Adolescence is an important ontogenetic period that is characterized by behaviors such as enhanced novelty-seeking, impulsivity, and reward preference, which can give rise to an increased risk for ...substance use. While substance use rates in adolescence are generally on a decline, the current rates combined with emerging trends, such as increases in e-cigarette use, remain a significant public health concern. In this review, we focus on the neurobiological divergences associated with adolescent substance use, derived from cross-sectional, retrospective, and longitudinal studies, and highlight how use of these substances during adolescence may relate to behavioral outcomes. Identifying and understanding the associations between adolescent substance use and changes in cognition, mental health, and future substance use risk may assist our understanding of the consequences of drug exposure during this critical window.
Abstract
Purpose
Nicotine and alcohol-containing products are some of the most commonly used substances of abuse and are both leading causes of preventable death. These substances also have ...significant interactions that have additive and, in some cases, multiplicative effects on the health consequences of their use. Thus, to reduce these negative consequences, it is important to understand the abuse liability of nicotine and alcohol in combination, especially in the most relevant use cases among those who are most vulnerable. Specifically, as tobacco cigarette use is continually decreasing, vaping is quickly replacing cigarettes as the primary mode of nicotine use. This pattern is especially true in adolescent populations in which vaping has grown considerably. Particularly concerning is that adolescents are more vulnerable than adults to the negative consequences of substance use. It is therefore imperative to revisit the literature as it relates to the rising state of co-use of vaping products with alcohol. Here, we review the clinical outcomes of nicotine and alcohol co-use as they relate to the abuse liability of each individually. Special attention is paid to adolescent findings, where available, as well as investigations that use nontobacco nicotine products as these may more accurately reflect the more recent trends of co-use.
Implications
Though nicotine alone has previously been considered a proxy for tobacco and tobacco cigarette use, combustible routes of administration have been decreasing. They are, instead, being replaced by e-cigarettes that do not involve other tobacco constituents and contain additional nonnicotine constituents of their own. Unfortunately, the literature remains limited with regard to e-cigarettes and their interactions with other substances, especially their prevalent co-use with alcohol. This review attempts to discuss the current literature on nicotine and alcohol co-use in the context of the vaping epidemic, predominantly focusing on addiction-related outcomes and why e-cigarette use may be unique.
Smoking remains the leading cause of preventable death worldwide. A combination of biological and environmental risk factors make women especially vulnerable to nicotine addiction, making it harder ...for them to quit smoking. Smoking during pregnancy, therefore, is still a major health concern, with epidemiological data suggesting a role for gestational nicotine exposure in the development of several behavioural disorders. Given there are significant sex-specific behavioural outcomes related to smoking in adolescence and adulthood, it is probable that the behavioural outcomes following gestational nicotine or tobacco exposure are similarly sex-dependent. This is an especially relevant topic as the current landscape of nicotine use shifts toward vaping, a mode of high doses of nicotine delivery that is largely believed to be a safer alternative to cigarettes among the public as well as among pregnant women. Here we review existing clinical and preclinical findings regarding the sex-dependent behavioural outcomes of prenatal nicotine exposure. We also highlight the challenges within this literature, particularly those areas in which further research is necessary to improve consistency within, and between, clinical and preclinical findings.
Abstract
Introduction
Co-occurrence of e-cigarette use and alcohol consumption during adolescence is frequent. Here, we examined whether adolescent co-exposure to alcohol drinking and vaporized ...nicotine would impact reward- and cognition-related behaviors in adult male and female rats during adulthood.
Aims and Methods
Four groups of male and female Sprague Dawley rats (n = 8–11/group/sex) received either nicotine (JUUL 5% nicotine pods) or vehicle vapor for 10 minutes daily between postnatal days 30–46, while having continuous voluntary access to ethanol and water during this time in a two-bottle preference design. Upon reaching adulthood, all rats underwent behavioral testing (ie, Pavlovian conditioned approach testing, fear conditioning and a two-bottle alcohol preference).
Results
A sex-dependent effect, not related to adolescent nicotine or alcohol exposure, on alcohol drinking in adulthood was found, such that females had a higher intake and preference for alcohol compared to males; both male and female adult rats also had greater alcohol preference compared to their alcohol preference as adolescents. Male rats exposed to vaporized nicotine with or without alcohol drinking during adolescence exhibited altered reward-related learning in adulthood, evidenced by enhanced levels of sign-tracking behavior. Male rats that drank alcohol with or without nicotine vapor in adolescence showed deficits in associative fear learning and memory as adults. In contrast, these effects were not seen in female rats exposed to alcohol and nicotine vapor during adolescence.
