Disrupting Reconsolidation of Conditioned Withdrawal Memories in the Basolateral Amygdala Reduces Suppression of Heroin Seeking in Rats

Recent data from our laboratory have demonstrated that appetitive drug memories undergo protein synthesis-dependent reconsolidation in the basolateral amygdala (BLA), an area important in the formation of emotional memories. We here investigated the importance of the BLA in the reconsolidation of opiate conditioned withdrawal memories. Rats with bilateral cannulas implanted in the BLA were trained to respond for heroin (0.12 mg/kg, i.v.) under a seeking–taking schedule, which required responding on a seeking lever to gain the opportunity to self-administer heroin by a single response on a taking lever. After induction of opiate dependence with subcutaneously implanted, heroin-filled osmotic minipumps (3 mg · kg−1 · d−1 heroin), rats received five consecutive pairings of a conditioned stimulus (CS) (tone, light, and odor compound) paired with naloxone (0.10 mg/kg, s.c.)-precipitated withdrawal. We replicated our previous findings that heroin seeking is suppressed in the presence of the withdrawal-associated CS. However, infusion of Zif268 antisense oligodeoxynucleotide into the BLA before reactivation of the CS–withdrawal association abolished this conditioned suppression in a reactivation-dependent manner. We also report that reconsolidation of CS–withdrawal memories upregulates Zif268 protein in the basolateral but not central nucleus of the amygdala and that Zif268 knockdown occurs selectively in the BLA. These results demonstrate that drug withdrawal memories undergo protein synthesis-dependent reconsolidation in the BLA and suggest a common mechanism for the reconsolidation of both appetitive and aversive drug memories.

[1]  S. Tenen,et al.  Retrograde amnesia. , 2020, Science.

[2]  C. Le Moine,et al.  A Specific Limbic Circuit Underlies Opiate Withdrawal Memories , 2005, The Journal of Neuroscience.

[3]  A. Wikler,et al.  Interoceptive conditioning through repeated suppression of morphine-abstinence , 1979, The Pavlovian journal of biological science.

[4]  K. Nader,et al.  Characterization of Fear Memory Reconsolidation , 2004, The Journal of Neuroscience.

[5]  A. Wikler Recent progress in research on the neurophysiologic basis of morphine addiction. , 1948, The American journal of psychiatry.

[6]  B. Everitt,et al.  Independent Cellular Processes for Hippocampal Memory Consolidation and Reconsolidation , 2004, Science.

[7]  A. Dickinson,et al.  Cocaine-seeking by rats: regulation, reinforcement and activation , 2000, Psychopharmacology.

[8]  A. Wikler,et al.  Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats , 2004, Psychopharmacologia.

[9]  B. Balleine,et al.  Consolidation and Reconsolidation of Incentive Learning in the Amygdala , 2005, The Journal of Neuroscience.

[10]  T. Robbins,et al.  Associative Processes in Addiction and Reward The Role of Amygdala‐Ventral Striatal Subsystems , 1999, Annals of the New York Academy of Sciences.

[11]  B. Balleine,et al.  The Role of Learning in the Operation of Motivational Systems , 2002 .

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

[13]  B. Everitt,et al.  Induction of the learning and plasticity‐associated gene Zif268 following exposure to a discrete cocaine‐associated stimulus , 2003, The European journal of neuroscience.

[14]  J. D. McGaugh,et al.  Anisomycin infused into the hippocampus fails to block "reconsolidation" but impairs extinction: the role of re-exposure duration. , 2006, Learning & memory.

[15]  F. E. Bloom,et al.  Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal , 2004, Psychopharmacology.

[16]  B. Balleine,et al.  Motivational control of goal-directed action , 1994 .

[17]  B. Everitt,et al.  Cellular Imaging of zif268 Expression in the Hippocampus and Amygdala during Contextual and Cued Fear Memory Retrieval: Selective Activation of Hippocampal CA1 Neurons during the Recall of Contextual Memories , 2001, The Journal of Neuroscience.

[18]  Karim Nader,et al.  Directly reactivated, but not indirectly reactivated, memories undergo reconsolidation in the amygdala. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Rosen,et al.  An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning. , 2004, Learning & memory.

