Date of Award

January 2012

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

David Russell

Second Advisor

Ronald Duman

Subject Area(s)

Psychobiology

Abstract

Nonreceptor, proline-rich tyrosine kinase 2 (Pyk2) is a member of the

focal adhesion kinase (FAK) family. Of the three known isoforms, the

unspliced form of Pyk2 is most highly expressed in the CNS and has the

highest abundance in striatum, cortex, lateral septum, and

hippocampus(1, 2)(1, 2). Through regulation of NMDA receptor activity,

Pyk2 has been shown to play a crucial role in synaptic plasticity.

Given the high abundance of Pyk2 in the striatum and its known role in

synaptic plasticity, we hypothesized that disruption of Pyk2 function would

diminish the observed behavioral response to chronic cocaine. We

created a transgenic mouse line using the tetracycline inducible

transgene system. Quantitative real-time PCR was utilized to measure

mRNA levels and to characterize the mutant mice. In addition,

immunoprecipitation experiments were conducted to verify the presence

of mutant Pyk2 protein in the striatum and nucleus accumbens.

Disruption of behavioral sensitization in response to cocaine was

observed in the transgenic mice, while sensitization was preserved in

wild-type mice. There was no significant difference in phosphorylation of

NMDAR-NR2B. These findings, however, do not allow us to definitively

conclude that the presence of mutant Pyk2 diminishes the locomotor

effects of the cocaine mediated synaptic plasticity. Taken together, Pyk2

could be a potential target for pharmacologic therapy in drug addiction.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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