Conclusions
The present study provides evidence that co-exposure to alcohol and vaporized nicotine during adolescence in male, but not female, rats produces long-term changes in reward- and cognition-related behaviors.
Implications
These findings enhance our understanding of the effects of alcohol drinking and nicotine vapor exposure in adolescence. Moreover, they highlight potential sex differences that exist in the response to alcohol and nicotine vapor, underscoring the need for follow-up studies elucidating the neurobiological mechanisms that drive these sex differences, as well as the long-term effects of alcohol and nicotine vapor use.
Though vaping likely represents a safer alternative to smoking, it is not without risks, many of which are not well understood, especially for vulnerable populations. Here we evaluate the sex- and ...age-dependent effects of JUUL nicotine vapour in rats. Following passive nicotine vapour exposures (from 59 mg/ml JUUL nicotine pods), rats were evaluated for reward-like behaviour, locomotion, and precipitated withdrawal. Pharmacokinetics of nicotine and its metabolites in brain and plasma and the long-term impact of nicotine vapour exposure on functional magnetic resonance imaging-based brain connectivity were assessed. Adult female rats acquired conditioned place preference (CPP) at a high dose (600 s of exposure) of nicotine vapour while female adolescents, as well as male adults and adolescents did not. Adult and adolescent male rats displayed nicotine vapour-induced precipitated withdrawal and hyperlocomotion, while both adult and adolescent female rats did not. Adult females showed higher venous and arterial plasma and brain nicotine and nicotine metabolite concentrations compared to adult males and adolescent females. Adolescent females showed higher brain nicotine concentration compared to adolescent males. Both network-based statistics and between-component group connectivity analyses uncovered reduced connectivity in nicotine-exposed rats, with a significant group by sex interaction observed in both analyses. The short- and long-term effects of nicotine vapour are affected by sex and age, with distinct behavioural, pharmacokinetic, and altered network connectivity outcomes dependent on these variables.
Cannabis and alcohol co-use is prevalent in adolescence, but the long-term behavioural effects of this co-use remain largely unexplored. The aim of this study is to investigate the effects of ...adolescent alcohol and Δ9-tetrahydracannabinol (THC) vapour co-exposure on cognitive- and reward-related behaviours. Male Sprague-Dawley rats received vapourized THC (10 mg vapourized THC/four adolescent rats) or vehicle every other day (from post-natal day (PND) 28–42) and had continuous voluntary access to ethanol (10% volume/volume) in adolescence. Alcohol intake was measured during the exposure period to assess the acute effects of THC on alcohol consumption. In adulthood (PND 56+), rats underwent behavioural testing. Adolescent rats showed higher alcohol preference, assessed using the two-bottle choice test, on days on which they were not exposed to THC vapour. In adulthood, rats that drank alcohol as adolescents exhibited short-term memory deficits and showed decreased alcohol preference; on the other hand, rats exposed to THC vapour showed learning impairments in the delay-discounting task. Vapourized THC, alcohol or their combination had no effect on anxiety-like behaviours in adulthood. Our results show that although adolescent THC exposure acutely affects alcohol drinking, adolescent alcohol and cannabis co-use may not produce long-term additive effects.
•Co-use of alcohol and cannabis is prevalent amongst adolescents.•Long-term effects of alcohol and cannabis co-use on behaviour are not well understood.•Adolescent rats showed greater alcohol preference during acute THC abstinence.•Vapourized THC and alcohol co-exposure may not produce additive behavioural effects.
•Electronic cigarette use is rapidly increasing amongst adolescents.•High-dose nicotine exposure models this use in adolescent rats.•Adult rats with high-dose nicotine exposure in adolescence take ...more nicotine.•They also show higher rates of nicotine seeking.•This effect occurs even after a prolonged ‘abstinence’ period.
While cigarette smoking rates have been steadily decreasing over the past decade, there has been a dramatic increase in nicotine use via e-cigarettes, especially during adolescence. Adolescent e-cigarette use is associated with a greater risk of future cigarette smoking, and increased rates of cigarette smoking in individuals who may have otherwise never tried cigarettes. In humans and rodents, early initiation of nicotine use has been associated with greater consumption, dependence, and persistent nicotine use. The present study sought to investigate the long-lasting effect of daily high-dose nicotine exposure during adolescence on nicotine consumption in adulthood.
Male Sprague-Dawley rats were exposed daily to nicotine (1.0 mg/kg, subcutaneous), or vehicle (1 mL/kg saline, subcutaneous) during adolescence (post-natal day P 28–41). Adult nicotine self-administration (0.02 mg/kg/infusion, intravenous) was assessed beginning on P75 on fixed-ratio 1 (FR1), fixed-interval 1 min (FI1), and progressive ratio (PR) schedules of reinforcement.
