Adolescent Exposure Research Articles

Abuse-like toluene exposure during early adolescence alters subsequent ethanol and cocaine behavioral effects and brain monoamines in male mice

Currently, there is a gap in understanding the neurobiological impact early adolescent toluene exposure has on subsequent actions of other drugs. Adolescent (PND 28–32) male Swiss-Webster mice (N = 210) were exposed to 0, 2000, or 4000 ppm of toluene vapor for 30 min/day for 5 days. Immediately following the last toluene exposure (PND 32; n = 15) or after a short delay (PND 35; n = 15), a subset of subjects' brains was collected for monoamine analysis. Remaining mice were assigned to one of two abstinence periods: a short 4-day (PND 36) or long 12-day (PND 44) delay after toluene exposure. Mice were then subjected to a cumulative dose response assessment of either cocaine (0, 2.5, 5, 10, 20 mg/kg; n = 60), ethanol (0, 0.5, 1, 2, 4 g/kg; n = 60), or saline (5 control injections; n = 60). Toluene concentration-dependently increased locomotor activity during exposure. When later challenged, mice exposed previously to toluene were significantly less active after cocaine (10 and 20 mg/kg) compared to air-exposed controls. Animals were also less active at the highest dose of alcohol (4 g/kg) following prior exposure to 4000 ppm when compared to air-exposed controls. Analysis of monoamines and their metabolites using High Pressure Liquid Chromatography (HPLC) within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and ventral tegmental area (VTA) revealed subtle effects on monoamine or metabolite levels following cumulative dosing that varied by drug (cocaine and ethanol) and abstinence duration. Our results suggest that early adolescent toluene exposure produces behavioral desensitization to subsequent cocaine-induced locomotor activity with subtle enhancement of ethanol's depressive effects and less clear impacts on levels of monoamines.

Exercise leads to sex-specific recovery of behavior and pathological AD markers following adolescent ethanol exposure in the TgF344-AD model.

Human epidemiological studies suggest that heavy alcohol consumption may lead to earlier onset of Alzheimer's Disease (AD), especially in individuals with a genetic predisposition for AD. Alcohol-related brain damage (ARBD) during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study investigates if voluntary exercise in mid-adulthood can recover memory deficits caused by the interactions between adolescence ethanol exposure and AD-transgenes. Male and female TgF344-AD and wildtype F344 rats were exposed to an intragastric gavage of water (control) or 5 g/kg of 20% ethanol (adolescent intermittent ethanol; AIE) for a 2 day on/off schedule throughout adolescence (PD27-57). At 6 months old, rats either remained in their home cage (stationary) or were placed in a voluntary wheel running apparatus for 4 weeks and then underwent several behavioral tests. The number of cholinergic neurons in the basal forebrain and measure of neurogenesis in the hippocampus were assessed. Voluntary wheel running recovers spatial working memory deficits selectively in female TgF344-AD rats exposed to AIE and improves pattern separation impairment seen in control TgF344-AD female rats. There were sex-dependent effects on brain pathology: Exercise improves the integration of recently born neurons in AIE-exposed TgF344-AD female rats. Exercise led to a decrease in amyloid burden in the hippocampus and entorhinal cortex, but only in male AIE-exposed TgF344-AD rats. Although the number of basal forebrain cholinergic neurons was not affected by AD-transgenes in either sex, AIE did reduce the number of basal forebrain cholinergic neurons in female rats. These data provide support that even after symptom onset, AIE and AD related cognitive decline and associated neuropathologies can be rescued with exercise in unique sex-specific ways.

Adolescent Exposure to Restorative Practices and Their Perceptions of Support, Structure, and Bullying in the School Climate

Adolescent Exposure to Restorative Practices and Their Perceptions of Support, Structure, and Bullying in the School Climate

Early life stress enhances the susceptibility to depression and interferes with neuroplasticity in the hippocampus of adolescent mice via regulating miR-34c-5p/SYT1 axis

