Research objectives and hypothesis

An important target for combating drug addiction is to understand the
neurobiological mechanisms that sub-serve relapse to drug use (Mantsch et al., 2010).
Drug addiction is thought to usurp the neural mechanisms of learning and memory
(Hyman, 2005) and affect long term plasticity as a result of changes in gene expression
(McClung & Nestler, 2008). Memory of the rewarding effects of drugs of abuse is stored
in the brain even after prolonged periods of abstinence. This memory can resurface when
an individual is re-exposed to priming doses of the drug itself, drug-related cues or to
certain stressors (Shaham et al., 2003).
The CPP paradigm represents a valuable tool for investigating the incentive value
of drugs of abuse and the reinstatement of drug seeking behavior following extinction.
Traditional CPP studies employ a fixed dose regimen of the drug during training.
However, since the transition from drug use to addiction involves an escalation in drug
intake (Gawin, 1991), I posit that a paradigm that can effectively simulate increases in
drug intake will better model the human drug use pattern. Research investigating
differences in the pattern of cocaine dosing in a CPP paradigm have shown that the
schedule of cocaine administration, rather than the dose of cocaine, has a significant
impact on the development of drug associated memory (Itzhak & Anderson, 2012;
Conrad et al., 2013). This suggests that different mechanisms may govern the formation
of cocaine-associated memory that was developed by different schedules of cocaine
administration during conditioning. As such, the generalization of the involvement of
specific signaling molecules in the formation of cocaine-associated memory may be
misleading. Therefore an investigation of the contribution of different signaling
molecules to diverse types of drug-memory will be beneficial to identify a potent
pharmacotherapy for addiction management. Although the NMDAR and downstream
signaling molecules have been implicated in relatively ‘weak’ cocaine-associated
memory, it is unclear if the same molecular factors will be involved in ‘strong’ cocaineassociated
I hypothesize that mice conditioned by the traditional fixed daily dose of cocaine
(Fix-C) versus mice conditioned by escalating doses of cocaine (Esc-C) will show
differential expression of specific genes and their corresponding proteins. I further
hypothesize that the acquisition, extinction and reinstatement of cocaine-associated
memory developed by Fix-C and Esc-C engage different signaling molecules.
In Chapter 2 of this thesis, the molecular mechanisms underlying the effect of
conditioning schedule on the acquisition and reconsolidation of cocaine –associated
memory developed by Fix-C and Esc-C are described. Specifically, the contribution of
different genes and their proteins to the development of Fix-C and Esc-C memory as well
as pharmacological approaches for attenuating the acquisition and reconsolidation of Fix-
C and Esc-C memory were investigated. Results generated from this chapter were
accepted for publication in the following manuscript:
Liddie S, Itzhak Y (2014) Variations in the stimulus salience of cocaine reward
influences drug-associated contextual memory. Addiction Biology (In Press).
In Chapter 3, extinction of Esc-C memory following repeated unreinforced
exposures to the training context was investigated. Specifically, the effect of different
phosphodiesterase (PDE) inhibitors on extinction learning was investigated. Results from
this chapter were published in the following paper:
Liddie S, Anderson KL, Paz A, Itzhak Y (2012) The effect of phosphodiesterase
inhibitors on the extinction of cocaine-induced conditioned place preference in mice. J
Psychopharmacol 26: 1375-1382.
In Chapter 4, the effects of a) conditioning schedule and b) different
pharmacological agents on attenuation of stress-induced reinstatement of CPP were
investigated. Results from this chapter are currently being prepared for a manuscript.
Finally, Chapter 5 is a general discussion and review of the central findings in this
thesis. The significance of my findings as well as potential future lines of research
stemming from my findings is discussed.

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