Learning to be a cocaine addict: behavioral, pharmacological, and molecular characterization of individual differences in initial learning of cocaine-environment associations
Cocaine addiction is a chronic, relapsing disease affecting millions of Americans, and differences between individuals modulate the progression from cocaine use to addiction. Learned associations between cocaine and environmental stimuli develop in the subset of patients who become addicted, and exposure to these stimuli facilitates relapse to cocaine-taking. Classical conditioning underlies the development and expression of these learned associations, and several systems implicated in both the behavioral response to cocaine and in learning and memory—e.g., serotonin2 receptors (5-HT2R), ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor subunit 1 (GluR1), and a signaling system associated with these receptors (i.e., the mitogen-activated protein kinase extracellular-signal regulated kinase; ERK) in the cortical-limbic regions--may modulate the acquisition and expression of cocaine-environment associations. Individual differences play a major role in the development of addiction, and behavioral models are needed study these implications in the learning of cocaine-environment associations. We utilized the conditioned place preference (CPP) paradigm in laboratory rats to model cocaine-environment associations and developed a new method for the analysis of CPP data that allows for identification of factors that modulate individual sensitivity to the development of cocaine-environment associations, pharmacological treatments that are effective only in subpopulations of subjects, and molecular neuroadaptations that differ among subjects susceptible to the development of cocaine-environment associations and non-susceptible individuals. We uncovered roles for 5-HT2R in the acquisition and expression of cocaine-environment associations formed after a single pairing of cocaine and environment, suggesting a role for these receptors in modulating the development and retrieval of initial cocaine-environment associations. We observed an increase in the phosphorylation of GluR1 and enhanced expression of total ERK protein in the prefrontal cortex upon retrieval of cocaine-environment associations. These studies suggest that the ability to learn strong cocaine-environment associations is associated with a unique set of neuroadaptations and is a predictor of those who will initiate development of a cocaine addiction.