Developmental Neurocircuitry of Motivation in Adolescence: A Critical Period of Addiction Vulnerability

OBJECTIVE: Epidemiological studies indicate that experimentation with addictive drugs and onset of addictive disorders is primarily concentrated in adolescence and young adulthood. The authors describe basic and clinical data supporting adolescent neurodevelopment as a biologically critical period of greater vulnerability for experimentation with substances and acquisition of substance use disorders. METHOD: The authors reviewed recent literature regarding neurocircuitry underlying motivation, impulsivity, and addiction, with a focus on studies investigating adolescent neurodevelopment. RESULTS: Adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity, and addiction. Adolescent impulsivity and/or novelty seeking as a transitional trait behavior can be explained in part by maturational changes in frontal cortical and subcortical monoaminergic systems. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. CONCLUSIONS: An exploration of developmental changes in neurocircuitry involved in impulse control has significant implications for understanding adolescent behavior, addiction vulnerability, and the prevention of addiction in adolescence and adulthoodProfound psychophysiological change occurs during adolescence. Adolescents acquire increasingly adult-like cognitive and emotional styles (104, 105) and become increasingly motivated by adult environmental stimuli (106). In childhood, motivation to play promotes nonparticipatory learning about adult experiences, a process that minimizes damaging outcomes (43). In adolescence, motivation to play progresses to participation in novel adult experiences, without the benefits of contextual experiential knowledge to guide decision making (107). From an adult perspective, novelty-driven adolescent behavior may seem of poor judgment and impulsive (34, 35).

Promotional Motivation Substrates
Developmental alterations in primary motivation circuitry during adolescence may promote novelty-seeking behavior and augment incentive motivational processes. Neuropsychiatric disorders involving central dopamine function follow developmental patterns consistent with this notion. Tic disorders, treated by blocking dopamine activity, are most prevalent in late childhood and early adolescence and tend to remit in adulthood (108). In contrast, the incidence of Parkinson’s disease, involving deficient dopamine function, increases with advancing age (57). That these observations reflect general developmental themes is supported by animal studies showing differences in peri-adolescent behavior involving dopamine systems function (109). Peri-adolescent rats show heightened exploratory behavior in a novel open field and engage more in social play than younger and older rats (110). Peri-adolescent rats show motoric hyporesponsivity to prodopaminergic agents and hypersensitivity to dopamine blockade, suggesting that their dopamine system operates at baseline closer to a functional ceiling before pharmacological challenge (110). Peri-adolescent mice show a greater baseline preference for novel environments than adult mice (111). Upon amphetamine treatment, adults show increases in novelty preferences and peri-adolescents exhibit decreases, preferring instead the familiar environment previously paired with amphetamine delivery (111). Peri-adolescent rats show greater behavioral sensitization and striatal dopamine release after repeated psychostimulant injections than adult rats (112, 113). Together, these findings suggest that adolescent experimentation with and vulnerability to addictive drugs involve developmental differences in dopamine system activity and sensitization.

Maturational differences in promotivational dopamine systems and inhibitory 5-HT systems may contribute to adolescent novelty seeking/impulsivity. CSF concentrations of dopamine and 5-HT metabolites decline during childhood and decrease to near adult levels by age 16 (114). However, the ratio of the dopamine metabolite homovanillic acid to the 5-HT metabolite 5-hydroxyindoleacetic acid increases, suggesting a higher rate of dopamine to 5-HT turnover (114). In monkeys, the density of dopamine-bearing presynaptic endings in the prefrontal cortex increases from one-half of adult levels at 6 months of age to adult levels by late adolescence (2 years), when the density of dopamine axonal input is approximately threefold that of 5-HT (115). In contrast, 5-HT production sites on prefrontal cortex neurons reach adult levels by the second week after birth (115). Together, these findings indicate that adolescence may be characterized by greater activity in promotivational dopamine systems than in inhibitory 5-HT systems.

Adolescent hormonal changes affecting secondary motivation circuitry may also contribute to promotivational functioning of dopamine systems. Sex steroid receptors mediating profound neuroplastic effects are highly expressed in the hippocampus and the hypothalamus (116, 117). Neuroplastic revision during puberty may alter representations of contextual motivational stimuli in these structures, changing the nature of motivational drives represented in primary motivation circuitry (118, 119). For example, surges in sex hormones contribute to greater sexual motivation, sensitivity to novel sexual and social stimuli, sexual competition, and adolescent aggression (43, 120, 121).

