Adolescent neurodevelopmental vulnerability; Peri-adolescent psychopharmacology
Adolescence is a major developmental phase in which the body, brain, mind, and behavior of the child progress to those of an adult. Although it has long been known that mental functioning and behavior differ significantly between children and adults, an emerging body of evidence indicates that these changes are driven by changes in brain architecture and function. To the extent that these changes are the most robust in, or exclusive to, adolescence, this phase may also represent a context in which drugs impacting the central nervous system produce especially potent and long-lasting alterations.
Current Concepts and State of Knowledge
Adolescence encompasses the growth and alteration of many neural and somatic systems and spheres of function that evolve with differing developmental timelines both within and between individuals (Cicchetti and Cohen 2006). Given this complexity, precise definitions of its start and end are elusive. Adolescence is a phase of continuous change within a lifespan of continuous change, while cultural-legal demarcations of the onset of adulthood vary widely. Behavioral neuroscience assumes a general concept of peri-adolescence as the passage of the individual from characteristics of mind, brain and behavior specific to, and shared among, children of different ages (i.e., from birth to ages 10–15) to characteristics shared among healthy adults (i.e., from age 18 to 25 and older) (Erickson and Chambers 2006; Romer and Walker 2007). Fundamentally, children are the recipients of teaching and caretaking; their role is to learn about their environment through instruction and play while inviting and acquiescing to caretaking. Adults are the providers of teaching and caretaking; their role is to manipulate, and work within, the environment in the service of caretaking. Between these age ranges (from approximately 13 to 23 years), adolescent neurodevelopment revises the brain from a design best adapted to play, learning, experimentation, and receiving care to one best adapted to acting on what has been learned and delivering care.
Changes in Mind and Behavior
Adolescent neurodevelopment involves changes spanning multiple spheres of higher-order central nervous system function and anatomy, including those that subserve cognition, emotion, and motivation (Romer and Walker 2007). Cognition in childhood, initially dependent on concrete interpretations of the physical world and yet prone to fantasy and make-believe, becomes increasingly efficient and accurate with respect to classifying and predicting complex contingencies. Emotions are used less unidimensionally for engendering caretaking or exploring relationships with specific caregivers. They become more complex, and at times volatile, both for asserting independence from caregivers and for experimenting with and learning effective emotional conduct across a potentially large variety of peer and other social relationships spanning diverse personal and occupational domains (Nelson et al. 2004). Motivation becomes extremely sensitive to novelty and social competition, especially with respect to stimuli or situations that characterize adult social, sexual, or occupational roles and skill sets (Chambers et al. 2003). Reflecting a desire to achieve adult abilities, and even adult levels of power, the adolescent is motivated to act as an adult, even though prior experience has been largely limited to imaginative play and verbal or role-modeled instruction. Instead of playing with toy cars, the adolescent is suddenly motivated to drive real ones.
Changes in Brain Form and Function
Profound changes involving multiple brain regions underlie the adolescent transformation. Those changes occurring in the prefrontal cortex (PFC) are currently the best characterized (Erickson and Chambers 2006; Romer and Walker 2007). The PFC functions as the brain’s closest analogue to the central processing unit of a computer; it governs decision-making and regulates cognitive working memory, attention, and emotional awareness. Its central functional role and high degree of connectivity with a diversity of cortical and subcortical brain regions, which are more directly specialized in memory formation, emotion, and motivation, probably relate to its keystone position as the last cortical structure to undergo significant micro- and macrostructural revision prior to adulthood. Within the PFC, both excitatory and inhibitory neurons undergo shifts in patterns of connectivity, in which many short-range connections are eliminated (e.g., synaptic pruning) and long-range (e.g., transcortical) connections undergo final stages of myelination, rendering them more efficient for transferring information. Macrostructurally, these changes correspond to overall declines in PFC energy demands and PFC gray matter thickness. In totality, these changes correspond to the development of greater computational efficiency, adult cognitive styles, and the ability of PFC cognitive processes to intervene in or regulate complex emotional and motivational processes.