Early life events are major risk factors for the onset of depression and have long-term effects on the neurobiological changes and behavioral development of rodents. However, little is known about the specific mechanisms of early life adversity in the susceptibility to subsequent stress exposure in adolescence. This study characterized the effect of maternal separation (MS), an animal model of early life adversity, on the behavioral responses to restraint stress in mice during adolescence and investigated the molecular mechanism underlying behavioral vulnerability to chronic stress induced by MS. Our results showed that MS exposure could further reinforce the depressive vulnerability to restraint stress in adolescent mice. In addition, miR-34c-5p expression was obviously up-regulated in the hippocampi of MS mice at postnatal day (P) 14 and P42. Further, synaptotagmin-1 (SYT1) was deemed as a target gene candidate of miR-34c-5p on the basis of dual luciferase assay. It was found that the downregulation of miR-34c-5p expression in the hippocampi of MS mice could ameliorate dysfunction of synaptic plasticity by targeting molecule SYT1, effects which were accompanied by alleviation of depressive and anxious behaviors in these mice. The results demonstrated that the miR-34c-5p/SYT1 pathway was involved in the susceptibility to depression induced by MS via regulating neuroplasticity in the hippocampi of mice.

Frequent low-impact exposure to THC during adolescence causes persistent sexually dimorphic alterations in the response to viral infection in mice

Adolescent exposure to Δ9-tetrahydrocannabinol (THC) has enduring effects on energy metabolism and immune function. Prior work showed that daily administration of a low-impact dose of THC (5 mg/kg, intraperitoneal) during adolescence alters transcription in adult microglia and disrupts their response to bacterial endotoxin or social stress. To explore the lasting impact of adolescent THC exposure on the brain’s reaction to viral infection, we administered THC (5 mg/kg, intraperitoneal) in male and female mice once daily on postnatal day (PND) 30–43. When the mice reached adulthood (PND 70), we challenged them with the viral mimic, polyinosinic acid:polycytidylic acid [Poly(I:C)], and assessed sickness behavior (motor activity, body temperature) and whole brain gene transcription. Poly(I:C) caused an elevation in body temperature which was lessened by prior THC exposure in female but not male mice. Adolescent THC exposure did not affect the locomotor response to Poly(I:C) in either sex. Transcriptomic analyses showed that Poly(I:C) produced a substantial upregulation of immune-related genes in the brain, which was decreased by THC in females. Additionally, the viral mimic caused a male-selective downregulation in transcription of genes involved in neurodevelopment and synaptic transmission, which was abrogated by adolescent THC treatment. The results indicate that Poly(I:C) produces complex transcriptional alterations in the mouse brain, which are sexually dimorphic and differentially affected by early-life THC exposure. In particular, adolescent THC dampens the brain’s antiviral response to Poly(I:C) in female mice and prevents the transcriptional downregulation of neuron-related genes caused by the viral mimic in male mice.

Fine-Regional Role of the Claustrum in Anxiety and Higher Sensitivity to Cocaine in Adolescent Cocaine-Exposed Male Mice during Adulthood.

Adolescent cocaine exposure (ACE) induces anxiety and higher sensitivity to substances abuse during adulthood. Here, we show that the claustrum is crucial for controlling these psychiatric problems in male mice. In anxiety-like behavioral tests, the CaMKII-positive neurons in the median portion of the claustrum (MClaustrum) were triggered, and local suppression of these neurons reduced the anxiety-like behavior in ACE mice during adulthood. In contrast, the CaMKII-positive neurons in the anterior portion of the claustrum (AClaustrum) were more activated in response to subthreshold dose of cocaine induced conditioned place preference (CPP), and local suppression of these neurons blocked the acquisition of cocaine CPP in ACE mice during adulthood. Our findings for the first time identified the fine-regional role of the claustrum in regulating the anxiety and susceptibility to cocaine in ACE mice during adulthood, extending our understanding of the claustrum in substance use disorder.

Studying illicit substance exposure among urban adolescents using forensic science

There are critical challenges to measuring substance use exposure, particularly among adolescents, with major limitations to the most common methods of assessment – self-report and biomarker (urine, saliva) analysis. This study examines the use of wipe sampling as a measure of adolescent illicit substance exposure. Among low-income families, this study compared forensically analyzed wipe samples from 51 adolescents’ homes and cell phones with self-reported substance use to identify overlaps and discrepancies. There were major gaps between adolescents reporting any substance use in the past year and adolescents whose homes and/or cell phones tested positive for illicit substances via wipe sample analysis. This study builds upon previous adolescent substance use and exposure research, highlighting the profound limitations of self-reported use, and introducing wipe sampling as an effective measure of toxicant exposure. Wipe samples also provide a means to examine environmental contexts in new novel ways.

