Neurobehavioral evidence for changes in dopamine system activity during adolescence

Abstract

Human adolescence has been characterized by increases in risk-taking, emotional lability, and deficient patterns of behavioral regulation. These behaviors have often been attributed to changes in brain structure that occur during this developmental period, notably alterations in gray and white matter that impact synaptic architecture in frontal, limbic, and striatal regions. In this review, we provide a rationale for considering that these behaviors may be due to changes in dopamine system activity, particularly overactivity, during adolescence relative to either childhood or adulthood. This rationale relies on animal data due to limitations in assessing neurochemical activity more directly in juveniles. Accordingly, we also present a strategy that incorporates molecular genetic techniques to infer the status of the underlying tone of the dopamine system across developmental groups. Implications for the understanding of adolescent behavioral development are discussed.

Introduction

Adolescence is a transitional period between childhood and adulthood characterized by behavioral, hormonal, and neurochemical changes designed to prepare organisms for independent survival (Casey et al., 2008, Doremus-Fitzwater et al., 2010, Spear, 2003). Although these transitions are largely positive, adolescence can be conceptualized as a period of vulnerability. Risk-taking increases during this time (Steinberg, 2008), as does vulnerability to psychiatric disorders (Kessler et al., 2005, Paus et al., 2008). Theories abound to explain these patterns, most of which suggest that adolescent behavior patterns are attributable to changes in brain maturation during this period of the lifespan (Casey et al., 2008, Fareri et al., 2008, Steinberg, 2008). Many frameworks focus on one of two neural substrates, considering one or both. These include (a) the prefrontal cortex (PFC), which is structurally and functionally under-developed, leading to deficiencies in behavioral regulation, as well as (b) limbic and striatal structures, which may be characterized by relatively heightened patterns of activation, conferring a state of motivational “over-drive”. Simplistically put, it is hypothesized that “go” signals are strong, while regulatory “stop” or monitoring signals are weak. These processes may be inter-related in that sub-cortical signaling can be excessive due to a lack of overarching cortical control. Accordingly, it is unknown whether adolescents’ behavior patterns are due to deficiencies in the PFC's structural and functional maturation, to a subcortical system that is in over-drive and could not be controlled even in the presence of an adequately functioning PFC, or to some combination of both factors. It should also be mentioned at the outset that not all models adhere to the formulation that motivational circuits are in a state of over-drive; some propose that the opposite is true (Comings and Blum, 2000, Volkow et al., 2007). Although the brain is undergoing structural refinement during adolescence, adolescents’ difficulties with behavioral regulation may be exacerbated by other neurodynamic processes.

We have offered a unifying account of adolescent behavior that explains it in terms of the development of the dopamine (DA) system (Wahlstrom et al., 2010). Briefly, our perspective builds upon the theory that DA underlies a behavioral activation system that modulates incentive-motivated approach behavior (Depue and Collins, 1999). This system promotes reward-seeking through activity in limbic, striatal, and frontal networks, facilitating an individual's ability to translate positive motivations into adaptive actions. The adaptive pursuit of positive incentives is critical to independent future-directed behavior. Our perspective is that activity in this system increases during adolescence to meet the demands associated with the transition to independent living. The increase occurs via a tonic increase in DA availability and impacts both subcortical (limbic and striatal) and cortical (prefrontal) circuits.

Operating within the context of continued structural brain development, heightened DA activity within this system may result in an apparent over-activation of incentive motivation in the absence of reliable levels of behavioral control. Unfortunately, the assessment of neurochemistry in human adolescents has proven elusive due to methodological limitations and human subjects concerns. The purpose of the current review is to describe developmental changes in the DA system through adolescence and to suggest a genetic model for how the integrity of the system can be assessed non-invasively in healthy adolescents. In addressing this aim, we will (i) provide an overview of brain development during adolescence; (ii) provide a brief overview of the DA system from a neurophysiological perspective, (iii) review the development of the DA system, presenting data from the animal literature; this review represents the major portion of this paper and is intended to provide a rationale for why this system should be scrutinized in humans for its role in adolescent behavior; finally, we will (iv) present a molecular genetic strategy for the indirect assessment of human neurochemical development. We have chosen DA, the COMT Val¹⁵⁸Met single nucleotide polymorphism, and working memory to illustrate this strategy. Although working memory does not necessarily reflect the risk taking behaviors that are of primary interest in adolescents, it was chosen because there are well-established literatures regarding inter-relationships between it, COMT, and dopamine, allowing for more straightforward developmental inferences. However, similar models could be derived for other behavioral domains, particularly those associated with the processing of motivational signals, and other neurochemical systems.