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Front Behav Neurosci ; 13: 242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680897


Reconsolidation normally functions to update and maintain memories in the long-term. However, this process can be disrupted pharmacologically to weaken memories. Exploiting such experimental amnesia to disrupt the maladaptive reward memories underpinning addiction may provide a novel therapeutic avenue to prevent relapse. Here, we tested whether targeted disruption of the reconsolidation of instrumental (operant) lever pressing for cocaine resulted in protection against different forms of relapse in a rat self-administration model. We first confirmed that systemic injection of the non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 did impair reconsolidation to reduce spontaneous instrumental drug-seeking memory at test. This deficit was not rescued by pharmacological induction of stress with the anxiogenic α2-noradrenergic receptor antagonist yohimbine. In contrast, cocaine-seeking was restored to control levels following priming with cocaine itself, or presentation of a cocaine-associated cue. These results suggest that while stress-induced relapse can be reduced by disruption of instrumental memory reconsolidation, the apparent sparing of the pavlovian cue-drug memory permitted other routes to relapse. Therefore, future reconsolidation-based therapeutic strategies for addictive drug-seeking may need to target both instrumental and pavlovian memories.

Learn Mem ; 25(9): 492-500, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30115771


Addiction is a chronic, relapsing disorder. The progression to pathological drug-seeking is thought to be driven by maladaptive learning processes which store and maintain associative memory, linking drug highs with cues and actions in the environment. These memories can encode Pavlovian associations which link predictive stimuli (e.g., people, places, and paraphernalia) with a hedonic drug high, as well as instrumental learning about the actions required to obtain drug-associated incentives. Learned memories are not permanent however, and much recent interest has been generated in exploiting the process of reconsolidation to erase or significantly weaken maladaptive memories to treat several mental health disorders, including addictions. Normally reconsolidation serves to update and maintain the adaptive relevance of memories, however administration of amnestic agents within the critical "reconsolidation window" can weaken or even erase maladaptive memories. Here we discuss recent advances in the field, including ongoing efforts to translate preclinical reconsolidation research in animal models into clinical practice.

Condicionamento Clássico , Condicionamento Operante , Consolidação da Memória , Prevenção Secundária , Transtornos Relacionados ao Uso de Substâncias/terapia , Animais , Humanos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
Neuroscience ; 370: 112-120, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28736133


Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like 'response' memory, but not an instrumental goal-directed 'place' memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories.

Corpo Estriado/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Recompensa , Animais , Condicionamento Clássico/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Técnicas de Silenciamento de Genes , Hábitos , Masculino , Distribuição Aleatória , Ratos
eNeuro ; 2(2)2015.
Artigo em Inglês | MEDLINE | ID: mdl-26464973


Stored memories are dynamic and, when reactivated, can undergo a process of destabilization and reconsolidation to update them with new information. Reconsolidation has been shown for a variety of experimental settings; most recently for well-learned instrumental memories, a class of memory previously thought not to undergo reconsolidation. Here we tested, in rats, whether a weakly-trained lever-pressing memory destabilized following a shift in reinforcement contingency. We show that lever-pressing memory for both sucrose and cocaine reinforcement destabilized under appropriate conditions, and that the reconsolidation of this memory was impaired by systemic administration of the NMDA receptor (NMDAR) antagonist [5R,10S]-[+]-5-methyl-10,1-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801). We went on to investigate the potential role of the nucleus accumbens (NAc) in the reconsolidation of sucrose-reinforced instrumental memories, showing that co-infusion of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP-5) and the dopamine-1 receptor (D1R) antagonist 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol (SCH23390) into the NAc prior to memory reactivation impaired reconsolidation; however, there was no effect when these drugs were infused alone. Further investigation of this effect suggests the combined infusion disrupted the reconsolidation of pavlovian components of memory, and we hypothesize that coactivation of accumbal D1Rs and NMDARs may contribute to both the destabilization and reconsolidation of appetitive memory. Our work demonstrates that weakly-trained instrumental memories undergo reconsolidation under similar parameters to well-trained ones, and also suggests that receptor coactivation in the NAc may contribute to memory destabilization. Furthermore, it provides an important demonstration of the therapeutic potential of reconsolidation-based treatments that target the instrumental components of memory in maladaptive drug seeking.

Behav Brain Res ; 278: 375-84, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25453746


Memories are not static imprints of past experience, but rather are dynamic entities which enable us to predict outcomes of future situations and inform appropriate behaviours. In order to maintain the relevance of existing memories to our daily lives, memories can be updated with new information via a process of reconsolidation. In this review we describe recent experimental advances in the reconsolidation of both appetitive and aversive memory, and explore the neuronal mechanisms that underpin the conditions under which reconsolidation will occur. We propose that a prediction error signal, originating from dopaminergic midbrain neurons, is necessary for destabilisation and subsequent reconsolidation of a memory.

Condicionamento Clássico/fisiologia , Memória/fisiologia , Animais , Dopamina/metabolismo , Objetivos , Humanos , Mesencéfalo/citologia , Neurônios Motores/fisiologia , Optogenética , Valor Preditivo dos Testes , Recompensa
Learn Mem ; 21(9): 468-77, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25135195


Once consolidated, memories are dynamic entities that go through phases of instability in order to be updated with new information, via a process of reconsolidation. The phenomenon of reconsolidation has been demonstrated in a wide variety of experimental paradigms. However, the memories underpinning instrumental behaviors are currently not believed to reconsolidate. We show that well-learned lever pressing in rats does undergo reconsolidation, which can be disrupted by systemic administration of the noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) when administered prior to a switch to a variable, but not fixed, ratio schedule. Disruption of reconsolidation resulted in a reduction in long-term lever pressing performance and diminished the sensitivity of behavior to contingency change. Further investigation demonstrated that expression of the reconsolidation impairment was not affected by outcome value, implying a deficit in a stimulus-response (S-R) process. The ability to disrupt the performance of well-learned instrumental behaviors is potentially of great importance in the development of reconsolidation-based clinical treatments for conditions that involve compulsive seeking behaviors.

Memória/efeitos dos fármacos , Animais , Condicionamento Operante/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Rememoração Mental/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Recompensa