Date of Degree

2-2014

Document Type

Dissertation

Degree Name

Ph.D.

Program

Psychology

Advisor(s)

Shirzad Jenab

Subject Categories

Neuroscience and Neurobiology | Social and Behavioral Sciences

Keywords

Cocaine, conditioned place preference, intracellular signaling

Abstract

The aim of this dissertation was to investigate the intracellular responses associated with the acquisition and expression of cocaine-context associations. ERK (extracellular regulated kinase), CREB (cAMP responsive element binding protein), FosB and deltaFosB proteins were of particular interest due to their involvement in cocaine reward and in synaptic plasticity underlying learning and memory. We used the conditioned place preference (CPP) paradigm, which employs a Pavlovian conditioning procedure to establish an association between a drug-paired environment and the drug's rewarding effects, to study the role of these signaling pathways in cocaine-context associations. N-methyl-D-aspartate receptor (NMDAR) antagonism prior to cocaine administration during conditioning blocked the acquisition of cocaine CPP and reduced Nucleus Accumbens (NAc) phosphorylated-ERK (pERK) levels following the CPP test (drug-free). NAc pERK levels increased after re-exposure to the cocaine-paired environment regardless of CPP expression. Conversely, Caudate Putamen (CPu) pERK and FosB protein levels only increased after CPP expression and re-exposure to the cocaine chamber. These results suggest that NAc ERK phosphorylation may be involved with retrieving the contextual information of a cocaine-association, without the expression of the behavior. Finally, we investigated whether ERK/CREB intracellular responses underlying cocaine environmental associations are sexually dimorphic. Following CPP expression, cocaine treated rats showed increased NAc pERK and pCREB and CPudeltaFosB levels. Cocaine females had a larger increase in CPu deltaFosB levels than cocaine males; partly due to lower protein levels in saline female rats when compared to saline males. CPP scores were positively correlated to NAc pERK and CPu FosB protein levels, suggesting that similar to males, the ERK/CREB intracellular pathway undergoes cocaine induced neuroplasticity in female rats. However, there seem to be intrinsic sexual dimorphisms that may contribute to responses expressed after cocaine-CPP. Taken together, the different patterns of intracellular responses in the NAc and CPu likely indicate region specific roles for pERK/pCREB/FosB signaling in the acquisition and retrieval of cocaine-context associations. These results will aid in the advancement of general knowledge about the molecular formation and retrieval of cocaine-associated memories that can be used in the future when designing treatments for cocaine addiction that target both prevention and relapse.

 
 

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