It has been well established that there is a great deal of individual variability in the response to drugs of abuse as well as to stressful life events. The overall aim of this dissertation is to simply ask what are the neurobiological mechanisms that may make some individuals more to prone to succumb to addictive properties of drugs of abuse, and how may stressful life events alter susceptibility? In humans, the personality trait of sensation seeking has been highly correlated to “risky” behaviors including drug taking. In rats, there exists an animal model of sensation seeking in which a population of outbred rats can be termed High Responders (HR), or Low Responders (LR), based on their exploration of a novel environment. Past research has demonstrated that this model has predictive validity in that HR animals are more likely to become behaviorally sensitized to, and self-administer drugs of abuse than LR rats.

In the first aim of this dissertation we ask what changes in gene expression within the mesolimbic circuitry may occur as a result of behavioral sensitization. In this study, adult Sprague-Dawley rats were injected daily with amphetamine (1mg/kg, i.p.) or saline for 9 days followed by a challenge injection seven days later. Our results showed that HR rats, but not LR rats, developed behavioral sensitization to the locomotor activating effects of amphetamine. Furthermore, only HR rats pretreated with amphetamine exhibited an increase in dopamine transporter mRNA in the ventral tegmental area (VTA) and substantia nigra (SN). These results demonstrate the existence of individual differences in behavioral sensitization to amphetamine and suggest that the dopamine transporter may be a critical factor in the development and expression of behavioral sensitization to the locomotor activating effects of amphetamine.

In the second aim of this dissertation, we sought to examine in the context of individual differences, if exposure to repeated psychosocial stress, social defeat in particular, would alter the locomotor stimulating effects of an acute injection (0.5, 1.0, and 1.5 mg/kg i.p.) of amphetamine. In an effort to understand what mechanisms underlie stress-induced sensitization to amphetamine, we examined long-term changes in striatal gene expression of the D1 and D2 receptors, as well as TH and DAT expression in the VTA and SN. Additionally, we examined if repeated social defeat stress led to an increase in corticosterone release in response to an acute injection of amphetamine. Finally, we investigated if repeated social defeat was associated with changes in dendritic spine density in the hippocampus, prefrontal cortex and nucleus accumbens of rats that exhibit stress-induced sensitization. Following repeated social defeat, LR rats and HR rats were behaviorally identical in response to acute injections of amphetamine. Furthermore, HR non-defeated rats had less D2 mRNA expression in the nucleus accumbens core and dorsal striatum than did LR non-defeated rats. However, after repeated social defeat, HR and LR rats had identical D2 mRNA expression in both the core and dorsal striatum. Additionally, we have shown that in comparison to non-defeated rats, there is an enhancement of corticosterone release in LR defeated but not HR defeated rats in response to an amphetamine injection. Finally, there were no changes in TH, D1 and DAT expression in any of the areas examined nor did social defeat stress induce a change in dendritic spine density in any of the brain areas examined in LR rats.

One fascinating aspect of sensation seeking in humans is that despite similar hormonal responses during risk taking behaviors, these individuals report a lower level of anxiety in these situations when compared to non-sensation seekers. Interestingly, in rats, it has been demonstrated that some individuals will find the “stress” hormone, corticosterone, reinforcing. Specifically, it has been demonstrated that HR rats will self administer corticosterone at levels that mimic circulating plasma levels of corticosterone observed during mildly stressful events. Furthermore, in humans, chronic use of glucocorticoids has been reported to have euphoric effects in some individuals, but aversive effects in others. As such, in the final aim of this work, we asked if corticosterone itself has intrinsic rewarding properties. For these experiments we used a well established model of reward, termed conditioned place preference (CPP), in which a context is associated with the repeated pairing of a drug and subsequently tested to see if the chamber becomes preferred over the non-drug paired chamber. Here we report that corticosterone is not rewarding, nor is it aversive to rats. Furthermore, despite the reinforcing effects of corticosterone in HR rats, we observed no individual differences in the rewarding aspects of corticosterone.