Adolescents and Addiction

Adolescence is a time of life associated with many changes both physically and behaviourally. It is defined by the World Health Organization as the age between 10-19 years of age, but more broadly, researchers define adolescence as anywhere between 10-24, which correlates to the age at which scientists feel the brain has fully matured. The behavioural changes, including risk taking and sensation seeking often associated with adolescence, concomitant with the dramatic physical changes occurring in the brain create a the window of vulnerability. The combination of adolescent-onset drug use and this vulnerability results in a significantly higher rate of lifetime addiction. If drug use is initiated under the age of 13, for example, the probability of a lifetime abuse problems is about 35%, decreasing substantially to 15% if the age of onset is 17 years old; by adulthood a person is four times less likely to have an addiction problem than the early onset users.[1] These figures illustrate the importance in understanding the causes and implications of adolescent drug use and that adolescents seem to be highly vulnerable to forming addictions. Governments around the world are concerned with the personal, social, and health costs related to addiction and much research effort is directed towards causes and prevention. The implications of recent studies suggesting that adolescent drug onset is becoming younger are therefore particularly concerning.[2]

Adolescent Addiction Stories
Figure 1, Foundation for a Drug Free World

The Window of Vulnerability

Behavioural Changes

The onset of puberty, with all of its hormonal changes, brings huge physical and behavioural changes. Children on the way to adulthood are emotionally and behaviourally distancing themselves from their parents, developing independence and a sense of “self”. Peers become increasing important. Adolescence is associated with novelty seeking and risk-taking and is the time when most teens are introduced to and experiment with drugs.

Adolescent behaviours appear to have an evolutionary element to them. Studies have shown many mammalian species show similar behaviour in adolescence. It is hypothesized that the importance of peer groups and conforming to peer behaviours associated with adolescence is linked with the drive to reproduce: finding a sexual partner. As a strategy to avoid inbreeding depression, it is suggested that risk-taking and novelty seeking facilitates the adolescent’s willingness to leave the safety of the family and familiar surroundings.[3]

Structural and Developmental Changes

The Changing Adolescent Brain
Figure 2, D News

The underlying neurobiology concerned with the adolescent behaviour and window of vulnerability is not well understood. The structural changes in the adolescent brain are the focus of intensive research, but answers are still far from clear. What is known is that the brain is undergoing tremendous change and remodelling. Grey matter volume reduces due to significant “synaptic pruning” in order to simplify the neural circuitry.[4] This synaptic pruning is paired with the strengthening of remaining synapses and leads to enormous plasticity in the adolescent brain. Both NMDA and dopamine receptors decrease in density in the dorsolateral prefrontal cortex (DLPFC),[5] and there are significant differences in the signaling of the neurotransmitters glutamate, GABA and dopamine.[4] White matter increases with myelination of intracorticial axons (which continues into adulthood).[6]

Importantly, specific areas of the brain are maturing and being rewired at different rates. In addition to the maturation of specific cortical structures, synaptic circuitry between the DLPFC and the mesocorticolimbic system is being dramatically altered. This circuitry is the last to fully mature at about 17 years. These two regions of the brain control very different behavioural functions. The PFC is the area involved in higher cognitive processes, reasoning, decision-making and working memory. The mature PFC is involved in impulse control and the suppression of inappropriate behaviour.[7] The mesocorticolimbic system is involved in rewards and emotions, and is also undergoing tremendous change. This difference in development between the immature cognitive functioning of the PFC and the reward/emotional high input areas of the mesocorticolimbic system is hypothesized to be a contributing factor to risk-taking during adolescence.[6] For example, MRI imaging has shown a significant increase in amygdala activity in adolescents versus adults in cognitive tasks that involve an emotional component.[7]

Adolescent Binge Drinking & the Hippocampus

Binge Drinking
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Figure 3

One of the most popular drugs during adolescence is alcohol.[8] According to a report completed in 2012, 70% of Grade 12 students had consumed alcohol and 33% had been drunk in the past month.[5] The most common pattern of drinking in adolescents and young adults is binge drinking. It is estimated that 44% of college students binge drink every two weeks, and more than half of teens aged 12-17 do so. Binge drinking is defined as having 5 drinks in one time frame for males (4 for females), and has been implicated as an early step towards alcohol abuse. Cognitive problems such as memory and learning deficiencies appear in adolescents who meet the clinical measures of an alcohol abuse disorder within only a few years of binge drinking. These deficits are associated with hippocampal and PFC grey matter size reduction.[6][9]

