Dopaminergic signalling is necessary,

Pharmacological targeting of memory reconsolidation is a promising therapeutic strategy for the treatment of fear memory-related disorders. However, the success of reconsolidation-based approaches depends upon the effective destabilisation of the fear memory by memory reactivation. Here, we show that the nootropic nefiracetam stimulates tone fear memory destabilisation to facilitate reconsolidation disruption by the glucocorticoid receptor antagonist mifepristone. Moreover, the enhancing effect of nefiracetam was dependent upon dopamine D1 receptor activation, although direct D1 receptor agonism was not sufficient to facilitate destabilisation. Finally, while the combined treatment with nefiracetam and mifepristone did not confer fear-reducing effects under conditions of extinction learning, there was some evidence that mifepristone reduces fear expression irrespective of memory reactivation parameters. Therefore, the use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear.

[1]  Jonathan L. C. Lee,et al.  Different temporal windows for CB1 receptor involvement in contextual fear memory destabilisation in the amygdala and hippocampus , 2019, PloS one.

[2]  Kristen H. Jardine,et al.  Involvement of classical neurotransmitter systems in memory reconsolidation: Focus on destabilization , 2018, Neurobiology of Learning and Memory.

[3]  Jae-Ick Kim,et al.  β-Adrenergic signaling is required for the induction of a labile state during memory reconsolidation , 2018, Brain Research Bulletin.

[4]  B. Everitt,et al.  A Novel Retrieval-Dependent Memory Process Revealed by the Arrest of ERK1/2 Activation in the Basolateral Amygdala , 2018, The Journal of Neuroscience.

[5]  Abbas Ali Vafaei,et al.  Infralimbic dopamine D2 receptors mediate glucocorticoid-induced facilitation of auditory fear memory extinction in rats , 2018, Brain Research.

[6]  C. Chiamulera,et al.  Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine , 2018, Psychopharmacology.

[7]  Jonathan L. C. Lee,et al.  On the transition from reconsolidation to extinction of contextual fear memories , 2017, Learning & memory.

[8]  R. Pitman,et al.  Consolidation and reconsolidation are impaired by oral propranolol administered before but not after memory (re)activation in humans , 2017, Neurobiology of Learning and Memory.

[9]  M. Kindt,et al.  In Search for Boundary Conditions of Reconsolidation: A Failure of Fear Memory Interference , 2017, Front. Behav. Neurosci..

[10]  M. E. Pedreira,et al.  The fate of memory: Reconsolidation and the case of Prediction Error , 2016, Neuroscience & Biobehavioral Reviews.

[11]  C. Schmahl,et al.  Modification of Fear Memory by Pharmacological and Behavioural Interventions during Reconsolidation , 2016, PloS one.

[12]  M. Kindt,et al.  New avenues for treating emotional memory disorders: towards a reconsolidation intervention for posttraumatic stress disorder , 2016, Therapeutic advances in psychopharmacology.

[13]  P. Roullet,et al.  Effects of Propranolol, a β-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation in Mice , 2016, Front. Behav. Neurosci..

[14]  M. Kindt,et al.  An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent , 2015, Biological Psychiatry.

[15]  M. Fendt,et al.  Differential effects of wake promoting drug modafinil in aversive learning paradigms , 2015, Front. Behav. Neurosci..

[16]  B. Winters,et al.  Cholinergic manipulations bidirectionally regulate object memory destabilization , 2015, Learning & memory.

[17]  B. Everitt,et al.  Amygdala Dopamine Receptors Are Required for the Destabilization of a Reconsolidating Appetitive Memory, , 2015, eNeuro.

[18]  Jonathan L. C. Lee,et al.  Updating memories—The role of prediction errors in memory reconsolidation , 2015, Behavioural Brain Research.

[19]  Marie-France Marin,et al.  Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: Three negative psychophysiological studies , 2015, Psychiatry Research.

[20]  V. Molina,et al.  The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine , 2015, The international journal of neuropsychopharmacology.

[21]  C. Stern,et al.  PTSD-Like Memory Generated Through Enhanced Noradrenergic Activity is Mitigated by a Dual Step Pharmacological Intervention Targeting its Reconsolidation , 2014, The international journal of neuropsychopharmacology.

[22]  M. Kindt,et al.  Noradrenergic Blockade of Memory Reconsolidation: A Failure to Reduce Conditioned Fear Responding , 2014, Front. Behav. Neurosci..

[23]  Abbas Ali Vafaei,et al.  Propranolol–induced Impairment of Contextual Fear Memory Reconsolidation in Rats: A similar Effect on Weak and Strong Recent and Remote Memories , 2014, Basic and clinical neuroscience.

[24]  B. Everitt,et al.  The CB1 Receptor Antagonist AM251 Impairs Reconsolidation of Pavlovian Fear Memory in the Rat Basolateral Amygdala , 2014, Neuropsychopharmacology.

[25]  Jonathan L. C. Lee,et al.  Inhibition and enhancement of contextual fear memory destabilization , 2014, Front. Behav. Neurosci..

[26]  B. Everitt,et al.  Reconsolidation and Extinction Are Dissociable and Mutually Exclusive Processes: Behavioral and Molecular Evidence , 2014, The Journal of Neuroscience.

[27]  Gonzalo P Urcelay,et al.  Memory destabilization is critical for the success of the reactivation–extinction procedure , 2013, Learning & memory.

[28]  L. Alvares,et al.  Reactivation enables memory updating, precision-keeping and strengthening: Exploring the possible biological roles of reconsolidation , 2013, Neuroscience.

