Increased exploration, risk-taking and reward-seeking are the hallmarks of adolescence. These and related behaviors prepare the young to transition from the parent’s nest to independent living. Adolescence is also a period of heightened structural and functional brain reorganization, particularly within the mesocorticolimbic dopamine system, frontal cortex, striatum and amygdala - an interconnected network of brain regions that supports reward-directed behavior. The goal of this dissertation to further our understanding of ways in which the adolescent brain interacts with rewards. In Chapter 2, I present the results of a set of experiments demonstrating that adolescent rats do not differ from adults in a simple form of stimulus-reward learning but are willing to invest greater effort to obtain larger rewards. While previous studies have focused on the role of neurodevelopmental changes in the dopamine system and within the striatum in heightened reward seeking in adolescence, our data suggest that synaptic remodeling within the frontal cortex and amygdala may also contribute to enhanced reward sensitivity. Chapter 3 explores the long-term consequences of prescription drug exposure during the adolescent period of heightened reward sensitivity in rats. The data suggest that adolescent exposure to both fluoxetine and methylphenidate impairs learning and cognitive flexibility in adulthood in male rats long after the drug administration has been terminated. Adolescent methylphenidate exposure has the direst consequences, impairing both the initial learning and reversal of reward contingencies. The data also reveal sex differences: while females take longer to learn the task, they are also less vulnerable to the negative effects of drug exposure. In Chapter 5, I compare adult and adolescent humans in their approaches to solving the credit assignment problem (i.e., the problem of discovering which choices are responsible for rewards, introduced in Chapter 4). The data provide preliminary evidence for enhanced contingent credit assignment in adolescence. While adults integrate information about their previous decisions and past outcomes to guide their subsequent choices, adolescents are more narrowly focused on the most recent choice-reward history. In Chapter 6, I discuss the implications of the present work and offer cautious advice on drug abuse prevention and improvements in pedagogical practice.

Our decisions often involve consideration of prospective outcomes, which allow us to assess the consequences of our possible responses before deciding on a course of action. This process requires a detailed representation of how events are related so we can recall this information when appropriate. While normally adaptive, disruptions in this learning process can give rise to maladaptive behaviors underpinning neuropsychiatric disorders, such as with substance abuse. This dissertation investigates the neural substrates for the formation of associative maps between rewarding cues and outcomes, and how these neural circuits are changed with drug experience to contribute to maladaptive decision-making. Inhibition of GABAergic neurons in the lateral hypothalamus (LH) revealed the LH to be important for helping to learn detailed associations between cues and rewards that can be used to influence behavior. Targeted inhibition and stimulation of dopaminergic projections from the ventral tegmental area (VTA) to the LH were identified as facilitating learning about detailed cue-reward associations in LH. A history of methamphetamine experience was shown to increase the control that reward cues have over decision-making and to strengthen LH-VTA circuits. To examine endogenous dopamine activity in the LH and how this might change following drug exposure, we measured dopamine release across learning of cue-reward associations in rats with or without a prior history of methamphetamine self-administration. Dopamine release in the LH was shown to increase to cues and rewards across learning, which constitutes a unique profile of dopamine activity. Importantly, prior methamphetamine self-administration was found to amplify dopamine release to reward cues that emerges across learning. Altogether, these data characterize a circuit between the hypothalamus and the midbrain that supports the acquisition of detailed cue-reward associations that are strengthened with prior drug experiences to heighten the control that reward cues have over behavior.