Hippocampal function may be important to sex-hormone-related changes in novelty-oriented behavior. By means of broad connectivity with the cortex, the hippocampus compares immediate environmental contexts with past memories to detect environmental novelty (122). Resultant information can become encoded in motivational drives by means of hippocampal regulation of the amplitude or impact of dopamine discharge into the nucleus accumbens or by direct influences on neuronal activity of the nucleus accumbens (51, 123, 124). This notion is consistent with anatomical and physiological data showing that hippocampal damage alters quantitative dopamine release into the nucleus accumbens and behavioral responses to novel environments (69). Together, these data suggest a mechanism by which hormonal conditions in specific stages of life (childhood, adolescence, adulthood) may influence promotivational dopamine systems to orient behavior most adaptive to the developmental stage.

Inhibitory Motivation Substrates
Changes in promotional motivation substrates occur concurrently with developmental events in the prefrontal cortex. In adolescence, the prefrontal cortex has not yet maximized a variety of cognitive functions that may include its capacity to inhibit impulses. Measures of prefrontal cortex function, including working memory, complex problem solving, abstract thinking, and sustained logical thinking, improve markedly during adolescence (104, 105, 125). Although the ability to inhibit psychomotor responses improves through childhood, peaking by late adolescence (126), more direct measures of adolescent impulsivity (e.g., decision making) remain largely unexplored.

Changes in brain anatomy and function correspond temporally to changes in cognitive function. Throughout adolescence, changes in EEG measures of cortical activity and responses to sensory stimuli are observed (104, 127). From ages 6 to 12, the ratio of lateral ventricle to brain volume remains constant; it then increases steadily from ages 12 to 18 (128). From ages 4 to 17, there is a progressive increase in white matter density in the frontal cortex, likely due to increased myelination of neurons and axonal diameters and contributing to increased efficiency of action potential propagation (129). Changes in brain metabolism reflecting altered neuroplasticity and information processing are also observed. Globally, the brain increases energy use, matching adult levels by age 2, increasing to twofold greater than adult levels by age 9, and declining to adult levels by the end of adolescence (130, 131). Compared to subcortical regions, cortical areas undergo similar but more pronounced temporal fluctuations of metabolic rates and exhibit these changes later, with frontal cortical regions transitioning last (131).

Gross developmental changes in the prefrontal cortex are paralleled by neuroplastic changes, as shown by densities of dendritic processes, synapses, and myelination, rates of neuronal membrane synthesis, and emergence of adult cognitive styles (129, 132–134). Declines in metabolic activity in frontal and other cortical regions may reflect synaptic pruning, whereby reductions are made in energy-consuming neuronal connections that do not efficiently transmit information pertaining to accumulating experience. In the human prefrontal cortex, synaptic density in major axonal reception zones increases to 17x108 per mm3 between the ages of 1 and 5 and declines to adult levels of 11x108 per mm3 by late adolescence (135). Synaptic pruning in peri-adolescent monkeys occurs in components of cortical microarchitecture indicative of specific effects on information processing (134). Reductions in prefrontal cortex synapses are greater for those of axons originating from local cortical regions rather than from distant association cortices and are proposed to reflect a relative increase in the reliance of local prefrontal cortex circuits on highly processed multimodal information (125). This feature may allow top-down processing, whereby a larger, more sophisticated repertoire of past experience stored in distant structures has greater computational influence (134). Peri-adolescent synaptic pruning decreases both excitatory and inhibitory inputs (136). These counterbalanced reductions may increase the stability of firing patterns of cortical neurons (137) and enhance the capacity for ensembles of prefrontal cortex neurons to fire in a sustained, concerted fashion (134, 138), facilitating short-term storage of an increasing amount of information. Consistent with this notion, improved working memory performance in adolescent monkeys corresponds positively with the percentage of prefrontal cortex neurons showing sustained activity during the task’s delay period (139).

Neural network simulations suggest that the increase in cortical interconnectivity in childhood followed by a decline to adult levels over adolescence reflects optimization of learning potential, corresponding to decreases in rates of neuroplastic change (125, 140). These processes determine a tradeoff between the capacity to learn new information versus that to use and elaborate on previously learned information (140). As accumulating information is stored in connections within neural networks, learning rates, or the capacities for neuroplasticity as represented by the number of synaptic connections, should decrease, resulting in a system that operates to prevent loss of previously learned information (140). Synaptic pruning and other developmental processes in the prefrontal cortex, concomitant with greater motivational drives toward novel adult experiences, may work in combination to facilitate adolescent acquisition of an increasingly sophisticated cognitive and perceptual understanding of the environment. Maturation of the prefrontal cortex is thus facilitated by motivational drives to participate in novel adult-like experiences, eventually leading to experience-based motivation that guides the enactment of more "appropriate" decision making