Notably, research suggests that the pattern of habitual binge drinking often continues into adulthood, so there is increased likelihood of addiction. Clinical reports indicate that adolescents between 16-19 who binge drink are six times more likely to experience depression.[10] Given this adolescent pattern of alcoholic intake and the seriousness of the ramifications, researchers have focused substantial research on mimicking it in animal models in an attempt to determine what effects binge drinking may have on the human adolescent brain to aid in prevention and treatment. The hippocampus in particular has been an area of intense focus, with many studies indicating it is especially susceptible to alcohol-related damage. [5][11][12]

Inhibition of Hippocampal Neurogenesis in the Dentate Gyrus

Cell Survival Rate 28 d after binge treatment
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Figure 5, Light Bars-Control, Dark Bars-Alcohol[14]

New cell proliferation 1 hr after binge treatment
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Figure 4,[14]

Postnatal neurogenesis takes place in two areas of the brain: the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus, an area involved in learning and spatial and working memory.[10][13] Many researchers feel that neurogenesis and the neural stem cells (NSC) produced in the dentate gyrus are implicated in hippocampal function.[14] A cogent report done by Morris et al. in 2010[14] found in a rat model of binge drinking, there was a 21% decrease in new cell proliferation immediately after binge treatment as compared to a control group. This suggests that there was a decrease in the number of cells in the S-phase (when DNA is replicated) of cell proliferation in the dentate gyrus. The group did a follow-up measurement of the BrdU-stained cells after 28 days – the generally accepted time required for new neurons to be incorporated into the existing hippocampal neuronal network as mature neurons. They found that there was over a 50% decrease in the number of neurons compared to control, with three markers of cell death significantly higher than controls. Importantly, the markers indicated that death was not apoptotic but necrotic, suggesting death was caused by damage. These findings indicate that binge-pattern alcohol consumption both inhibits new cell proliferation and reduces the survival rate of newborn neural cells. The authors postulated that the reduction of neurogenesis is responsible for the reduced hippocampal grey matter volume seen in adolescent (but not necessarily adult) alcohol abuse brains. McClain et al.[15] followed up the Morris experiment in 2011 finding a significant reduction in the length of S phase in the cell cycle and in the proportion of cells in S phase compared to cells in other stages of the cell cycle which led to a reduction of total cell cycle length. Their conclusion was that cell death pathways were triggered, perhaps by damage caused to daughter cells in the accelerated cell cycle, diminishing the survival rate of the neural progenitor cells, and therefore reducing hippocampal neurogenesis.

Non-human primate models also support the rodent models. A report by Taffe et al.[16] demonstrated marked neural degradation (11) months after the end of the binge drinking treatment, with a reduction in the neural progenitor pool. Changes were seen in the proportion of neural progenitor cells in different stages of development. A reduction of radial glial-like cells, the source of neural proliferation, was an important finding. In addition to illustrating lower levels of neurogenesis, they confirmed that the decrease in the survival of neural progenitor cells not due to apoptosis. Although more research is needed, the current thinking is that the hippocampal volume reduction is at least in part caused by the decrease in neurogenesis in the SGZ.

Alteration of Microglial Morphology in the Hippocampus

Microglia moving to injury site
Figure 5. Davalos et al. 2005[18]

Microglia function as the brain’s immune cells, patrolling the CNS for any disturbances in homeostasis that might be threatening. Upon activation caused by changes in the CNS environment, microglia of certain phenotypes undergo a change in their morphology, producing a graded inflammatory immune response. The severity of the response depends on the degree of perceived injury, and causes cytokine production and upregulation of cell receptors.[17] In addition to their function as immune cells, microglia support adult hippocampal neurogenesis. Microglial activation and its subsequent change in morphology is a controversial area in the study of neurodegeneration. There is debate whether the changes in morphology that occur upon microglial activation cause neurodegeneration or whether the neurodegeneration causes the microglial activation. Because microglia are a marker in most neurodegenerative diseases,[15] researchers are looking at the effects binge drinking may have on them.

