Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

Abstract

Repeated exposure to psychostimulant drugs such as cocaine or amphetamine can promote drug-seeking and -taking behavior. In rodent addiction models, persistent changes in excitatory glutamatergic neurotransmission in the nucleus accumbens (NAc) appear to drive this drug-induced behavioral plasticity. To study whether changes in glutamatergic signaling are shared between or exclusive to specific psychostimulant drugs, we examined synaptic transmission from mice following repeated amphetamine or cocaine administration. Synaptic transmission mediated by AMPA-type glutamate receptors was potentiated in the NAc shell 10-14 days following repeated amphetamine or cocaine treatment. This synaptic enhancement was depotentiated by re-exposure to amphetamine or cocaine. By contrast, in the NAc core only repeated cocaine exposure enhanced synaptic transmission, which was subsequently depotentiated by an additional cocaine but not amphetamine injection during drug abstinence. To better understand the drug-induced depotentiation, we replicated these in vivo findings using an ex vivo model termed 'challenge in the bath,' and showed that drug-induced decreases in synaptic strength occur rapidly (within 30 min) and require activation of metabotropic glutamate receptor 5 (mGluR5) and protein synthesis in the NAc shell, but not NAc core. Overall, these data demonstrate the specificity of neuronal circuit changes induced by amphetamine, introduce a novel method for studying drug challenge-induced plasticity, and define NAc shell medium spiny neurons as a primary site of persistent AMPA-type glutamate receptor plasticity by two widely used psychostimulant drugs.

Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

“…The two major subdivisions of the NAc, the shell and core, are distinguished based on anatomic connectivity and their role in reward-related behavior (6,(30)(31)(32)(33). In the present study, no significant adaptations in synaptic strength (A/N ratios) or glutamate release probability were observed in either D1R-or D2R-MSNs of the NAc core.…”

“…In the present study, no significant adaptations in synaptic strength (A/N ratios) or glutamate release probability were observed in either D1R-or D2R-MSNs of the NAc core. Although repeated exposure to cocaine produces enduring increases in synaptic strength in both NAc shell and core, we recently demonstrated NAc synaptic plasticity following repeated amphetamine (22,24,(32)(33)(34), which raises a question of whether cocaine, rather than morphine, may be unusual in regards to plasticity in the NAc core. That said, given that the behavioral and neurochemical effects of opiates are dependent on activation of mu opioid receptors (2,35), the regional differences in morphine-induced plasticity demonstrated here may be related to the higher prevalence of mu opioid receptors in the NAc shell compared with the core (36,37).…”

Neural mechanisms of MK-801 induced sensitisation

“…One day after repeated cocaine treatment the AMPAR/NMDAR in the NAc is decreased and with increasing withdrawal from the induction phase the AMPAR/NMDAR ratio becomes increased (Kourrich et al, 2007). Subsequent to a drug challenge the AMPAR/NMDAR ratio becomes rapidly 'de-potentiated', returning to the potentiated state after withdrawal from the challenge (Jedynak et al, 2016, Kourrich et al, 2007, Thomas et al, 2001. These changes in excitatory synaptic strength are reflective of altered synaptic plasticity mechanisms.…”

“…GABAergic medium spiny neurons (MSNs) are the majority cell type of the NAc (Tepper and Bolam, 2004). Accumulating evidence indicates that, in the NAc shell, excitatory synaptic plasticity is increased during the expression of behavioural sensitisation (Jedynak et al, 2016, Kourrich et al, 2007. The ratio of AMPAR to NMDAR evoked synaptic currents is a widely used assay of excitatory synaptic strength (Bellone and Luscher, 2006, Saal et al, 2003a, Thomas et al, 2001, Ungless et al, 2001.…”

“…In recent years, technical advancements have led to the development of Bacterial Artificial Chromosome (BAC) transgenic mice that express differentiating fluorescent proteins in the D1 and D2 MSNs (Shuen et al, 2008). Emerging evidence suggests that increases in synaptic strength and plasticity occur in a cell-type specific manner on the D1 'reward-promoting' MSNs, following withdrawal from drugs of abuse including morphine (Hearing et al, 2016), cocaine (Pascoli et al, 2012) and ethanol (Jeanes et al, 2014, Renteria et al, 2016. Thus this suggests that drug-induced sensitisation is facilitated by enhanced glutamatergic synaptic input onto the 'direct' striatal dopaminergic pathway.…”