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Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y - Nat. Neurosci. (2013)

Bottom Line: However, the circuit-level adaptations mediating this plasticity remain elusive.We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving.As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

ABSTRACT
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

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Time courses of cocaine incubation, disappearance of silent synapses, and emergence of CP-AMPARs after withdrawal from cocaine self-administration(A) Summary showing cue-induced cocaine seeking increased after 10 withdrawal days. Data were from four independent groups; rats given extinction test on withdrawal day 10 but were not tested on day 1. (B) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after saline self-administration. (C) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after withdrawal from cocaine self-administration. (D) Summary showing that the level of silent synapses within the BLA-to-NAc projection decreased toward the basal (saline control) level after withdrawal from cocaine. (E–F) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 1 day after withdrawal from saline (E) or cocaine (F) self-administration. (G–H) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 10 days after withdrawal from saline (G) or cocaine (H) self-administration. (I) Summary showing that the sensitivity of EPSCs from BLA-to-NAc synapses to Naspm exhibited a small but significant increase after 10 days of withdrawal from cocaine. (J) Time courses of incubation, disappearance of silent synapses, and insertion of CP-AMPARs after cocaine withdrawal. Data are normalized by setting the withdrawal scores to 0% and withdrawal day 45 scores to 100%. Error bar, s.e.m. * p<0.05, *** p<0.001.
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Figure 4: Time courses of cocaine incubation, disappearance of silent synapses, and emergence of CP-AMPARs after withdrawal from cocaine self-administration(A) Summary showing cue-induced cocaine seeking increased after 10 withdrawal days. Data were from four independent groups; rats given extinction test on withdrawal day 10 but were not tested on day 1. (B) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after saline self-administration. (C) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after withdrawal from cocaine self-administration. (D) Summary showing that the level of silent synapses within the BLA-to-NAc projection decreased toward the basal (saline control) level after withdrawal from cocaine. (E–F) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 1 day after withdrawal from saline (E) or cocaine (F) self-administration. (G–H) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 10 days after withdrawal from saline (G) or cocaine (H) self-administration. (I) Summary showing that the sensitivity of EPSCs from BLA-to-NAc synapses to Naspm exhibited a small but significant increase after 10 days of withdrawal from cocaine. (J) Time courses of incubation, disappearance of silent synapses, and insertion of CP-AMPARs after cocaine withdrawal. Data are normalized by setting the withdrawal scores to 0% and withdrawal day 45 scores to 100%. Error bar, s.e.m. * p<0.05, *** p<0.001.

Mentions: The above results support the possibility that disappearance of silent synapses after prolonged withdrawal from cocaine is mediated by “maturation” or unsilencing process that at least partially involves recruitment of CP-AMPARs. We tested this possibility by assessing both silent synapse formation and CP-AMPARs accumulation on withdrawal day 10 using identical cocaine/saline training and extinction test conditions to those described above. At the behavioral level, cue-induced cocaine seeking in the extinction tests was higher after 10 withdrawal days than after 1 day [withdrawal day (1, 10) × nose-poke operandum interaction, F(1,37)=10.9, p<0.0001] (Fig. 4A). At this intermediate withdrawal day, the level of silent synapses was decreased toward basal levels [saline, 3.9±2.9%; cocaine, 10.1±3.3%; t(19)=1.4, p=0.18; Figs. 4B–D]. Additionally, sensitivity to Naspm, indicative of CP-AMPAR accumulation, had begun to emerge at the BLA-NAc projection in cocaine-trained rats on withdrawal day 10. Planned-comparison contrasts demonstrated a significant effect of Naspm in cocaine-trained rats on withdrawal day 10 [F (1, 20)=16.1; p=0.04], but not in saline-trained rats (p>0.99; Fig. 4E–I). This is a more rapid appearance of CP-AMPARs than found previously7, possibly related to our selective assessment of BLA-to-NAc projection or the initial overnight session that is used in our study but not in previous studies (see above).


Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.