A study by researchers[15] found that binge drinking in an adolescent rat model induced proliferation of microglia in the dentate gyrus, hilus, CA1 and CA3 regions in the hippocampus. As much as four weeks later (in adulthood), 61% of the neural cells in the dentate gyrus (which were proliferating at treatment as stained by BrdU) were microglial cells, compared to only 2% in the control group. In addition, morphological changes were seen in microglial cells immediately after treatment, which were retained into adulthood, demonstrating long-lasting changes in microglia. The researchers proposed that the microglia were sensitized to an “intermediate stage” of activation, and hypothesized that this state of readiness could predispose the brain to an inflammatory reaction at some later time. This implies that an overly sensitive immune reaction created by this intermediate stage of activation could cause further neurodegeneration later in life in adolescent-onset binge drinkers. Microglial research is continuing to receive a lot of attention as researchers enquire into whether alcohol or other drug abuse could cause the presence of microglial-induced proinflammatory cytokines.

Microglia & TLR4 Signaling in the Nucleus Accumbens

In addition to the potential of producing proinflammatory cytokines in the CNS in their role as immune cells, there has been a substantial body of research implicating microglia as having a role in drug-induced reinstatement. Research supports the argument that people who begin using drugs during adolescence have a significantly higher probability of relapse, and thus a higher probability of becoming addicted.[19] The research demonstrates that TLR4 receptors on microglia in the nucleus accumbens (a component of the important reward pathway) become upregulated in adolescent-onset morphine use, inducing an inflammatory reaction and creating long-lasting changes in microglial function. The data also indicates that, in the presence of a glial proinflammation inhibitor, upregulation of TLR4 receptors is prevented, as is the higher probability of relapse. This research strongly implicates microglial activity, via TLR4 receptors, as a factor in relapse and addiction.


Damage to many receptors, including dopamine D2 receptors, nicotinic, CB1 cannabinoid, µ-opioid, AMPA and glutamatergic GABA and NMDA receptors,[20] has been implicated in both adult and adolescent studies of drug addiction. Once again, there are significant differences in the mechanisms of adolescent (rat) brains both during treatment and in withdrawal.

For example, NMDA receptor subunit alterations may be part of the reason for cognitive deficits seen in adolescents with alcohol abuse problems. The age-related differences in NMDA receptor subunits in early adolescent alcohol use include a downregulation of the NR1 and NR2A subunits in the hippocampus, not seen in adult onset alcohol abuse.[8] These subunits comprise the synaptic NMDA receptors at the postsynaptic density and are strongly implicated in long term potentiation (LTP), learning and memory. Other studies have shown alcohol triggers Sigma-1 receptors, which inhibit the excitatory signals that trigger action potentials during LTP. Again this effect was seen in adolescent, but not adult brains.[21] This suggests that, by virtue of their involvement with LTP, both NMDA receptor downregulation and Sigma-l receptor upregulation may be a cause of the cognitive deficiencies seen in adolescent drug use.

Adolescent Addiction Treatments

Supportive Parenting in Recovery
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Figure 6

Research suggests that adolescents require strategies specific to their age group to maximize their chances of successful abstinence.[22] Clinical practitioners generally agree that for a given severity of addiction, adolescents require greater intensity of treatment than adults.[2] Over the last twenty years, there has been considerable attention on finding ways to treat adolescents. One of the problems is that unlike addicted adults, adolescents arriving for treatment almost never enter voluntarily, but are referred by a parent, school office or community institution.[2] Therefore there may be less commitment to an abstinence program. The strategy for clinical treatment focuses on moving the adolescent to a more receptive frame of mind in which to accept behavioral change. [23]

After initial treatment, family-based behavioral therapy models have proved to be the most effective treatment for adolescent drug abuse. High levels of supportive parenting have consistently shown a reduction in the probability of relapse. Without the commitment of parents, adolescents show less than 10% participation with maintenance programs.[24][25]

