Publication Date

2014-09-02

Availability

Open access

Embargo Period

2014-09-02

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2014-08-11

First Committee Member

Yossef Itzhak

Second Committee Member

Philip McCabe

Third Committee Member

Claes Wahlestedt

Fourth Committee Member

Juan Young

Fifth Committee Member

David Wolgin

Abstract

An important target for combating drug addiction is to understand the neurobiological mechanisms that sub-serve relapse to drug use. Drug addiction is thought to usurp the neural mechanisms of learning and memory. The conditioned place preference (CPP) paradigm which employs the principles of Pavlovian learning is often used to investigate the incentive value of drugs of abuse and the formation of drug-associated memory. One caveat to conditioned reward studies is the use of a fixed daily dose of the addictive drug during training. However, the transition from drug use to addiction in human addicts involves an escalation in drug intake. I posit that a paradigm that can effectively simulate increases in drug intake will better model the human drug use pattern. Evidence suggests that conditioning by escalating doses of cocaine (Esc-C) confers higher magnitude and more persistent cocaine-memory than conditioning by a fixed daily dose of cocaine (Fix-C). Thus, my research objective was to investigate the contribution of different signaling molecules to the acquisition, reconsolidation, extinction and reinstatement of cocaine associated memory developed by Esc-C versus Fix-C. At the cellular level, I found that the formation of Esc-C memory was associated with markedly increased hippocampal expression of the mRNA and protein that codes for the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR) compared to formation of Fix-C memory, suggesting a positive correlation between the strength of cocaine associated memory and levels of NR2B subunit expression. Pharmacologically, the development (acquisition) of Fix-C and Esc-C memory was attenuated by antagonism of NR2B-containing NMDARs. However, inhibition of the neuronal nitric oxide synthase (nNOS) which is downstream of the NMDAR attenuated the acquisition of Fix-C but not Esc-C memory. This suggests that the acquisition of Fix-C memory is NO-dependent while Esc-C memory is NO-independent. Regarding memory reconsolidation, NR2B antagonism disrupted reconsolidation of both Fix-C and Esc-C memory. However, while reconsolidation of Fix-C memory was NO-dependent similar to acquisition, reconsolidation of Esc-C memory was NO-insensitive. Conversely, inhibition of the extracellular signal-related kinase (ERK) signaling pathway disrupted reconsolidation of Esc-C but not Fix-C memory. With respect to extinction learning, I investigated the use of phosphodiesterase (PDE) inhibitors as cognitive enhancer to facilitate elimination of extinction-resistant Esc-C CPP. I found that specific inhibition of PDE9, which increases levels of cGMP in the hippocampus and amygdala, induced extinction learning and prevented cocaine-primed reinstatement in mice conditioned by Esc-C. This suggests that PDE9 has a prominent role in consolidation of extinction learning. Stress is a major contributor to relapse to drug use in human addicts. I found that stress-induced reinstatement of Fix-C and Esc-C CPP (following their extinction) was unperturbed by ifenprodil. However, stress-induced reinstatement of Fix-C CPP, but not Esc-C CPP, was attenuated by MK-801, 7-NI and the corticotrophin releasing hormone receptor subtype 1 (CRH-R1) antagonist antalarmin. This suggests that stress-induced reinstatement of Esc-C CPP may engage alternative signaling pathways. Taken together, my studies have shown that variations in the stimulus salience of cocaine reward from a fixed dose to escalating doses engage different neural substrates in the formation of cocaine-associated memory. Furthermore, my studies highlight the importance of understanding the significance of drug memory strength, which could be relevant to the severity of addiction, as it relates to the development of pharmacotherapeutics for the management of addiction.

Keywords

addiction; cocaine; memory; reconsolidation; conditioned place preference; phosphodiesterase inhibitors

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