Date of Award

1-1-2017

Embargo Period

1-1-2022

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Jacqueline F. McGinty

Second Advisor

Peter W. Kalivas

Third Advisor

Joseph B. Blumer

Fourth Advisor

John J. Woodward

Fifth Advisor

Howard C. Becker

Abstract

Cocaine addiction and relapse to drug use remain an important public health issue. Following acquisition of drug use, persistent neuroadaptations occur in mesocorticolimbic circuits that facilitate compulsive drug seeking. For this reason, the most viable therapeutic targets are those that normalize druginduced neuroadaptations in these circuits to prevent relapse to drug use. The glutamatergic projection neurons from the prelimbic (PrL) cortex to the nucleus accumbens core (NAc) are specifically implicated in reinstatement to drug seeking in preclinical models. We have shown that a single infusion of brain derived neurotrophic factor (BDNF) into the PrL cortex during early abstinence from cocaine self-administration results in attenuation of context, cue, and cocaine prime-induced drug seeking up to three weeks post-BDNF infusion. The attenuating effects of this BDNF infusion are contingent upon normalization of p- ERK and p-CREB levels in the PrL cortex and require both NMDA activation and TrkB (BDNF’s receptor) activation in the PrL cortex. This dissertation is focused on delineating the neural mechanisms underlying the need for dual activation of TrkB and NMDA receptors following this single BDNF infusion. Src family kinases (SFKs) are activated by TrkB and phosphorylate NMDA receptors at critical tyrosine sites to enhance glutamatergic signaling. My Aims test the hypothesis that both SFKs and NMDA receptors are necessary for BDNF’s long-term suppressive effects on cocaine-seeking following cocaine self-administration. In Aim 1, we demonstrated that inhibition of SFKs blocked cocaine’s ability to dephosphorylate ERK MAP kinase and GluN2A and GluN2B subtype-containing receptors thereby preventing the suppressive effects of intra-PrL infusion of BDNF on cocaine-seeking. In Aim 2, we demonstrated that inactivation of glutamatergic pyramidal neurons in the PrL cortex that project to the NAc immediately before a BDNF infusion blocked BDNF’s long term attenuating effects on cocaine-seeking. These studies indicate that BDNF-mediated enhancement of excitatory signaling and concurrent synaptic activation of PrLNAc neurons is necessary for BDNF’s suppressive effects on cocaine-seeking, contributing to our understanding of both the mechanism by which BDNF reverses cocaine-induced neuronal deficits and the dynamic relationship between BDNF and synaptic activity.

Rights

All rights reserved. Copyright is held by the author.

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