Doctor of Philosophy / Department of Psychological Sciences / Mary E. Cain / Drug addiction is a chronic cyclical disease characterized by periods of drug use and abstinence. Drug craving increases as a function of abstinence period, such that longer periods of abstinence result in greater feelings of craving. Longer periods of abstinence may render cues to become more powerful motivators of drug seeking behavior because of the greater craving response. Neurobiological evidence suggests that changes in glutamatergic transmission in the nucleus accumbens (NAc) plays a pivotal role in the incubation of craving and drug seeking motivation. Specifically, the upregulation of Ca²⁺ permeable AMPA receptors may increase drug seeking following the presentation of a drug cue. Environmental housing manipulations also change the expression of metabotropic glutamate receptors (mGlur) and psychostimulant self-administration. In the current experiments, Sprague-Dawley rats were reared in enriched (EC) or isolated (IC) conditions from PND 21-51. Then rats were implanted with indwelling jugular catheters and allowed to self-administer amphetamine (0.1 mg/kg/infusion) or saline paired with a cue light for 16 days for 1h. Then rats went through a forced abstinence period of 1 day and were then tested in a cue-induced seeking test. Immediately after the seeking test, half the rats were sacrificed and the NAc was dissected and prepared for western blot analyses. The other half of rats rested for 40 days and were tested again in the cue-induced seeking test. Immediately following the seeking test, rats were sacrificed and their NAc was dissected. Factorial ANOVA results indicate that rearing in the IC environment increased drug seeking when compared to EC rats after 1 day of abstinence and after 40 days of abstinence, but drug seeking did not increase after 40 days. Rats in the saline groups showed an increase in seeking after 40 days of abstinence, providing evidence of increased responding. Saline responding was significantly lower when compared to rats that responded for amphetamine. When rats self-administered saline, generally IC rats had more responding than EC rats. Western blot analyses indicated that expression of AMPA subunits GluA1, and GluA2, as well as metabotropic glutamate receptors 1 and 5 (mGlur1, and mGlur5) were not different across the experimental groups, suggesting another mechanism could be implicated in drug seeking after short and long abstinence periods. These results suggest that early life experience can have long lasting effects into adulthood and increase the vulnerability of drug abuse. Our results provide mixed results of incubated seeking. Positive early life experiences reduce drug seeking motivation after short and long abstinence periods, providing evidence for further research to examine how early life experience changes the reward seeking and subsequent structures in the mesocorticolimbic pathway.

Doctor of Philosophy / Department of Psychology / Mary E. Cain / Glutamate contributes to the neurological and behavioral changes that occur during differential rearing, and those that occur during conditioned hyperactivity and sensitization. Metabotropic glutamate receptor 5 (mGluR5) in particular contributes to the psychostimulant reward pathway, plasticity, and differential rearing. The present study examined the role of mGluR5 in conditioning and sensitization in differentially reared rats. Rats were reared in an enriched (EC), impoverished (IC), or social (SC) condition for 30 days, after which they received repeated amphetamine (0.3 mg/kg) or saline injections. Following training, rats received an injection of the mGluR5 antagonist MTEP or saline prior to undergoing conditioned hyperactivity and sensitization tests. Results showed that MTEP attenuated conditioned hyperactivity and sensitization in IC but not EC and SC rats, suggesting that glutamatergic changes occur during differential rearing that alter the effects of MTEP on amphetamine conditioning and sensitization. Additionally, results demonstrated that enrichment rearing has a protective effect against conditioned hyperactivity at low doses of amphetamine.

Master of Science / Department of Psychological Sciences / Mary Cain / Research has demonstrated that an enriched rearing environment improves learning in many tasks. However, growing evidence suggests that an enriched environment may not provide the same benefits during a fear conditioning paradigm. In fact, it appears that an isolated rearing environment may facilitate acquisition of fear to an aversive stimulus. The neural mechanisms responsible for this disparity in fear learning among differentially reared animals are currently unknown. The NR2B subunit of the NMDA receptor has been shown to be involved in the acquisition of fear and influenced by differential rearing, making it a prime candidate to begin investigating these underlying neural mechanisms. Therefore, this study assessed the expression of the NR2B subunit in brain regions important for the acquisition of fear (amygdala and hippocampus) among differentially reared rats. Rats were reared in an enriched, an isolated, or a standard condition for 30 days. They received four tone-footshock pairings, after which their brains were removed and expression of the NR2B subunit was quantified in the basolateral amygdala (BLA), central nucleus of the amygdala (ACe), and the CA3 region of the hippocampus. Analyses found that the isolated rats began to acquire fear to the aversive stimulus faster than the enriched and standard housed rats. However, the isolated rats showed the least amount of NR2B expression in the BLA while there were no rearing differences in expression within the ACe or the CA3. The results from this study provide further insight to the importance of the rearing environment in learning and memory, especially the learning of fear, and its central neural basis.