The Role of Context Preference and Age on Single Trial Nicotine Conditioned Place Preference, and the Role of Dosing Context on MAPK Activation in the Ventral Striatum

Gina Fernandez

Advisor: Robert F Smith, PhD, Department of Psychology

Committee Members: Karl J. Fryxell, Craig G. McDonald

Research Hall, #161
May 29, 2014, 01:00 PM to 10:00 AM


Adolescents are prone to risk taking behaviors that often lead to experimentation with drugs, such as nicotine. This behavioral profile coincides with a sensitization of the mesocorticolimbic dopamine pathway that receives input from the developing prefrontal cortex. Drug-seeking behaviors are also maintained through reinforced drug- cue associations, and can be tested using conditioned place preference (CPP). CPP is a behavioral measure of drug reward, in which a drug- cue relationship is established through associative learning. Previous work in our lab has demonstrated that adolescent Sprague Dawley rats, but not adults, form single trial nicotine CPP. Developmental differences in the establishment of a nicotine- context association could be due to differences in the cellular mechanisms underlying synaptic plasticity. One molecular substrate critical for the formation of long-term memory, as well as drug related neural plasticity is the mitogen activated protein kinase (MAPK) pathway. We conducted a series of experiments to examine the relationship between age, nicotine exposure and MAPK activity on reward related behavior. Adult (~ P70) and adolescent (P28) Sprague Dawley rats were trained for single trial nicotine CPP (0.5 mg/kg), and their initial CPP chamber preference was correlated with the strength of the nicotine-cue relationship. Adolescent rats with relatively higher dark CPP chamber preference (HDP) on day 1 of testing formed single trial nicotine CPP, an effect not seen in HDP adults. Adults with relatively lower dark CPP chamber preference (LDP) on day 1 of testing also formed single trial nicotine CPP, an effect not seen in LDP adolescents. Single trial nicotine CPP was abolished in HDP adolescents pre-exposed to an MEK inhibitor (SL327; 50 mg/kg) during conditioning. There was no effect of SL327 in LDP adolescents. In a final experiment, adult and adolescent Sprague Dawley rats were exposed to a CPP conditioning session or a single nicotine versus saline injection in the homecage. Brains were processed for immunohistochemistry to visualize phosphorylated MAPK in the nucleus accumbens (NAc) and basolateral amygdala (BLA). In the adolescent NAc shell, there was a trend for increased amounts of pMAPK labeled cells following a nicotine injection in the CPP chamber versus the homecage, an effect not seen in the adult group. There was a significant increase in the number of pMAPK labeled cells in adults following a saline injection in the CPP versus homecage context, an effect not seen in the adolescent group. In the NAc core, there was a significant increase in pMAPK labeled cells in both age groups after dosing in the CPP versus homecage environment, regardless of drug treatment. In the NAc shell and core, there were no differences in the amount of pMAPK labeled cells between saline or nicotine in the CPP chamber in either age group, suggesting that pMAPK labeling was not specific to nicotine but may be related to injection stress. There were no effects of drug treatment, dosing context or age on pMAPK labeled cells in the BLA. Our results suggest that context preference can modulate the strength of a drug cue relationship across age groups, and during adolescence, this modulation involves MAPK activity. NAc shell and core MAPK activity also seem to be involved in an animal’s immediate response to an arousing stimulus based on context.