Date of Award

2007

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Jacqueline F. McGinty

Second Advisor

Gary Aston-Jones

Third Advisor

Ronald E. See

Fourth Advisor

Howard Becker

Fifth Advisor

Peter W. Kalivas

Abstract

Glutamatergic pyramidal cells arising from the prefrontal cortex (PFC) are critical mediators of reinstatement to cocaine-seeking. A potent modulator of PFC activity is brain derived neurotrophic factor (BDNF), a molecule that has been implicated in the regulation of glutamatergic neurotransmission. In this study, the role of BDNF in the PFC was investigated in an animal model of cocaine addiction. First, a cocaine-induced decrease in BDNF mRNA within the PFC was documented following 22 h of abstinence, followed by an increase in BDNF protein expression within the PFC following 21 d of extinction training. Second, an intra-PFC infusion of BDNF attenuated relapse to cocaine seeking following drug abstinence and reinstatement of cocaine seeking after extinction training. Furthermore, the intra-PFC infusion of BDNF prevented cocaine-induced decreases in phosphor-ERK expression in the nucleus accumbens (NAc), implicating the PFC-NAc pathway in BDNF's suppression of cocaine seeking. Disturbance in this pathway underlies the decrease in extracellular glutamate levels in the NAc during withdrawal from chronic cocaine and an increase in glutamate levels after cocaine-primed reinstatement of drug seeking. BDNF prevented the decrease in basal extracellular glutamate levels following cocaine self administration and the increase in cocaine prime-induced glutamate levels in the NAc. These data indicate that cocaine-induced neuroadaptations within the PFC-NAc pathway are normalized by intra-PFC BDNF treatment. Considering that 1) these effects are long-lasting and are the result of a single dose of BDNF and 2) the infusion is only efficacious when administered shortly after the end of cocaine self-administration, the possible therapeutic implications are significant and serve as the impetus for future investigation into the mechanisms involved in the ability of intra-PFC BDNF infusions to suppress cocaine seeking behavior.

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