[20]  S. Goldberg,et al.  Conditioned suppression by a stimulus associated with nalorphine in morphine-dependent monkeys. , 1967, Journal of the experimental analysis of behavior.

[21]  A. Childress,et al.  Abstinent opiate abusers exhibit conditioned craving, conditioned withdrawal and reductions in both through extinction. , 1986, British journal of addiction.

[22]  C. Le Moine,et al.  Neural correlates of the motivational and somatic components of naloxone‐precipitated morphine withdrawal , 2002, The European journal of neuroscience.

[23]  D. J. Lewis,et al.  Psychobiology of active and inactive memory. , 1979, Psychological bulletin.

[24]  Osamu Kitamura,et al.  Conditioned Withdrawal Drives Heroin Consumption and Decreases Reward Sensitivity , 2006, The Journal of Neuroscience.

[25]  Karim Nader,et al.  Memory traces unbound , 2003, Trends in Neurosciences.

[26]  D. J. Lewis,et al.  Retrograde Amnesia Produced by Electroconvulsive Shock after Reactivation of a Consolidated Memory Trace , 1968, Science.

[27]  R. Dai,et al.  IL‐6 Modulates Hyperglycemia‐Induced Changes of Na+ Channel Beta‐3 Subunit Expression by Schwann Cells , 2003, Annals of the New York Academy of Sciences.

[28]  R. Yuste,et al.  The role of withdrawal in heroin addiction : enhances reward or promotes avoidance ? , 2001 .

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

[30]  V. F. Gellert,et al.  A comparison of the effects of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine-dependent rats. , 1977, The Journal of pharmacology and experimental therapeutics.

[31]  B. Everitt,et al.  Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex , 2002, Neuroscience & Biobehavioral Reviews.

[32]  A. Wikler,et al.  Dynamics of drug dependence. Implications of a conditioning theory for research and treatment. , 1973, Archives of general psychiatry.

[33]  Trevor W Robbins,et al.  Appetitive Behavior , 2003, Annals of the New York Academy of Sciences.

[34]  B. Balleine,et al.  The Effect of Lesions of the Basolateral Amygdala on Instrumental Conditioning , 2003, The Journal of Neuroscience.

[35]  A. Wikler,et al.  Interoceptive conditioning through repeated suppression of morphine-abstinence , 1979, The Pavlovian journal of biological science.

[36]  Bruno Bozon,et al.  How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning? , 2003, Behavioural Brain Research.

[37]  T. Abel,et al.  Behavioral impairments caused by injections of the protein synthesis inhibitor anisomycin after contextual retrieval reverse with time. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. H. Ahmed,et al.  Conditioning and opiate withdrawal , 2000, Nature.

[39]  B. Everitt,et al.  Disrupting Reconsolidation of Drug Memories Reduces Cocaine-Seeking Behavior , 2005, Neuron.

[40]  J. Woods,et al.  Morphine: Conditioned Increases in Self-Administration in Rhesus Monkeys , 1969, Science.

[41]  M. Fendt,et al.  Injections of the NMDA Receptor Antagonist Aminophosphonopentanoic Acid into the Lateral Nucleus of the Amygdala Block the Expression of Fear-Potentiated Startle and Freezing , 2001, The Journal of Neuroscience.

[42]  James L. McGaugh,et al.  Amygdala modulates memory for changes in reward magnitude: Reversible post-training inactivation with lidocaine attenuates the response to a reduction in reward , 1993, Behavioural Brain Research.

[43]  A. Dickinson,et al.  Motivational control of heroin seeking by conditioned stimuli associated with withdrawal and heroin taking by rats. , 2006, Behavioral neuroscience.

[44]  S. Goldberg,et al.  Conditioned nalorphine-induced abstinence changes: persistence in post morphine-dependent monkeys. , 1970, Journal of the experimental analysis of behavior.

[45]  B. Everitt,et al.  Cue-Induced Cocaine Seeking and Relapse Are Reduced by Disruption of Drug Memory Reconsolidation , 2006, The Journal of Neuroscience.