Lee BR, Ma YY, Huang YH, Wang X, Otaka M, Ishikawa M, Neumann PA, Graziane NM, Brown TE, Suska A, Guo C, Lobo MK, Sesack SR, Wolf ME, Nestler EJ, Shaham Y, Schlüter OM, Dong Y - Nat. Neurosci. (2013)

Time courses of cocaine incubation, disappearance of silent synapses, and emergence of CP-AMPARs after withdrawal from cocaine self-administration(A) Summary showing cue-induced cocaine seeking increased after 10 withdrawal days. Data were from four independent groups; rats given extinction test on withdrawal day 10 but were not tested on day 1. (B) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after saline self-administration. (C) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after withdrawal from cocaine self-administration. (D) Summary showing that the level of silent synapses within the BLA-to-NAc projection decreased toward the basal (saline control) level after withdrawal from cocaine. (E–F) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 1 day after withdrawal from saline (E) or cocaine (F) self-administration. (G–H) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 10 days after withdrawal from saline (G) or cocaine (H) self-administration. (I) Summary showing that the sensitivity of EPSCs from BLA-to-NAc synapses to Naspm exhibited a small but significant increase after 10 days of withdrawal from cocaine. (J) Time courses of incubation, disappearance of silent synapses, and insertion of CP-AMPARs after cocaine withdrawal. Data are normalized by setting the withdrawal scores to 0% and withdrawal day 45 scores to 100%. Error bar, s.e.m. * p<0.05, *** p<0.001.
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Figure 4: Time courses of cocaine incubation, disappearance of silent synapses, and emergence of CP-AMPARs after withdrawal from cocaine self-administration(A) Summary showing cue-induced cocaine seeking increased after 10 withdrawal days. Data were from four independent groups; rats given extinction test on withdrawal day 10 but were not tested on day 1. (B) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after saline self-administration. (C) Example EPSCs (left) and their trial course (right) from the minimal stimulation assay of BLA-to-NAc synapses from a rat 10 days after withdrawal from cocaine self-administration. (D) Summary showing that the level of silent synapses within the BLA-to-NAc projection decreased toward the basal (saline control) level after withdrawal from cocaine. (E–F) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 1 day after withdrawal from saline (E) or cocaine (F) self-administration. (G–H) Example EPSCs from BLA-to-NAc synapses (left) and their trial course (right) before and during perfusion of Naspm from rats 10 days after withdrawal from saline (G) or cocaine (H) self-administration. (I) Summary showing that the sensitivity of EPSCs from BLA-to-NAc synapses to Naspm exhibited a small but significant increase after 10 days of withdrawal from cocaine. (J) Time courses of incubation, disappearance of silent synapses, and insertion of CP-AMPARs after cocaine withdrawal. Data are normalized by setting the withdrawal scores to 0% and withdrawal day 45 scores to 100%. Error bar, s.e.m. * p<0.05, *** p<0.001.
Mentions: The above results support the possibility that disappearance of silent synapses after prolonged withdrawal from cocaine is mediated by “maturation” or unsilencing process that at least partially involves recruitment of CP-AMPARs. We tested this possibility by assessing both silent synapse formation and CP-AMPARs accumulation on withdrawal day 10 using identical cocaine/saline training and extinction test conditions to those described above. At the behavioral level, cue-induced cocaine seeking in the extinction tests was higher after 10 withdrawal days than after 1 day [withdrawal day (1, 10) × nose-poke operandum interaction, F(1,37)=10.9, p<0.0001] (Fig. 4A). At this intermediate withdrawal day, the level of silent synapses was decreased toward basal levels [saline, 3.9±2.9%; cocaine, 10.1±3.3%; t(19)=1.4, p=0.18; Figs. 4B–D]. Additionally, sensitivity to Naspm, indicative of CP-AMPAR accumulation, had begun to emerge at the BLA-NAc projection in cocaine-trained rats on withdrawal day 10. Planned-comparison contrasts demonstrated a significant effect of Naspm in cocaine-trained rats on withdrawal day 10 [F (1, 20)=16.1; p=0.04], but not in saline-trained rats (p>0.99; Fig. 4E–I). This is a more rapid appearance of CP-AMPARs than found previously7, possibly related to our selective assessment of BLA-to-NAc projection or the initial overnight session that is used in our study but not in previous studies (see above).

Bottom Line: However, the circuit-level adaptations mediating this plasticity remain elusive.We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving.As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs).

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA. [2] Program in Neuroscience, Washington State University, Pullman, Washington, USA. [3].

ABSTRACT
In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

Show MeSH
Related in: MedlinePlus