Um estudo sobre a interação dos sistemas colinérgico nicotínico e dopaminérgico na persistência de memórias aversivas






Long-term memory (LTM) storage requires activation of the ventral tegmental area (VTA)- hippocampus dopaminergic loop and synthesis of brain-derived neurotrophic factor (BDNF) late after learning (Bekinschtein et al., 2007; Rossato et al., 2009). Nicotinic acetylcholine receptors (nAChR) modulate VTA function. Therefore, we analyzed the involvement of these receptors on the lasting storage of fear memory in adult male Wistar rats. Intra-VTA infusion of nicotine 12 h after a weak inhibitory avoidance (IA) training session facilitated LTM retention 14 days but not 2 days later. Conversely, administration of the non-subtype specific nAChR antagonist mecamylamine, or of the α7-nAChR antagonist methyllycaconitine 12 h after a strong IA training session impaired LTM persistence. The α2/β4-nAChR antagonist dihydro-β-erythroidine had no effect on memory. Intra-CA1 infusion of the D1/D5 receptor antagonist SCH38393 blocked the promnesic action of intra-VTA nicotine. On the contrary, intra-CA1 administration of the D1/D5 receptor agonist SKF38393 reversed the amnesia induced by intra-VTA mecamylamine. Modulation of excitatory synaptic transmission requires interaction between the pedunculopontine tegmental nuclei (PPN), the VTA, and the medial pre-frontal cortex (mPFC). Particularly, PPN controls glutamate release from mPFC, sustaining the activity of dopaminergic neurons in the VTA. We found that reversible inactivation of the PPN 12h after strong training impaired IA LTM persistence. Intra-VTA infusion of nicotine and intra-CA1 infusion of SKF38393 reversed the amnesia induced by PPN inactivation. Likewise, temporary inactivation of the mPFC hindered LTM persistence, and this effect was reversed by infusion of nicotine and NMDA in the VTA and also by SKF38393 and BDNF given in dorsal CA1 12 h posttraining. Together with previous results, this set of experiments indicates that PPN/mPFC interactions mediated by α7-nAChR control the activation state of the VTA-hippocampus dopaminergic loop and the expression of hippocampal BDNF to modulate the persistent storage of aversive memories.


medicina gerontologia biomÉdica envelhecimento memÓria persistÊncia medicina

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