Date of Award

2015

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Peter Kalivas

Second Advisor

John J. Woodward

Third Advisor

Jacqueline McGinty

Fourth Advisor

Jeffrey Jones

Fifth Advisor

Bryan Toole

Abstract

Chronic cocaine abuse causes maladaptive neuroadaptations that underlie vulnerability to relapse, even after protracted abstinence. A great deal of work has examined mechanisms of neuroplasticity by which these occur. However, the majority of experimentation has focused on intracellular signaling cascades, while the extracellular compartment has been largely ignored. In the past decade, work has emerged in the learning and memory literature that indicates that extracellular matrix remodeling and signaling is required for adaptive forms of neuroplasticity (e.g. learning and memory), although it has not been thoroughly examined in models of maladaptive neuroplasticity. Throughout this dissertation a drug self-administration, extinction and reinstatement paradigm is used. I first examine the role of the matrix metalloproteinases (MMPs) in the nucleus accumbens core (NAcore) in both the persistent synaptic potentiation that occurs following extinction of cocaine self-administration, and in the rapid, transient potentiation that is required for cue-induced reinstatement. By measuring both the expression and activity of MMPs, this work shows that relapse to multiple classes of drugs of abuse (cocaine, nicotine, and heroin) each are accompanied by an induction of MMP activity. Furthermore, this work goes on to show that inhibiting MMP activity also reverses or blocks synaptic potentiation. A second set of experiments examines nitric oxide (NO) signaling as a mechanism of MMP activation. These experiments used biochemical examination of neuronal nitric oxide synthase (nNOS) activity following extinction and reinstatement of cocaine seeking, and a small molecule inhibitor of nNOS to determine the effects of nNOS activity on MMP activity and relapse behavior. Finally, by using NOS1-Cre transgenic mice this work shows that selectively chemogenetically stimulating a small population of interneurons that express nNOS drives reinstatement of drug seeking. This dissertation concludes that nNOS-expressing interneurons may comprise a ‘master-switch’ by MMPs are activated, synapses are potentiated, and strongly motivated behaviors are initiated.

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