The suppression of gaping by URB was reversed by pre-treatment with the CB1 antagonist/inverse agonist, SR141716A, suggesting a CB1 mechanism of action. URB also interfered with the establishment of conditioned gaping when administrated before each pairing of the contextual stimuli with LiCl. This finding was consistent with that recently reported by Cross-Mellor et al. demonstrating that URB interfered with the establishment of conditioned gaping elicited by exposure to a LiCl-paired flavor. Presumably, URB reduced the nausea produced by the LiCl resulting in weaker conditioning. The potential of CBD or URB to suppress the gaping reactions during re-exposure to the context previously paired with LiCl-induced nausea might also be accounted for by interference with memory for the previously established association, rather than by interference with conditioned nausea perse. The design of the present experiments cannot discriminate between these two potential mechanisms; however, a memory deficit explanation is less tenable in light of the finding in experiment 1 that the highest dose of CBD did not modify the expression of gaping. Furthermore, at a dose of 5 mg/kg CBD neither affected the acquisition nor retrieval of a floor-amphetamine association in a conditioned place preference task or of a flavor-lithium association in a conditioned taste avoidance task . Finally, Varvel et al. reported that mice pre-treated with the FAAH inhibitor, OL-135, as well as FAAH knockout mice with elevated central AEA levels,vertical farm equipment did not display memory impairment or motor disruption in a spatial memory task ; in fact, the FAAH knockouts displayed a significant increase in acquisition rate.
The unpleasant experience of AN reported by chemother apy patients may impact the patient’s resolve to continue treatment. Because classic anti-emetics such as OND have proven ineffective in the alleviation of AN, there is a need to develop effective pharmacotherapies. The current findings, along with past research provide support for the role of the EC system in the suppression of nausea to a context previously paired with illness. Through the use of the FAAH inhibitor URB, the action of AEA is prolonged, interfering with the expression of the conditioned gaping response to a context paired with illness, as a model for anticipatory nausea in rats. As URB administration modulates the EC system, it may be a preferred therapeutic over exogenously adminis tered cannabinoids, in the alleviation of conditioned nausea.The past 50 years of research supported by the National Institute on Alcohol Abuse and Alcoholism have resulted in an accumulation of invaluable data to address the multifaceted problems surrounding underage drinking. Youth use of alcohol remains a pervasive social and public health concern in the United States and a leading cause of disability and mortality during adolescence.Alcohol use in adolescence has a distinct pattern from adult drinking, whereby adolescents may have fewer drinking occasions but consume relatively high levels per occasion, referred to as binge or heavy episodic drinking and defined as consuming four or more standard ethanol consumption units on an occasion for females and five or more for males.Highly prevalent among youth in Western countries is an intermittent pattern of heavy alcohol consumption that typically is associated with social leisure occasions on weekend nights.6 Moreover, adolescent alcohol use, along with smoking and illicit drug use, has undergone changes in prevalence and patterns in recent decades.
For example, alcohol use peaked in the mid-1990s, with approximately 50% of 12th graders reporting past-month alcohol use, followed by a steady long term decline to 30% in 2018. In 2020, the downward trend reversed course, with 34% of 12th graders reporting past month alcohol use.1 Recent reports indicate that prevalence estimates for 2021 will need to account for impacts of the COVID-19 global pandemic on underage substance use behavior and availability.High-risk alcohol consumption patterns and associated problems alone increase risk for adverse outcomes—such as motor vehicle accidents, high-risk sexual behaviors, other illicit substance use, and mental health challenges—for adolescents who drink. These risks are further compounded by the fact that adolescence is a period of crucial brain development and maturation.Neuroimaging studies have provided clear evidence that the brain continues to develop throughout adolescence and into adulthood, and undergoes important structural and functional changes in synaptic plasticity and neural connectivity during adolescence. These changes and the enormous plasticity of the teen brain make adolescence a time of both great risk and great opportunity.This article begins with an overview of typical adolescent brain development, followed by a summary of four key themes in the current understanding of alcohol and the adolescent brain: predictors of underage drinking; consequences of alcohol on adolescent brain structure and function; moderating and confounding factors, including age of onset, sex disparities, family history, co-use of other substances, and mental health comorbidities; and reversibility of and recovery from alcohol misuse. The article concludes with a discussion of where the data lead us to reach the next milestones in NIAAA-supported research. The brain of an adolescent, much like teenage behavior, undergoes significant developmental changes.