A moderated mediation model of the relationship between adolescent screentime, online privacy cognitions and exposure to online substance marketing

AbstractAdolescent exposure to substance‐related marketing is associated with subsequent substance initiation and progression. The extent to which adolescents are exposed to such content may be associated with adolescent cognitions about digital privacy and media‐specific parenting behaviours. The present study assesses whether the relationship between screentime and online marketing risk is mediated by adolescent digital privacy‐related cognitions and moderated by media‐specific parenting behaviours. Parents and their 10–14‐year‐old adolescents (n = 960) completed an online survey on media parenting techniques and adolescent media use and attitudes. Associations between screentime, Adolescent Cognitions about Online Privacy (ACOP; comprising privacy‐related attitudes, subjective norms and perceived behavioural control), TECH parenting (Talk, Educate, Co‐Use, House Rules) and adolescent online marketing exposure were explored via a moderated mediation model. A significant total effect between screentime and online marketing exposure was identified, including an indirect path via ACOP. TECH parenting significantly strengthened ACOP's mediation of the relationship between screentime and online marketing risk. This study indicates that adolescent privacy‐related cognitions may be an important mechanism for future studies related to adolescent online risk behaviour. Implications for child and family social work are discussed.

Adolescent morphine exposure changes the endogenous vlPAG opioid response to inflammatory pain in rats.

Adolescence is one of the most critical periods for brain development, and exposure to morphine during this period can have long-life effects on pain-related behaviors. The opioid system in the periaqueductal gray (PAG) is highly vulnerable to drug exposure. However, the impact of adolescent morphine exposure (AME) on the endogenous opioid system in the PAG is currently unknown. This study aims to investigate the long-lasting effects of AME on the endogenous opioid system and its involvement in altering nociceptive behaviors. Adolescent rats were given escalating doses of morphine (2.5-25mg/kg, subcutaneous) or an equal volume of saline twice daily for 10 consecutive days (PND 31-40). After a 30-day washout period, adult rats underwent formalin tests following microinjection of morphine, naloxone, or saline into the ventrolateral PAG (vlPAG) region. The results indicated that morphine microinjection into the vlPAG of the adolescent morphine-treated group significantly reduced the nociceptive score. However, the analgesic response to morphine in this group was significantly lower compared to the saline-treated group during adolescence. Additionally, the nociceptive score significantly increased following naloxone but not saline microinjection into the vlPAG of the saline-treated group during adolescence, rather than the morphine-treated one. These findings indicate that AME has long-lasting effects on the endogenous opioid system in the vlPAG, which can consequently alter behaviors related to inflammatory pain in adulthood.

Examining gender differences in adolescent exposure to food and beverage marketing through go-along interviews

This study explores how adolescents engage with unhealthy food and beverage marketing in online settings, from a gender perspective. Employing an online ethnography approach and using go-along interviews, we explored the experiences of adolescent boys and girls aged 13–17 as they navigated their online experiences with digital food and beverage marketing. Notable themes emerged, including the identification of predatory actions by food companies, the role of protective factors such as family, and the influence of social media influencers in shaping adolescent dietary preferences. Importantly, this research unearthed gender disparities in the participants' responses. Girls, in particular, exhibited a heightened awareness of the protective role played by their families, emphasized the influence of color in marketing strategies, recognized the significance of gender in marketing, and reported exposure to alcohol advertisements—findings that boys less frequently echoed. The study underscores the importance of adolescence as a critical phase in development, during which food companies target these impressionable individuals, driven by their independence and potential for brand loyalty. Moreover, it highlights the potential avenue of gender-specific marketing, offering valuable insights into the gendered dimensions of adolescents' food marketing experiences.By examining the interplay between digital food marketing and gender, this research addresses a critical gap in the literature, shedding light on how gender influences adolescents' perceptions, responses, and behaviors in the context of food marketing strategies. These findings have the potential to inform adolescents of the marketing techniques that target them and guide policymakers in developing and implementing evidence-based regulations aimed at safeguarding adolescents from exposure to unhealthy food marketing.

Evaluating How a School-Based Skin Cancer Prevention Program Can Change Behavior Among North Carolina Highschoolers.

