Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Jacqueline F. McGinty

Second Advisor

Lawrence J. Chandler

Third Advisor

John J. Woodward

Fourth Advisor

Howard C. Becker

Abstract

Infusion of BDNF into the dorsomedial prefrontal cortex (dmPFC) immediately after the last session of cocaine self-administration prevents cocaine-mediated malfunction of synaptic modulation in the dmPFC that mediates relapse to cocaine-seeking through both GluN2A subunit-containing NMDA receptors and GluN2B subunit-containing NMDA receptors (NMDARS). Intra-dmPFC BDNF is known to suppress cocaine-seeking by normalization of cocaine self-administration- induced disturbance of glutamatergic transmission in the nucleus accumbens (NAc) and by prevention of the cocaine self-administration-induced decrease in extracellular signal-regulated kinase (ERK) activity in the dmPFC through activation of tyrosine receptor kinase B (TrkB). Neuronal activity is required for BDNF-induced ERK activation and the interaction between TrkB receptors and synaptic NMDA receptors upregulates ERK activity. The current study found that infusion of a mixture of the AMPA receptor antagonist, CNQX, and the NMDA receptor antagonist, LY235959, (CNQX/LY235959), the GluN2Acontaining NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the dmPFC of rats immediately after the final session of cocaine self-administration inhibited BDNF’s suppressive effect on cocaine-seeking during a context-induced relapse test after home-cage abstinence and during a conditioned cue-induced reinstatement test. We also found that during early withdrawal from cocaine self-administration, intra-dmPFC BDNF infusion prevented cocaine self-administration-induced reduction of phosphorylated ERK, GluN2A (Y1325) and GluN2B (Y1472) levels in the dmPFC. TCN-201 infusion into the dmPFC blocked the BDNF-mediated increase in pGluN2A (Y1325) and Ro-25-6981 infusion into the dmPFC suppressed the BDNF-induced elevation of pGluN2B (Y1472) expression and both GluN2 antagonists blocked BDNF-mediated ERK phosphorylation, indicating that both GluN2A- and GluN2B-containing NMDA receptors mediate BDNF-mediated ERK phosphorylation. Together, these findings indicate that BDNF-mediated co-activation of GluN2A- or GluN2B-containing NMDA receptors induces ERK activation in the dmPFC, which prevents relapse to cocaine-seeking.

Rights

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