While research on developmental changes within subcortical regions primarily involved in memory formation (e.g., hippocampus), emotion (e.g., amygdala), and motivation (e.g., nucleus accumbens/mesolimbic dopamine system) is itself in an early developmental stage, growing evidence indicates that, like the PFC, all of these regions undergo peri-adolescent developmental revision (Cicchetti and Cohen 2006; Nelson et al. 2004). Changes spanning these areas include alterations in intrinsic and extrinsic neural connectivities involving multiple neurotransmitter, neuropeptide, and neurohormonal systems that collectively change the way these regions process information and communicate with each other and the PFC. For example, parameters of dopamine neurotransmission into the PFC and nucleus accumbens undergo peri-adolescent maturational changes implicated in the particularly robust aspects of adolescent motivation, such as behavioral sensitivity to novel stimuli (Romer and Walker 2007). While both the hippocampus and the amygdala are richly endowed with neurohormonal receptors related to stress responsivity (e.g., corticosteroids) and sexuality (e.g., estrogens and androgens), peri-adolescent changes in the levels and regulation of these hormones can have profound effects on cellular and local circuit functions (Chambers et al. 2003; Nelson et al. 2004). These changes in turn contribute to adolescent-age alterations in emotional, social, and sexual behavior and related motivational programming, as mediated in part via the connectivity of the hippocampus and the amygdala with the nucleus accumbens and PFC.
An important aspect shared among these modulatory neurotransmitters and neurohormonal factors is that they are powerful inducers and facilitators of neuroplasticity. While the information processing and learning and memory functions of neurons and local neural connections throughout the central nervous system are most directly carried by changes in the way excitatory and inhibitory transmitters (e.g., glutamate and GABA) send signals between individual neurons, these modulatory factors (e.g., dopamine and corticosteroids) can produce more broadly distributed influences on the manner, scope, quality, and depth of local neuroplastic changes. These effects are observable on the molecular, cellular, and physiological levels as changes in cellular mechanisms that govern glutamatergic/GABA transmission, neural firing properties, dendritic arborizations of individual neurons, birth of new neurons, and stimuli-induced activation patterns spanning whole neural networks. Thus, by hierarchically influencing mechanisms of local plasticity in a way that is broadly distributed throughout multiple brain regions in a coordinated fashion, these modulatory systems likely play a key role in the global theme of structural revision in adolescent neurodevelopment. Understanding how these neuromodulatory factors are themselves changed during adolescence, as a result of developmentally timed and environmentally triggered changes in gene expression, will increasingly form the focus of future research on adolescent neurodevelopment.
Impact of Drugs During Peri-Adolescent Neurodevelopment
Peri-adolescent changes in neural system function, architecture, and plasticity, unparalleled by neural events in middle childhood or adulthood, may reflect a transition that relates to the flexibility-stability dilemma, a fundamental concept of theoretical neuroscience. In this concept, neural systems are thought to operate optimally in the service of one of two goals: learning new information (flexibility) versus acting on what has been learned (stability) (Liljenstrom 2003). Importantly, while the brain is capable of serving both of these goals to some extent, it cannot serve them both to the highest degree possible simultaneously. The vast yet limited biological resources of the brain, and physical rules of neuroinformatics, would require that the brain operate in a way that optimizes one goal at the expense of the other. By developmental design, flexibility is favored in childhood, while stability is most adaptive in adulthood. In adolescent neurodevelopment, the brain must undergo a considerable revision of architecture and function to shift the brain toward the stability goal. During this phase, the artificial (e.g., pharmacological) perturbation of neural processes and systems, particularly those that impact the neuroplasticity of cognitive, motivational, and emotional substrates, could produce effects that are thereafter “locked-in,” in a semipermanent way, as the brain shifts its design toward the stability goal.
Impact of Drug Exposure on Motivation and Addiction Vulnerability
The most clear and broad-based evidence for such a pharmacological effect is the heightened capacity of addictive drug exposure during adolescence for determining future motivational programming with respect to the acquisition of addictive disorders (Chambers et al. 2003). The vast majority of adult-age addictions begin in adolescence (ages 15–25). Greater accumulated dose of drug exposure, earlier exposure, and the extent of multidrug experimentation during adolescence are all risk factors for adult addictions.
