Synaptic depotentiation and mGluR5 activity in the nucleus accumbens drive cocaine-primed reinstatement of place preference (2019)

J Neurosci. 2019 Apr 4. pii: 3020-17. doi: 10.1523/JNEUROSCI.3020-17.2019.

Benneyworth MA1,2, Hearing MC3, Asp AJ1, Madayag A3, Ingebretson AE1, Schmidt CE1, Silvis KA1, Larson EB1, Ebner SR1, Thomas MJ4.


Understanding the neurobiological processes that incite drug craving and drive relapse has the potential to help target efforts to treat addiction. The nucleus accumbens (NAc) serves as a critical substrate for reward and motivated behavior, in part due to alterations in excitatory synaptic strength within cortical-accumbens pathways. The present studies investigated a causal link between cocaine-induced reinstatement of conditioned place preference and rapid reductions of cocaine-dependent increases in NAc shell synaptic strength in male mice. Cocaine conditioned place preference behavior and ex vivo whole-cell electrophysiology showed that cocaine-primed reinstatement and synaptic depotentiation were disrupted by inhibiting AMPAR internalization via intra-NAc shell infusion of a Tat-GluA23Y peptide. Furthermore, reinstatement was driven by an mGluR5-dependent reduction in AMPAR signaling. Intra-NAc shell infusion of the mGluR5 antagonist MTEP blocked cocaine-primed reinstatement and corresponding depotentiation, while infusion of the mGluR5 agonist CHPG itself promoted reinstatement and depotentiated synaptic strength in the NAc shell. Optogenetic examination of circuit-specific plasticity showed that inhibition of infralimbic cortical input to the NAc shell blocked cocaine-primed reinstatement, while low frequency stimulation (10 Hz) of this pathway in the absence of cocaine triggered a reduction in synaptic strength akin to that observed with cocaine, and was sufficient to promote reinstatement in the absence of a cocaine challenge. These data support a model in which mGluR5-mediated reduction in GluA2-containing AMPARs at NAc shell synapses receiving input from the infralimbic cortex is a critical factor in triggering reinstatement of cocaine-primed conditioned approach behavior.SIGNIFICANCE STATEMENTThese studies identified a sequence of neural events whereby re-exposure to cocaine activates a signaling cascade that alters synaptic strength in the nucleus accumbens shell and triggers a behavioral response driven by a drug-associated memory.

PMID: 30948476

DOI: 10.1523/JNEUROSCI.3020-17.2019