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Consequences Of Adolescent Drug Use
Translational Psychiatry volume 13, Article number: 313 (2023) Cite this article
Abstract
Substance use in adolescence is a known risk factor for the development of neuropsychiatric and substance use disorders in adulthood. This is in part due to the fact that critical aspects of brain development occur during adolescence, which can be altered by drug use. Despite concerted efforts to educate youth about the potential negative consequences of substance use, initiation remains common amongst adolescents world-wide. Additionally, though there has been substantial research on the topic, many questions remain about the predictors and the consequences of adolescent drug use. In the following review, we will highlight some of the most recent literature on the neurobiological and behavioral effects of adolescent drug use in rodents, non-human primates, and humans, with a specific focus on alcohol, cannabis, nicotine, and the interactions between these substances. Overall, consumption of these substances during adolescence can produce long-lasting changes across a variety of structures and networks which can have enduring effects on behavior, emotion, and cognition.
Adolescence is a period of critical development in the brain and body. Developmental changes in the brain lead to adolescents exhibiting heightened impulsiveness, which can lead to risky behaviors that may have long-term consequences [1, 2]. In particular, the use of both licit and illicit substances in adolescence can produce both acute and enduring effects on brain function and behavior. Of great concern is the fact that the prevalence of substance use disorders as an adult is greater if substance use is initiated during adolescence [3], however, other issues can persist into adulthood both related and unrelated to continued use. Alcohol, cannabis, and nicotine are among the most commonly used substances in adolescents, in part due to their availability, perceived lack of risk, and use in social settings [4].
Importantly, these substances act on receptors widely expressed in the brain (i.e. dopamine, GABAergic, and glutamate receptors), particularly in regions important for reward and cognition. Moreover, these receptor systems and brain regions undergo critical developmental changes during adolescence including a reduction in gray matter volume (GMV) [5] accompanied by an increase in white matter volume [6], changes in connections from subcortical to cortical circuits for emotional control [7], elimination of excess neural connections [8], refinement of the GABAergic system in the neocortex [9, 10], increases in dopamine (DA) receptor expression [11, 12], and development of the mesocorticolimbic system [13], to name a few. The molecular and structural changes in the brain are accompanied by changes in mood, behavior, and cognition, including heightened reward sensitivity [14], reduced inhibitory control [15, 16], and deficits in executive function relative to adults [17]. Furthermore, increases in sex hormones, such as testosterone and estrogen, have been shown to influence the brain’s response to reward [18, 19]. These changes in the brain and behavior make adolescents particularly likely to engage in substance use and susceptible to the long-term negative consequences of drug use. Given the potential societal impact of adolescent drug use, a number of researchers have investigated the long-term consequences of adolescent drug exposure in both clinical and preclinical studies. Indeed, several recent reviews have highlighted much of this research [20,21,22,23,24,25], so the present review is focused on the most recent work investigating the consequences of adolescent use of alcohol [Tables 1 & 5], cannabis [Tables 2 & 5], nicotine [Tables 3 & 5], or polysubstance combinations [Tables 4 & 5] in the human, non-human primate.
Alcohol
Alcohol is one of the most commonly used recreational drugs in the world, with adolescents constituting a large group of consumers. However, alcohol has neurotoxic effects and can modify a number of structures and circuits in the brain, including the mesocorticolimbic and striatal systems [26,27,28]. During adolescence, important changes occur in brain circuits that respond to stress and emotional stimuli, which are sensitive to alcohol exposure [29]. Furthermore, there is a well-established relationship between adolescent alcohol exposure (AAE), brain development, and cognitive functioning [20, 30], as well as data indicating that AAE is associated with increased rate and severity of stress-related psychopathologies [31]. AAE also increases future alcohol consumption in rodents [32, 33], as well as humans [34]. Importantly, adolescents are less sensitive than adults to many of the intoxication cues that suppress drinking, such as motor-impairment, sedation, and hangover, and are more sensitive to the reinforcing effects of alcohol, such as social facilitation [35], which may explain why both human and laboratory animal adolescents will consume more alcohol (relative to body weight) per session of drinking than their adult counterparts [36]. Of equal importance is that repeated AAE can cause neuroinflammation via the release of pro-inflammatory cytokines, which can disrupt synaptic plasticity and lead to neuropathology and cell death [37,38,39].
In addition, AAE is known to trigger a series of behavioral effects than can often persist into adulthood, many of which are related to anxiety- and depression- like behavior [40,41,42,43,44]. For example, AAE is associated with increased rates of major depressive disorder [45, 46], particularly in females [47]. Studies in animal models suggest that these effects may have multiple sources, one of which is changes in glucocorticoid receptor density and corticotropin-releasing factor (CRF) expression [48]. For example, AAE via two-bottle choice has been shown to increase glucocorticoid receptor densities in the prelimbic cortex (PL), the paraventricular nucleus (PVN), the central amygdala (CeA,) and the basolateral amygdala (BLA) in both late adolescent and adult mice, as well as lead to higher levels of CRF expression in the PVN and CeA in male mice [42]. In addition to directly contributing to the development of anxiety- and depression-like behaviors, AAE can indirectly contribute to the development of anxiety- and depression-like behavior by altering the effect of stress on the brain, particularly in the nucleus accumbens (NAc). Voluntary AAE in rats has been reported to increase dopamine (D)1 receptor expression while decreasing D2 receptor expression in the NAc and alter postsynaptic excitatory signaling following stressors [49]. Epigenetic modifications have also been linked to AAE’s long-lasting effects on anxiety- and depression-like behavior. For example, AAE can lead to long-lasting histone modifications that alter synaptic function in the amygdala and likely contributes anxiety-like behavior [50]. Recent evidence points to AAE-induced epigenetic repression of the synaptic activity response element (SARE) within the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) in the central amygdala (CeA) [51, 52] as a critical mediator for anxiety-like behavior. Bohnsack and colleagues [52] found that restoring histone acetylation at the Arc SARE site of the CeA following voluntary AAE in male rats caused a reduction in anxiety-like behavior and excessive drinking to control levels.
AAE also has long-lasting effects on cognitive abilities [53]. Recent studies have reported deficits in recall of an extinguished fear response [54], deficits in reversal learning [43], and impaired working memory [55, 56] following AAE. Unsurprisingly, alcohol’s effect on the medial prefrontal cortex (mPFC) is an important factor in producing these cognitive deficits [57]. Indeed, AAE has been reported to cause a myriad of effects in the mPFC, including greater PL spine density [54], decreased infralimbic cortex (IL) spine density [58], altered PL pyramidal neuron excitability [55, 59], activation of microglia and pro-inflammatory factors [60], decreases in resting state connectivity between PFC subregions [61], and decreases in myelinated fiber density (in males but not females) [62]. AAE also impacts the hippocampus, which is critical in supporting cognitive abilities [63]. Researchers have found that AAE inhibits neurogenesis throughout the hippocampus [64, 65], produces long-lasting reductions in dendritic spine density and alterations in morphology [66], increased levels of astrocytic glial fibrillary acidic protein (GFAP), and decreased levels of brain-derived neurotrophic factor (BDNF) [56].
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