The advancement in our understanding of this developmental age vulnerability to addictions has been informed in part by research on dual diagnosis in mental illnesses such as schizophrenia, which involve both peri-adolescent developmental onset and high rates of addiction comorbidity. Adolescence is a normative period of heightened novelty seeking, behavioral disinhibition, and risk taking, all serving as component manifestations of the more general construct of impulsivity (Erickson and Chambers 2006). Impulsivity, whether occurring in normative adolescence or as an abnormal feature of adult mental illness, is a general trait marker of addiction vulnerability (Erickson and Chambers 2006; Redish et al. 2008). Moreover, it is often a manifestation of those immature or dysfunctional PFC substrates that are responsible for decision-making and response inhibition. As reviewed earlier, during adolescence the PFC is normally immature and thus incapable of adult levels of decision-making and behavioral control. At the same time, subcortical motivational systems (e.g., the nucleus accumbens/dopamine system) are operating in a particularly robust manner. This not only allows motivational programming to be relatively sensitive to novel or other reinforcing stimuli that promote dopamine transmission. By virtue of the capability of dopamine itself to regulate neuroplastic events in the PFC and nucleus accumbens, this robustness of function may also facilitate changes governing maturational plasticity underlying the installment of stable, long-lasting, motivational repertoires (Chambers et al. 2003, 2007). In adolescence, this scenario may be viewed simplistically as a car acquiring an accelerator before it acquires adequate brakes. Of course, only the accelerator can make the car go and give the driver cause for needing, and learning how and when to apply, the brakes. In normative adolescent neurodevelopment, this developmental plan, in which the PFC matures under conditions of robust motivational function, is thought to be a necessary aspect of initiating experiential-action learning, with all of its hazards (Chambers et al. 2003). With addictive drug exposure and by virtue of the shared pharmacological effect of addictive drugs to further augment dopamine transmission and exert neuroplastic effects, motivational-behavioral repertoires (and underlying neural systems) are potently and more semipermanently sculpted to include drug seeking and taking as frequent behavioral options (Chambers et al. 2007).
Impact of Drug Exposure on Cognition and Emotion
The centrality of dopamine in both natural motivation and in the reinforcing properties of drugs with diverse psychoactive and pharmacological profiles (e.g., nicotine, alcohol, cocaine, amphetamine, cannabinoids, and opiates) has rendered progress in our understanding of the responsiveness of adolescents to the motivational properties of drugs a relatively straightforward process. Expanding outward from this core of knowledge, research is beginning to explore the more complex task of understanding how adolescent neurodevelopmental change involving spheres of function other than motivation, and encompassing other neurotransmitter systems and brain regions, may make adolescents particularly vulnerable to long-lasting cognitive and emotional effects of drug exposure. In essence, this exploration is a contemporary variant of the long-pursued notion that drug use can cause or predispose to permanent acquisition of psychiatric illness or illness features. For many recreational drugs frequently used in the general population, this thesis has not proven easy to support with firm clinical and epidemiological data. However, new evidence detailing the unique and profound neurodevelopmental revision of the brain during adolescence, along with the recognition of the capacity of drugs to modulate cognitive and emotional functions during this developmental period, has renewed interest in this area. For instance, new findings indicate that peri-adolescent nicotine exposure can have an enduring impact on acetylcholine neurotransmission in the brain while producing long-lasting cognitive and emotional dysfunction potentially consistent with features of mental illness (Slotkin 2008). Similarly, alcohol as a drug active at glutamatergic and GABAergic synapses, and in a host of other neurotransmitter systems, may produce semipermanent cognitive and emotional changes (Clark et al. 2008). Since endogenous cannabinoids are robustly active in PFC and hippocampal networks as modulators of glutamatergic and GABAergic transmission and plasticity, marijuana smoking in adolescence could have particularly profound and long-lasting effects toward changing thresholds for developing mental disorders that involve these regions, including schizophrenia and depression.
As research on adolescent drug effects continues to evolve, it is expected that animal modeling, involving developmentally timed drug exposures in peri-adolescence, will play an especially crucial role in advancing understanding in this field, given the ethical boundaries, time and cost expenses, and lack of environmental control inherent to longitudinal prospective human studies. Examining adolescent developmental effects of recreational drugs is also expected to inform and inspire investigations that may reveal properties of therapeutic agents that may semipermanently ameliorate or abort illness trajectories for varieties of mental disorders of peri-adolescent onset or worsening.