This neurodevelopment continues after adolescence, typically until around age 25. The maturational processes in the brain occur in stages, with more basic functions maturing first and areas such as the lateral temporal and frontal lobes, which are responsible for higher cognitive function , developing later in adolescence.Its rate of change does not plateau until the third decade of life, in concert with typical developmental trajectories of cognitive abilities, such as decision-making, attention, and cognitive control.The late maturation of the prefrontal cortex has been linked to risky behavior during adolescence, particularly if the limbic subcortical system develops earlier.Executive functioning typically matures during this developmental stage,coincident with gray matter reductions and white matter growth.Functional magnetic resonance imaging studies of executive behaviors have demonstrated increasing prefrontal activity and better inhibitory control with adolescent age.Challenges in executive functioning have been observed in adolescents with a family history of alcohol use disorder ,repeated childhood trauma experiences,and poor sleep,all of which also have been identified as risk for adolescent binge drinking and AUD.Deficits in control circuitry have been linked to impulsivity, sensation seeking, and alcohol use into early adulthood.One of the studies investigating adolescent alcohol use and its effects is coordinated by the National Consortium on Alcohol and Neurodevelopment in Adolescence , which is conducting a multi-site longitudinal study supported by funding from NIAAA and other National Institutes of Health partner institutes. Launched in 2012, this five-site consortium recruited a community cohort of 831 diverse adolescents ages 12 to 21 from five U.S. regions . Half the sample was enriched for key characteristics conveying risk for heavy drinking among adolescents . Most of the sample reported very limited alcohol use at project entry; the remaining 15% exceeded typical age thresholds for alcohol at project entry in this cohort-sequential design.At project entry and annually thereafter, participants received neuroimaging , neurocognitive testing, detailed substance use and mental health interviews; provided urine samples for drug testing as well as saliva samples for genetics and pubertal hormone assays; and completed various self- and parent reports on personality, behaviors,vertical farm tower and environment.NCANDA will continue to examine the interactive effects of typical development as well as adolescent alcohol use and executive dysfunction into early adulthood. Resting-state fMRI findings from NCANDA and other studies have shown that intrinsic functional networks subserving cognitive control and limbic circuitry develop across adolescence and may be influenced by adolescent heavy drinking.Moreover, the adverse effects of alcohol may be more prominent in girls than in boys.Being able to identify youth at higher risk for alcohol misuse could lead to early intervention and ultimately help reduce the significant personal and public health burden of AUD; however, relatively few studies have explored individual-level precursors of adolescent alcohol use. Prospective longitudinal studies of substance-naïve youth are uniquely positioned to identify factors predating the onset of alcohol use. Squeglia et al. identified several markers of alcohol initiation by age 18 in 137 adolescents.These markers included demographic and behavioral factors , lower executive functioning, thinner cortices, and less brain activation in diffusely distributed brain regions. NCANDA seeks to expand on these findings using a greater number of measurements in a large sample to lead to more accurate individual-level forecasting. The consortium is employing machine learning models, which can avoid multiple-comparison correction and reduce measures to a single, individual-level prediction.
NCANDA developed a model that distinguished youth who drink heavily from those who drink little or no alcohol, based on patterns of macro-structural and micro-structural imaging metrics in multiple brain regions.The analyses suggested delayed development of white matter connectivity among the older youth in the sample who drank heavily, as well as increased risk of subsequent heavy drinking in youth with more externalizing symptoms. These findings fit closely with those from the IMAGEN Consortium, which found that variability in personality, cognition, life events, neural functioning, and drinking behavior features predicted Alcohol Use Disorders Identification Test scores at ages 14 and 16.Unlike white matter, gray matter volume peaks in the primary school-age years, around age 10.Squeglia et al. reported that youth who drank heavily showed accelerated reductions in gray matter volumes in cortical lateral frontal and temporal areas compared to those who drank no or little alcohol .These results were largely unchanged with co-use of marijuana and other drugs; also, similar patterns of developmental trajectory abnormalities existed in males and females. This finding was replicated in the NCANDA cohort, which examined the influence of alcohol use on gray matter structure in 483 adolescents ages 12 to 21 both before and 1 to 2 years after the onset of heavy drinking.For youth with no or low alcohol consumption, gray matter volumes declined throughout adolescence, with rates slowing in many brain regions in later adolescence. However, youth who initiated heavy drinking exhibited a steeper decline in frontal gray matter volumes. For both youth with no or low alcohol consumption and those with heavy drinking, cannabis use did not influence gray matter volume trajectories. These findings were confirmed in a recent analysis spanning five time points in the NCANDA study and using linear mixed effects models.A greater number of past-year binge drinking episodes was linked to greater decreases in gray matter volumes in 26 of 34 bilateral Desikan-Killiany cortical parcellations tested. The strongest effects were noted in frontal regions as well as among younger adolescents; moreover, the effects largely attenuated in later adolescence. The gray matter volumes decreased most for individuals with greater numbers of binge drinking episodes and recent binge drinking. These findings provide yet more evidence that adolescent binge drinking is linked to a greater risk of more prominent gray matter reductions during adolescence.Functional MRI studies further suggested that adolescents with histories of heavy drinking showed aberrant patterns of activation in response to cognitively challenging tasks,including tasks of working memory and inhibition. In adolescents with a history of 1 to 2 years of heavy drinking, the aberrant activation was not linked to detectable deficiencies in task performance. However, if heavy drinking persisted longer, reduced task performance was often evident in the adolescents.This pattern of results suggested that the brain may be able to compensate for subtle neuronal insults for a period of time, but if drinking patterns persist and become heavier, the brain may no longer be able to compensate and may be vulnerable to the effects of repeated and sustained heavy doses of alcohol.Throughout adolescence, white matter volume increases and matures, resulting in myelination that increases speed of neuronal transmission and modulates the timing and synchrony of neuronal firing patterns that convey meaning in the brain.Squeglia et al. reported that adolescents who drank heavily showed attenuated white matter growth of the corpus callosum and pons relative to adolescents who did not drink.Pfefferbaum et al. indicated that among those in the NCANDA sample who consumed no or little alcohol, white matter regions grew at faster rates in younger age groups and slowed toward young adulthood.To examine the potential for a neurotoxic effect of alcohol use on adolescent development of white matter, Zhao et al. conducted a whole-brain analysis of fractional anisotropy of NCANDA participants ages 12 to 21 at baseline.For 63 adolescents who initiated heavy drinking, the researchers examined white matter quality before and after drinking onset and compared it to the white matter maturation trajectory of 291 adolescents with no or low alcohol consumption.