The incidence of skin cancer has risen steadily over recent decades. Childhood and adolescent sun exposure remains a critical risk factor in skin cancer development, making education of high schoolers imperative for promoting sun-safe behaviors. Medical students in North Carolina recognized this need and designed a skin cancer education program focused on portraying skin cancer in individuals with all Fitzpatrick skin phototypes. Eighty-seven students completed the pre-survey, and 84 completed the post-session survey. In the post-survey, 88% of students listed actionable behavioral changes they plan to make following the presentation. Following an educational session, students were able to demonstrate their new knowledge and provide meaningful behavioral changes. This program navigated challenges posed by COVID-19 and addressed the need for more inclusive skin cancer educational material.

Adolescent social housing protects against adult emotional and cognitive deficits and alters the PFC and NAc transcriptome in male and female C57BL/6J mice.

Adolescence is a critical period in cognitive and emotional development, characterized by high levels of social interaction and increases in risk-taking behavior including binge drinking. Adolescent exposure to social stress and binge ethanol have individually been associated with the development of social, emotional, and cognitive deficits, as well as increased risk for alcohol use disorder. Disruption of cortical development by early life social stress and/or binge drinking may partly underlie these enduring emotional, cognitive, and behavioral effects. The study goal is to implement a novel neighbor housing environment to identify the effects of adolescent neighbor housing and/or binge ethanol drinking on (1) a battery of emotional and cognitive tasks (2) adult ethanol drinking behavior, and (3) the nucleus accumbens and prefrontal cortex transcriptome. Adolescent male and female C57BL/6J mice were single or neighbor housed with or without access to intermittent ethanol. One cohort underwent behavioral testing during adulthood to determine social preference, expression of anxiety-like behavior, cognitive performance, and patterns of ethanol intake. The second cohort was sacrificed in late adolescence and brain tissue was used for transcriptomics analysis. As adults, single housed mice displayed decreased social interaction, deficits in the novel object recognition task, and increased anxiety-like behavior, relative to neighbor-housed mice. There was no effect of housing condition on adolescent or adult ethanol consumption. Adolescent ethanol exposure did not alter adult ethanol intake. Transcriptomics analysis revealed that adolescent housing condition and ethanol exposure resulted in differential expression of genes related to synaptic plasticity in the nucleus accumbens and genes related to methylation, the extracellular matrix and inflammation in the prefrontal cortex. The behavioral results indicate that social interaction during adolescence via the neighbor housing model may protect against emotional, social, and cognitive deficits. In addition, the transcriptomics results suggest that these behavioral alterations may be mediated in part by dysregulation of transcription in the frontal cortex or the nucleus accumbens.

Etiological contributions of adolescent binge alcohol on onset of Alzheimer’s disease‐associated basal forebrain neuropathology in 5xFAD mice and post‐mortem human AUD brain

AbstractBackgroundHeavy alcohol use is an etiological factor for development of dementia and may contribute to onset of Alzheimer’s disease (AD). Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including basal forebrain cholinergic neuron degeneration and proinflammatory neuroimmune activation, and evidence suggest these systems are particularly sensitive to adolescent alcohol exposure. Using the 5xFAD mouse model of AD, we tested the hypothesis that adolescent intermittent ethanol (AIE), which models human adolescent binge drinking, would accelerate onset of AD‐associated pathology in the adult basal forebrain.MethodIn Experiment 1, non‐transgenic and 5xFAD male and female mice received AIE treatment (5.0 g/kg, i.g. 2‐days on/2‐days off; postnatal day [P]30 – P55) and basal forebrain tissue collected for immunohistochemistry and gene expression analysis on P100. In Experiment 2, 5xFAD female mice received AIE treatment as described above followed by glycyrrhizic acid (GA; 150 mg/L), a high mobility group box 1 (HMGB1) inhibitor, in drinking water from P56 – P100. At study conclusion, basal forebrain tissue was collected for immunohistochemistry and gene expression analysis on P100. In Experiment 3, AD‐associated neuropathology was assessed in the post‐mortem human basal forebrain of individuals with AUD relative to age‐matched moderate drinking CONs.ResultIn Experiment 1, AIE accelerated loss of basal forebrain cholinergic neurons and heterogeneous nuclear ribonucleoprotein (hnRNP) expression in 5xFAD females, but not males, relative to age‐matched 5xFAD CONs. This was accompanied by a female‐specific accelerated accumulation of plaque markers (e.g., Aβ1‐42, Thioflavin‐S, HMGB1) as well as microglial activation and proinflammatory neuroimmune signaling genes (e.g., HMGB1, RAGE) in the adult basal forebrain. In Experiment 2, post‐AIE treatment with the HMGB1 inhibitor GA reversed AIE‐induced accelerated loss of cholinergic neurons, accumulation of plaque markers, and upregulation of microglial activation markers and proinflammatory signaling molecules. In Experiment 3, AUD individuals exhibited decreased cholinergic and hnRNP markers and increased Aβ1‐42 immunoreactivity as well as cholinergic neuron co‐expression with Aβ1‐42 that negatively correlated with an adolescent age of drinking onset.ConclusionThese data reveal that adolescent binge ethanol exposure may be an etiological factor contributing to onset of AD‐associated neuropathology in the adult basal forebrain through HMGB1‐neuroimmune signaling.

