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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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Cocaine self-administration generates silent synapses in the BLA-to-NAc shell projection(A) Cocaine self-administration training. (B) Incubation of cue-induced cocaine craving: Data are numbers of active and inactive nose-pokes from the same groups of rats in extinction tests performed on withdrawal days 1 and 45 after self-administration training. (C) Saline self-administration training. (D) Extinction tests on withdrawal days 1 and 45 after saline self-administration. (E–H) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after cocaine self-administration: (E, G) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal (failures and successes are shown in gray and black traces, respectively). (F, H) Trials of EPSCs from the example neurons in E and G showing a higher failure rate at −70 mV (gray dots represent failures and black dots show successes) on withdrawal day 1 and a reduced failure rate on withdrawal day 45. (I–L) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after saline self-administration: (I, K) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal. (J, L) Trials of EPSCs from the example neurons in I and K. (M) Summarized results showing that silent synapses were increased on withdrawal day 1 and returned to the basal level on day 45. Error bar, s.e.m. ** p<0.01, *** p<0.001.
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Figure 2: Cocaine self-administration generates silent synapses in the BLA-to-NAc shell projection(A) Cocaine self-administration training. (B) Incubation of cue-induced cocaine craving: Data are numbers of active and inactive nose-pokes from the same groups of rats in extinction tests performed on withdrawal days 1 and 45 after self-administration training. (C) Saline self-administration training. (D) Extinction tests on withdrawal days 1 and 45 after saline self-administration. (E–H) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after cocaine self-administration: (E, G) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal (failures and successes are shown in gray and black traces, respectively). (F, H) Trials of EPSCs from the example neurons in E and G showing a higher failure rate at −70 mV (gray dots represent failures and black dots show successes) on withdrawal day 1 and a reduced failure rate on withdrawal day 45. (I–L) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after saline self-administration: (I, K) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal. (J, L) Trials of EPSCs from the example neurons in I and K. (M) Summarized results showing that silent synapses were increased on withdrawal day 1 and returned to the basal level on day 45. Error bar, s.e.m. ** p<0.01, *** p<0.001.

Mentions: To examine incubation of cue-induced cocaine craving, we trained rats to nose-poke for intravenous infusions of cocaine for 6 days (one overnight session followed by 2 h/d for 5 days); each infusion was paired with a light cue. As previously demonstrated21–23, this training procedure led to reliable cocaine self-administration over the 5-day training period (Fig. 2A). We then used a within-subjects repeated-measure procedure, previously used in studies on incubation of craving for cocaine and other drugs24,25, to test rats for cue-induced cocaine seeking in extinction sessions performed after 1 withdrawal day or 42–47 days (referred to herein as day 45). During testing, rats were re-exposed to the drug self-administration chambers (the drug environment), and nosepokes (the operational measure of drug seeking and craving) led to contingent presentations of the light cue but not cocaine26. We found that cue-induced cocaine seeking after 45 withdrawal days was higher than after 1 day (incubation of cocaine craving) [Withdrawal day (1, 45) × Nose-poke operandum (active, inactive) interaction, F(1,24)=25.3, p<0.0001, Fig. 2B]. In contrast, no significant time-dependent changes in responding to the light cue during testing were observed in drug-naïve rats that previously nose-poked for saline injections during the training phase (Fig. 2C,D). These dare are in agreement with several reports on incubation of cocaine craving in which a limited access (2-h daily sessions) cocaine self-administration training procedure was used26–28. [Note: in most studies on mechanisms of incubation of cocaine craving3,7,29, investigators have used an extended access (6-h daily sessions) training procedure, which leads to “stronger” incubation after withdrawal than the limited access training procedure26.]


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)

Cocaine self-administration generates silent synapses in the BLA-to-NAc shell projection(A) Cocaine self-administration training. (B) Incubation of cue-induced cocaine craving: Data are numbers of active and inactive nose-pokes from the same groups of rats in extinction tests performed on withdrawal days 1 and 45 after self-administration training. (C) Saline self-administration training. (D) Extinction tests on withdrawal days 1 and 45 after saline self-administration. (E–H) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after cocaine self-administration: (E, G) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal (failures and successes are shown in gray and black traces, respectively). (F, H) Trials of EPSCs from the example neurons in E and G showing a higher failure rate at −70 mV (gray dots represent failures and black dots show successes) on withdrawal day 1 and a reduced failure rate on withdrawal day 45. (I–L) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after saline self-administration: (I, K) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal. (J, L) Trials of EPSCs from the example neurons in I and K. (M) Summarized results showing that silent synapses were increased on withdrawal day 1 and returned to the basal level on day 45. Error bar, s.e.m. ** p<0.01, *** p<0.001.
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Related In: Results  -  Collection

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Figure 2: Cocaine self-administration generates silent synapses in the BLA-to-NAc shell projection(A) Cocaine self-administration training. (B) Incubation of cue-induced cocaine craving: Data are numbers of active and inactive nose-pokes from the same groups of rats in extinction tests performed on withdrawal days 1 and 45 after self-administration training. (C) Saline self-administration training. (D) Extinction tests on withdrawal days 1 and 45 after saline self-administration. (E–H) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after cocaine self-administration: (E, G) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal (failures and successes are shown in gray and black traces, respectively). (F, H) Trials of EPSCs from the example neurons in E and G showing a higher failure rate at −70 mV (gray dots represent failures and black dots show successes) on withdrawal day 1 and a reduced failure rate on withdrawal day 45. (I–L) Levels of silent synapses in BLA-to-NAc projection on withdrawal days 1 and 45 after saline self-administration: (I, K) EPSCs (at −70 and +50 mV) evoked by minimal stimulation in representative NAc neurons of rats after 1- or 45-day withdrawal. (J, L) Trials of EPSCs from the example neurons in I and K. (M) Summarized results showing that silent synapses were increased on withdrawal day 1 and returned to the basal level on day 45. Error bar, s.e.m. ** p<0.01, *** p<0.001.
Mentions: To examine incubation of cue-induced cocaine craving, we trained rats to nose-poke for intravenous infusions of cocaine for 6 days (one overnight session followed by 2 h/d for 5 days); each infusion was paired with a light cue. As previously demonstrated21–23, this training procedure led to reliable cocaine self-administration over the 5-day training period (Fig. 2A). We then used a within-subjects repeated-measure procedure, previously used in studies on incubation of craving for cocaine and other drugs24,25, to test rats for cue-induced cocaine seeking in extinction sessions performed after 1 withdrawal day or 42–47 days (referred to herein as day 45). During testing, rats were re-exposed to the drug self-administration chambers (the drug environment), and nosepokes (the operational measure of drug seeking and craving) led to contingent presentations of the light cue but not cocaine26. We found that cue-induced cocaine seeking after 45 withdrawal days was higher than after 1 day (incubation of cocaine craving) [Withdrawal day (1, 45) × Nose-poke operandum (active, inactive) interaction, F(1,24)=25.3, p<0.0001, Fig. 2B]. In contrast, no significant time-dependent changes in responding to the light cue during testing were observed in drug-naïve rats that previously nose-poked for saline injections during the training phase (Fig. 2C,D). These dare are in agreement with several reports on incubation of cocaine craving in which a limited access (2-h daily sessions) cocaine self-administration training procedure was used26–28. [Note: in most studies on mechanisms of incubation of cocaine craving3,7,29, investigators have used an extended access (6-h daily sessions) training procedure, which leads to “stronger” incubation after withdrawal than the limited access training procedure26.]

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