Long-lasting enhancement of aversive memory by acute high-dose ethanol: involvement of VTA α7nAChRs and mPFC D1R signaling

Acute ethanol intoxication is mainly associated with memory impairments, yet the circuit and receptor mechanisms through which it modulates aversive memory formation remain poorly understood. Here we report that a single high dose ethanol exposure (2.5 g/kg) produces a robust, long-lasting enhancement of aversive memory formation in rats, persisting for at least 21 days in an inhibitory avoidance task. We found that this enhancement depends on α7 nicotinic acetylcholine receptors (α7nAChRs) in the ventral tegmental area (VTA), as local blockade with methyllycaconitine (MLA, 5 ug/ul) abolished the effect. We further show that pharmacological activation of dopamine D1 receptors (D1R) in the medial prefrontal cortex (mPFC) with SKF-38393 (6.25 ug/ul) restored ethanol-induced memory enhancement following intra-VTA α7nAChR antagonism, suggesting the involvement of mPFC D1R signaling in this pathway. Together, these results provide a mechanistic framework for understanding how acute intoxicating ethanol exposure can produce aversive memory enhancement. Acknowledgements: University of Buenos Aires (UBACyT grant to VP), International Society for Neurochemistry (CDG grant to VP).