[29]  B. Everitt,et al.  Double Dissociation of the Requirement for GluN2B- and GluN2A-Containing NMDA Receptors in the Destabilization and Restabilization of a Reconsolidating Memory , 2013, The Journal of Neuroscience.

[30]  Jonathan L. C. Lee,et al.  Appetitive Pavlovian goal-tracking memories reconsolidate only under specific conditions. , 2012, Learning & memory.

[31]  F. Guimarães,et al.  On Disruption of Fear Memory by Reconsolidation Blockade: Evidence from Cannabidiol Treatment , 2012, Neuropsychopharmacology.

[32]  Jonathan L. C. Lee,et al.  Behavioural memory reconsolidation of food and fear memories , 2011, Nature communications.

[33]  K. Nader,et al.  Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect. , 2011, Behavioral neuroscience.

[34]  Alain Brunet,et al.  Trauma Reactivation Under the Influence of Propranolol Decreases Posttraumatic Stress Symptoms and Disorder: 3 Open-Label Trials , 2011, Journal of clinical psychopharmacology.

[35]  Abbas Ali Vafaei,et al.  Systemic and intrahippocampal administrations of the glucocorticoid receptor antagonist RU38486 impairs fear memory reconsolidation in rats , 2011, Stress.

[36]  R. Roesler,et al.  Modulatory influence of dopamine receptors on consolidation of object recognition memory , 2011, Neurobiology of Learning and Memory.

[37]  C. Cunha,et al.  Spironolactone and low-dose dexamethasone enhance extinction of contextual fear conditioning , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[38]  C. Alberini,et al.  Limited efficacy of propranolol on the reconsolidation of fear memories. , 2010, Learning & memory.

[39]  H. Maldonado,et al.  Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration , 2010, Neuropsychopharmacology.

[40]  M. Kindt,et al.  Beyond extinction: erasing human fear responses and preventing the return of fear , 2009, Nature Neuroscience.

[41]  C. Alberini,et al.  Preclinical Assessment for Selectively Disrupting a Traumatic Memory via Postretrieval Inhibition of Glucocorticoid Receptors , 2009, Biological Psychiatry.

[42]  P. Frankland,et al.  Activation of LVGCCs and CB1 receptors required for destabilization of reactivated contextual fear memories. , 2008, Learning & memory.

[43]  Lan Ma,et al.  Glucocorticoid receptors in the basolateral nucleus of amygdala are required for postreactivation reconsolidation of auditory fear memory , 2007, The European journal of neuroscience.

[44]  B. Everitt,et al.  Reconsolidation and Extinction of Conditioned Fear: Inhibition and Potentiation , 2006, The Journal of Neuroscience.

[45]  Karim Nader,et al.  NMDA receptors are critical for unleashing consolidated auditory fear memories , 2006, Nature Neuroscience.

[46]  R. Morris,et al.  Memory Reconsolidation: Sensitivity of Spatial Memory to Inhibition of Protein Synthesis in Dorsal Hippocampus during Encoding and Retrieval , 2006, Neuron.

[47]  K. Lu,et al.  Systemic and Intra-Amygdala Administration of Glucocorticoid Agonist and Antagonist Modulate Extinction of Conditioned Fear , 2006, Neuropsychopharmacology.

[48]  P. Gean,et al.  Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle. , 2006, Learning & memory.

[49]  JaneR . Taylor,et al.  Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A , 2006, Nature Neuroscience.

[50]  F. Bermúdez-Rattoni,et al.  Protein synthesis underlies post-retrieval memory consolidation to a restricted degree only when updated information is obtained. , 2005, Learning & memory.

[51]  Joseph E LeDoux,et al.  Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala , 2004, Neuroscience.

[52]  Alcino J. Silva,et al.  Memory Reconsolidation and Extinction Have Distinct Temporal and Biochemical Signatures , 2004, The Journal of Neuroscience.

[53]  Y. Dudai.  The neurobiology of consolidations, or, how stable is the engram? , 2004, Annual review of psychology.

[54]  S. Moriguchi,et al.  Potentiation of N-Methyl-d-aspartate-Induced Currents by the Nootropic Drug Nefiracetam in Rat Cortical Neurons , 2003, Journal of Pharmacology and Experimental Therapeutics.

[55]  Joseph E LeDoux,et al.  Cellular and Systems Reconsolidation in the Hippocampus , 2002, Neuron.

[56]  K. Nader,et al.  Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval , 2000, Nature.

[57]  I. Izquierdo,et al.  Participation of hippocampal metabotropic glutamate receptors, protein kinase A and mitogen-activated protein kinases in memory retrieval , 2000, Neuroscience.

[58]  T. Narahashi,et al.  Modulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetam , 1999, Brain Research.

[59]  T. Nabeshima,et al.  Nefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis study , 1998, Neuroscience Letters.

[60]  M. Yoshii,et al.  Cellular mechanisms underlying cognition-enhancing actions of nefiracetam (DM-9384) , 1997, Behavioural Brain Research.

[61]  C. Regan,et al.  Nefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: Delayed emergence of the memory retention effects , 1996, Neurochemical Research.

[62]  L. Olson,et al.  Effects of nefiracetam (DM-9384), a pyrrolidone derivative, on brain monoamine systems. , 1994, Archives internationales de pharmacodynamie et de therapie.

[63]  M. Yoshii,et al.  Enhancement of neuronal calcium channel currents by the nootropic agent, nefiracetam (DM-9384), in NG108-15 cells , 1994, Brain Research.

[64]  T. Robinson,et al.  Disrupting reconsolidation: memory erasure or blunting of emotional/motivational value? , 2018, Neuropsychopharmacology.

[65]  T. Nishizaki,et al.  Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways. , 1998, Molecular pharmacology.