Leveraging the adolescent brain cognitive development study to advance and promote adolescent health: Introduction to the special issue.

The empirical reports in this special issue of Health Psychology showcase the work of a diverse array of accomplished early-stage investigators who are members of the Adolescent Brain Cognitive Development (ABCD) study consortium and who are drawn from the community of female and underrepresented scientists. Their studies focus primarily on youth assessed during preadolescence and early adolescence, and they are based on the ABCD data that were available to the scientific community at the time this special issue was being prepared (e.g., baseline, Years 1 and 2 assessments). They address a variety of questions about adolescent health behavior, such as the effects of screen time and caffeine on sleep; individual lifestyle, neighborhood, and environmental factors associated with physical health conditions and brain development; and the antecedents and consequences of prenatal and adolescent substance exposure. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Long-lasting mechanical hypersensitivity and CRF receptor type-1 neuron activation in the BNST following adolescent ethanol exposure.

Adolescent alcohol use can produce long-lasting alterations in brain function, potentially leading to adverse health outcomes in adulthood. Emerging evidence suggests that chronic alcohol use can increase pain sensitivity or exacerbate existing pain conditions, but the potential neural mechanisms underlying these effects require further investigation. Here, we evaluate the impact of chronic ethanol vapor on mechanical sensitivity over the course of acute and protracted withdrawal in adolescent and adult male and female mice, and its potential association with alterations in corticotropin-releasing factor (CRF) signaling within the bed nucleus of the stria terminalis (BNST). Adolescent and adult male and female mice underwent intermittent ethanol vapor exposure on 4 days/week for 2 weeks. Mechanical thresholds were evaluated 5 h and 7, 14, 21, and 28 d after cessation of ethanol exposure using the von Frey test. For mice with a history of adolescent ethanol exposure, brains were collected for insitu RNAscope processing after the final test. Messenger RNA expression of c-Fos, Crfr1, and Crf in the BNST subregions was examined. Exposure to intermittent ethanol vapor induced persistent mechanical hypersensitivity during withdrawal in both adolescent and adult mice. Notably, the effect was more transient in mice exposed to ethanol during adulthood, resolving by day 28 after ethanol exposure. Furthermore, both male and female mice with a history of adolescent ethanol exposure exhibited increased activation of CRF receptor type 1 (CRFR1) neurons within the dorsolateral BNST. Our results support the conclusion that intermittent ethanol exposure can induce mechanical hypersensitivity, potentially through the activation of BNST CRFR1 neurons. These findings provide a basis for future studies aimed at evaluating specific subpopulations of BNST neurons and their contribution to pain in individuals with a history of alcohol use.

Transcriptomic analysis reveals mitochondrial pathways associated with distinct adolescent behavioral phenotypes and stress response

