Understanding the neurobiological processes that incite drug craving and drive relapse has the potential to help target efforts to treat addiction. The 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-GluA2 3Y 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, whereas 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, whereas 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 STATEMENT These studies identified a sequence of neural events whereby reexposure to cocaine activates a signaling cascade that alters synaptic strength in the NAc shell and triggers a behavioral response driven by a drug-associated memory.
Bibliographical noteFunding Information:
Received Oct. 19, 2017; revised March 1, 2019; accepted March 26, 2019. Author contributions: M.A.B., M.C.H., and M.J.T. designed research; M.A.B., M.C.H., A.J.A., A.M., A.E.I., C.E.S., K.A.S., E.B.L., and S.R.E. performed research; M.A.B., M.C.H., A.J.A., A.M., A.E.I., and E.B.L. analyzed data; M.A.B., M.C.H., and M.J.T. wrote the paper; M.J.T. edited the paper. This work was supported by National Institute on Drug Abuse Grants R01 DA019666, K02 DA035459, and R01 DA041808 to M.J.T., K99 DA038706 to M.C.H., and T32 DA007234 to A.E.I. and S.R.E. Behavioral studies were supported by the University of Minnesota Mouse Behavior Core, with funding from the National Institute for Neurological Disorders and Stroke P30 NS062158 to M.A.B. and M.J.T. We thank the MnDRIVE Optogenetics Core at the University of Minnesota for providing invaluable technical support for the neuromodulation studies. The authors declare no competing financial interests. *M.A.B. and M.C.H. contributed equally to this work. Correspondence should be addressed to Mark J. Thomas at firstname.lastname@example.org.
© 2019 the authors.
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