ mRNA expression were evaluated. Ad-deficient mice presented decreased hippocampal muscarinic M₄ subtype receptor mRNA expression compared to WT mice. In Ad-administered Ad-deficient mice, hippocampal muscarinic M₄ subtype receptor mRNA expression increased compared with vehicle-administered Ad-deficient mice. On the context day, atropine-administered WT mice presented decreased freezing behaviour compared to vehicle or methylatropine-administered WT mice. Moreover, Ad plus atropine-administered Ad-deficient mice led to decreased freezing behaviour compared to Ad-administered Ad-deficient mice. In conclusion, Ad-deficient mice's contextual fear memory impairment was associated with hippocampal muscarinic M₄ subtype receptor down expression, which was reversed by Ad. This may be related to contextual fear memory consolidation or retrieval induced by peripheral Ad. Furthermore, the effect of Ad contextual fear memory might be due to increased hippocampus muscarinic subtype M₄ expression, which may contribute to increased cholinergic activity in the central nervous system.