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

Self Cite

Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine selfadministration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1 d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short-and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.

Section: Circuitry Consequencesmentioning

confidence: 62%

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Neumann

Wang

Yan

et al. 2016

Self Cite

“…However, as in prior studies of UPS activation after fear conditioning (Jarome et al, 2011), our dissection did not differentiate subregions of the amygdala. Although the basolateral amygdala has a key role in cocaine memory reconsolidation (eg, Lee et al, 2006), it is the central nucleus that is strongly implicated in the incubation of cocaine craving (Lu et al, 2005a(Lu et al, ,b, 2007; also see Lee et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…We focused on the nucleus accumbens (NAc) because the expression of 'incubated' craving depends upon synaptic plasticity in this region (Conrad et al, 2008;Loweth et al, 2014). We also studied other regions-amygdala, prefrontal cortex (PFC) and dorsolateral striatum (DLS) -implicated in cue-induced cocaine seeking after withdrawal (Grimm et al, 2003;Fuchs et al, 2006;Lu et al, 2005aLu et al, , b, 2007See et al, 2007;Koya et al, 2009;Pacchioni et al, 2011;Lee et al, 2013;Ma et al, 2014;Pascoli et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

Werner

Milovanovic

Christian

et al. 2015

Self Cite

The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine-and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine-and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

“…While their role in dmPFC-BLA pathway remains unknown, silent synapses are formed in the nucleus accumbens of rats during cocaine self-administration, and are involved in cocaine-induced locomotor sensitization and cocaine craving by allowing incorporation of AMPAR (Brown et al, 2011;Lee et al, 2013;Ma et al, 2014). By the same mechanism, silent synapses may render the dmPFC-BLA pathway more prone to facilitation.…”

Section: Formation and Role Of Silent Synapsesmentioning

confidence: 99%

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

Ito

Erişir

Morozov

2015

Witnessing pain and distress in others can cause psychological trauma and increase odds of developing PTSD in the future, on exposure to another stressful event. However, the underlying synaptic process remains unknown. Here we report that mice exposed to a conspecific receiving electrical footshocks exhibited enhanced passive avoidance (PA) learning when trained 24 h after the exposure. The exposure activated neurons in the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) and altered synaptic transmission from dmPFC to BLA. It increased amplitude, slowed decay of NMDA receptor-mediated currents, and generated silent synapses. Administration of sub-anesthetic ketamine immediately after the exposure prevented the enhancement of PA learning and silent synapse formation. These findings suggest that ketamine can prevent pathophysiological consequences of psychological trauma.