1. Grant, B.F. & Dawson, D.A. Age of onset of drug use and its association with DSM-IV drug abuse and dependence: results from the national longitudinal alcohol epidemiologic survey. Journal of Substance Abuse 10, 163-173 (1998).
2. Muck, R. et al. An overview of the effectiveness of adolescent substance abuse treatment models. Youth & Society 33, 143-168 (2001).
3. Spear, L.P. Rewards, aversions and affect in adolescence: emerging convergences across laboratory animal and human data. Development Cognitive Neuroscience 1, 390-403 (2011).
4. Sturman, D.A. & Moghaddam, B. The neurobiology of adolescence: changes in brain architecture, functional dynamics, and behavioral tendef corticolimbic circuitry and behavior. Neuroscience 249, 3-20 (2013).
5. Gulley, J.M. & Juraska, J.M. The effects of abused drugs on adolescent development of corticolimbic circuitry and behavior. Neuroscience 249, 3-20 (2013).
6. Dayan et al. Adolescent brain development, risk-taking and vulnerability to addiction. Journal of Physiology - Paris 104, 279-286 (2010).
7. Casey, D.J. Galvan, A. & Hare, T.A. Changes in cerebral functional organization during cognitive development. Current Opinion in Neurobiology 15, 239-244 (2005).
8. Pian, J.P. et al. N-Methyl-D-Aspartate receptor subunit expression in adult and adolescent brain following chronic ethanol exposure. Neuroscience 170, 645-654 (2010).
9. Nixon, K. & McClain, J.A. Adolescence as a critical window for developing an alcohol use disorder: current findings in neuroscience. Current Opinion in Psychiatry 23, 227-232 (2010).
10. Briones, T.L. & Woods, J. Chronic binge-like alcohol consumption in adolescence causes depression-like symptoms possibly mediated by the effects of BDNF on neurogenesis. Neuroscience 254, 324-334 (2013).
11. Crews, F.T., Mdzinarishvili, A., Kim, D., He, J. & Nixon, K. Neurogenesis in adolescent brain is potently inhibited by ethanol. Neuroscience 137, 437-445 (2006).
12. Ehlers, L.L., Liu, W., Wills, D.N. & Crews, F.T. Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood. Neuroscience 244, 1-15 2013.
13. Whitlock, J.R., Heynen, A.J., Shuler, M.G. & Bear, M.F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093-1097 (2006).
14. Morris, S.A., Eaves, D.W., Smith, A.R. & Nixon, K. Alcohol inhibition of neurogenesis: a mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model. Hippocampus 20, 596-607 (2010).
15. McClain, J.A., Hayes, D.M., Morris, S.A. & Nixon, K. Adolescent binge alcohol exposure alters hippocampal progenitor cell proliferation in rats: effects of cell cycle kinetics. The Journal of Comparative Neurology 519, 2697-2710 (2011).
16. Taffe, M.A. et al. Long-lasting reduction in hippocampal neurogenesis by alcohol consumption in adolescent nonhuman primates. Proceedings of the National Academy of Sciences of the United States of America 107(24), 11104-11109 (2010).
17. Marshall, S.A. et al. Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: the importance of microglia phenotype. Neurobiology of Disease 54, 239-251 (2013).
18. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8(6), 752-758 (2005).
19. Schwarz, J.M. & Bilbo, S.D. Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addition. The Journal of Neuroscience 33, 961-971 (2013).
20. Marco, E.M. & al. Neurobehavioral adaptations to methylphenidate: the issue of early adolescent exposure. Neuroscience and Biobehavioral Reviews 35, 1722-1739 (2011).
21. Sabeti, J. Ethanol exposure in early adolescence inhibits intrinsic neuronal plasticity via Sigma-1 receptor activation in hippocampal CA1 neurons. Alchololism-Clinical and Experimental Research 35(5), 885-904 (2011).
22. Hser, Y.I. et al. An evaluation of drug treatments for adolescents in 4 US cities. Arch Gen Psychiatry 58, 689-695 (2001).
23. Bukstein, O.G. et al. Practice parameter for the assessment and treatment of children and adolescents with substance use disorders. J.Am. Acad. Child Adolesc. Psychiatry 44(6), 609-621 (2005).
24. Rowe, C.L.. Family therapy for drug abuse: review and updates 2003-2010. Journal of Marital and Family Therapy 38, 59-81 (2012).
25. Gonzales, R., Anglin, M.D., Glik, D.C. & Zavalza, C. Perceptions about recovery needs and drug-avoidance recovery behaviors among youth in substance abuse treatment. Journal of Psychoactive Drugs 45(4), 297-303 (2013).

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