Adolescent individuals exhibit great variability in cortical dynamics and behavioral outcomes. The developing adolescent brain is highly sensitive to social experiences and environmental insults, influencing how personality traits emerge. A distinct pattern of mitochondrial gene expression in the prefrontal cortex (PFC) during adolescence underscores the essential role of mitochondria in brain maturation and the development of mental illnesses. Mitochondrial features in certain brain regions account for behavioral differences in adulthood. However, it remains unclear whether distinct adolescent behavioral phenotypes and the behavioral consequences of early adolescent stress exposure in rats are accompanied by changes in PFC mitochondria-related genes and mitochondria respiratory chain capacity. We performed a behavioral characterization during late adolescence (postnatal day, PND 47–50), including naïve animals and a group exposed to stress from PND 31–40 (10 days of footshock and 3 restraint sessions) by z-normalized data from three behavioral domains: anxiety (light–dark box tests), sociability (social interaction test) and cognition (novel-object recognition test). Employing principal component analysis, we identified three clusters: naïve with higher-behavioral z-score (HBZ), naïve with lower-behavioral z-score (LBZ), and stressed animals. Genome-wide transcriptional profiling unveiled differences in the expression of mitochondria-related genes in both naïve LBZ and stressed animals compared to naïve HBZ. Genes encoding subunits of oxidative phosphorylation complexes were significantly down-regulated in both naïve LBZ and stressed animals and positively correlated with behavioral z-score of phenotypes. Our network topology analysis of mitochondria-associated genes found Ndufa10 and Cox6a1 genes as central identifiers for naïve LBZ and stressed animals, respectively. Through high-resolution respirometry analysis, we found that both naïve LBZ and stressed animals exhibited a reduced prefrontal phosphorylation capacity and redox dysregulation. Our findings identify an association between mitochondrial features and distinct adolescent behavioral phenotypes while also underscoring the detrimental functional consequences of adolescent stress on the PFC.

Folic Acid Ameliorates Anxiety- and Depressive-Like Behavior Induced by Nicotine Withdrawal Through Restoration of Behavioral and Biochemical Alterations in Adolescent Male Rats.

The present study aimed to assess the efficacy of folic acid (FA) on withdrawal following nicotine (Nic) administration in adolescent male rats. Adolescent male rats were divided into two groups: (1) vehicle and (2) Nic (Nic-2 mg/kg), and were under treatment from 21 to 42 days of age. After that, they continued the experiment without treatment and returned to a regular diet, except for one of those who received Nic. The rats were divided into four groups where they were treated with different doses of FA (5, 10, and 15 mg/kg) and bupropion (Bup) by oral gavage, and the final group included normal rats that received only FA (15 mg/kg) from 42 days of age for three weeks during which withdrawal occurred. Results showed that adolescent Nic exposure exacerbated the behavioral indices of anxiety- and depression-like behaviors, while FA attenuated the effects of Nic withdrawal on anxiety and depression as well as Bup. In support, the biochemical results demonstrated a balance between oxidant and antioxidant mediators in addition to the increase and decrease of serotonin and monoamine oxidase (MAO) activity in cortical tissue. TNF-α as an inflammatory agent was decreased, whereas IL-10 as an anti-inflammatory parameter was increased. The present findings suggest anxiety and depression caused by Nic withdrawal were attenuated by FA more likely through the reduction activity of MAO, the important enzyme responsible for serotonin metabolism along with balance between oxidant/antioxidant and pro-inflammatory/anti-inflammatory mediators. However, various mechanisms might be involved, which requires further investigation. Nic withdrawal-induced depression and anxiety like behavior in rats followed by neuro-oxidative damage and neuro-inflammation. FA supplementation as well as Bup improved cognitive disorders induced by Nic withdrawal by increasing neuro-inflammation and neuro-oxidative damage.

Adolescent ethanol exposure promotes mechanical allodynia and alters dopamine transmission in the nucleus accumbens shell.

Excessive alcohol consumption in adolescence can disrupt neural development and may augment pain perception. Recent studies have shown that the nucleus accumbens (NAc) shell is involved in mediating pain sensitivity after peripheral inflammation in rodent models of chronic pain and alcohol use disorder. Interestingly, there have been very few studies examining the impact of chronic ethanol exposure during adolescence on pain sensitivity in adulthood. Therefore, in this project, we investigated the impact of adolescent chronic intermittent ethanol (aCIE) exposure on mechanical allodynia. Furthermore, given the involvement of the NAc shell in pain processing and chronic ethanol-mediated changes, we measured changes in accumbal dopamine kinetics during protracted withdrawal. We found that both male and female aCIE rats show mechanical allodynia during withdrawal. Furthermore, male and female aCIE rats show greater evoked tonic dopamine release, maximal rate of dopamine reuptake, and dopamine affinity to the dopamine transporter in the NAc shell compared with controls. With phasic stimulation, aCIE rats also showed greater dopamine release compared with AIR-exposed rats. Inhibition of dopamine transmission targeted in the NAc shell reversed the aCIE-associated facilitation of mechanical allodynia in both sexes. These data suggest that aCIE exposure exacerbates pain sensitivity during withdrawal in an accumbal dopamine-dependent manner.

