Centrally formed acetaldehyde mediates ethanol-induced brain PKA activation

•EtOH administration in vivo enhances PKA activity in the brain.•cAMP-PKA pathway is involved in the behavioral response to EtOH.•Centrally formed acetaldehyde is responsible for several effects induced by EtOH.•EtOH-induced PKA activation is reduced when central acetaldehyde activity decreases.•cAMP-PKA signaling cascade promoted by EtOH in vivo is dependent on acetaldehyde. Centrally formed acetaldehyde has proven to be responsible for several psychopharmacological effects induced by ethanol. In addition, it has been suggested that the cAMP-PKA signaling transduction pathway plays an important role in the modulation of several ethanol-induced behaviors. Therefore, we hypothesized that acetaldehyde might be ultimately responsible for the activation of this intracellular pathway. We used three pharmacological agents that modify acetaldehyde activity (α-lipoic acid, aminotriazole, and d-penicillamine) to study the role of this metabolite on EtOH-induced PKA activation in mice. Our results show that the injection of α-lipoic acid, aminotriazole and d-penicillamine prior to acute EtOH administration effectively blocks the PKA-enhanced response to EtOH in the brain. These results strongly support the hypothesis of a selective release of acetaldehyde-dependent Ca2+ as the mechanism involved in the neurobehavioral effects elicited by EtOH.