Adolescent intermittent ethanol exposure alters adult exploratory and affective behaviors, and cerebellar Grin2b expression in C57BL/6J mice

Binge drinking is one of the most common patterns (more than 90%) of alcohol consumption by young people. During adolescence, the brain undergoes maturational changes that influence behavioral control and affective behaviors, such as cerebellar brain volume and function in adulthood. We investigated long-term impacts of adolescent binge ethanol exposure on affective and exploratory behaviors and cerebellar gene expression in adult male and female mice. Further, the cerebellum is increasingly recognized as a brain region integrating a multitude of behaviors that span from the traditional primary sensory-motor to affective functions, such as anxiety and stress reactivity. Therefore, we investigated the persistent effects of adolescent intermittent ethanol (AIE) on exploratory and affective behaviors and began to elucidate the role of the cerebellum in these behaviors through excitatory signaling gene expression. We exposed C57BL/6J mice to AIE or air (control) vapor inhalation from postnatal day 28–42. After prolonged abstinence (>34 days), in young adulthood (PND 77+) we assessed behavior in the open field, light/dark, tail suspension, and forced swim stress tests to determine changes in affective behaviors including anxiety-like, depressive-like, and stress reactivity behavior. Excitatory signaling gene mRNA levels of fragile X messenger ribonucleoprotein (FMR1), glutamate receptors (Grin2a, Grin2b and Grm5) and excitatory synaptic markers (PSD-95 and Eaat1) were measured in the cerebellum of adult control and AIE-exposed mice. AIE-exposed mice showed decreased exploratory behaviors in the open field test (OFT) where both sexes show reduced ambulation, however only females exhibited a reduction in rearing. Additionally, in the OFT, AIE-exposed females also exhibited increased anxiety-like behavior (entries to center zone). In the forced swim stress test, AIE-exposed male mice, but not females, spent less time immobile compared to their same-sex controls, indicative of sex-specific changes in stress reactivity. Male and female AIE-exposed mice showed increased Grin2b (Glutamate Ionotropic Receptor NMDA Type Subunit 2B) mRNA levels in the cerebellum compared to their same-sex controls. Together, these data show that adolescent binge-like ethanol exposure altered both exploratory and affective behaviors in a sex-specific manner and modified cerebellar Grin2b expression in adult mice. This indicates the cerebellum may serve as an important brain region that is susceptible to long-term molecular changes after AIE.

Adult consequences of repeated nicotine vapor inhalation in adolescent rats.

There has been a resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Almost five times as many US high-school seniors inhale nicotine vapor daily compared with those who smoke tobacco. This study was conducted to determine the impact of repeated adolescent vapor inhalation of nicotine on behavior in adulthood. Male and female Sprague-Dawley rats were exposed to 30-minute sessions of ENDS vapor inhalation, twice daily, from Post-Natal Day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle or nicotine (30mg/mL in the PG). Animals were assessed for effects of nicotine on open field (PND 74-105) and wheel activity (PND 126-180) and for volitional exposure to nicotine vapor (PND 285-395). Plasma nicotine and cotinine were assessed in separate groups of male and female Wistar and Sprague-Dawley rats after a single nicotine inhalation session. Group mean plasma nicotine ranged from 39 to 59ng/mL post-session with minimal strain differences detected. Adolescent nicotine exposure enhanced sensitivity to the locomotor stimulating effects of nicotine (0.1-0.8mg/kg, s.c.) in an open field in female rats, but didn't change effects of nicotine on wheel activity. Female rats exposed to nicotine (30mg/mL) vapor as adolescents responded more vigorously than PG exposed females for nicotine vapor in a FR5 challenge. Repeated adolescent nicotine vapor inhalation leads to enhanced liability for volitional exposure to nicotine vapor in adulthood in female rats, but minimal change in spontaneous locomotor behavior. These results show that adolescent vaping of nicotine can lead to lasting sensitization to the effects of nicotine in adulthood, including volitional responding for nicotine vapor. Demonstration of this in a controlled animal model establishes causality in a manner not possible from longitudinal evidence in human populations. These findings further highlight the importance of decreasing adolescent nicotine exposure by e-cigarettes to reduce consumption in adulthood.