Adolescent nicotine pre-exposure did not affect adult nicotine self-administration on the simple FR1 schedule, however increased intake and responding for nicotine was observed when a short delay was implemented on an FI1 schedule of reinforcement.
Adolescence is a critical period when the brain is especially vulnerable to the effects of nicotine. Nicotine exposure in adolescence enhances susceptibility to increased nicotine intake in adulthood on a reinforcement schedule more reflective of human nicotine intake patterns, and this effect can extend into adulthood even after termination of nicotine exposure during adolescence.
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Two-bottle choice tests are a widely used paradigm in rodents to determine preference between two liquids, with utility for testing animal models of addiction, depression and ...anhedonia. The following paper describes a 3D-printed, Arduino controlled two-bottle choice test that automatically reads and records drinking behavior in rats to allow for detailed analysis of their drinking microstructure. While commercial products exist use lickometers to measure the microstructure of licking, this design uniquely incorporates hydrostatic depth sensors to allow for real-time volumetric measurements in addition to traditional beam break lick sensing, allowing for licking and drinking microstructure analysis. The goal of this design is to provide a user friendly, affordable apparatus that can study unique, complex behaviors without requiring the purchase of specialized scientific equipment or software. Its applications range from studying alcohol preference in animal models of addiction to sucrose preference in motivational deficits and reward evaluation. This design costs less than $180 CAD to build with decreased cost on each additional device. This design has been successfully tested for accuracy and validated using alcohol preference as an example. The apparatus showed consistency between drinking bouts and volume consumed and is shown to be accurate to ±0.086 ml of the actual volume. This design makes using the two-bottle choice paradigm more accurate, while also making its data more robust and informative while allowing for microstructure analysis of both licking behavior and volume consumed.
Mitragyna speciosa
(“kratom”), employed as a traditional medicine to improve mood and relieve pain, has shown increased use in Europe and North America. Here, the dose-dependent effects of a purified ...alkaloid kratom extract on neuronal oscillatory systems function, analgesia, and antidepressant-like behaviour were evaluated and kratom-induced changes in ΔFosB expression determined. Male rats were administered a low or high dose of kratom (containing 0.5 or 1 mg/kg of mitragynine, respectively) for seven days. Acute or repeated low dose kratom suppressed ventral tegmental area (VTA) theta oscillatory power whereas acute or repeated high dose kratom increased delta power, and reduced theta power, in the nucleus accumbens (NAc), prefrontal cortex (PFC), cingulate cortex (Cg) and VTA. The repeated administration of low dose kratom additionally elevated delta power in PFC, decreased theta power in NAc and PFC, and suppressed beta and low gamma power in Cg. Suppressed high gamma power in NAc and PFC was seen selectively following repeated high dose kratom. Both doses of kratom elevated NAc-PFC, VTA-NAc, and VTA-Cg coherence. Low dose kratom had antidepressant-like properties whereas both doses produced analgesia. No kratom-induced changes in ΔFosB expression were evident. These results support a role for kratom as having both antidepressant and analgesic properties that are accompanied by specific changes in neuronal circuit function. However, the absence of drug-induced changes in ΔFosB expression suggest that the drug may circumvent this cellular signaling pathway, a pathway known for its significant role in addiction.
The endocannabinoid system is responsible for regulating a spectrum of physiological activities and plays a critical role in the developing brain. During adolescence, the endocannabinoid system is ...particularly sensitive to external insults that may change the brain’s developmental trajectory. Cannabinoid receptor type 2 (CB2R) was initially thought to predominantly function in the peripheral nervous system, but more recent studies have implicated its role in the mesolimbic pathway, a network largely attributed to reward circuitry and reward motivated behavior, which undergoes extensive changes during adolescence. It is therefore important to understand how CB2R modulation during adolescence can impact reward-related behaviors in adulthood. In this study, adolescent male rats (postnatal days 28–41) were exposed to a low or high dose of the CB2R antagonist/inverse agonist SR144528 and Pavlovian autoshaping and instrumental conditional behavioral outcomes were measured in adulthood. SR144528-treated rats had significantly slower acquisition of the autoshaping task, seen by less lever pressing behavior over time
F
(2, 19)
= 5.964,
p
= 0.010. Conversely, there was no effect of adolescent SR144528 exposure on instrumental conditioning. These results suggest that modulation of the CB2R in adolescence differentially impacts reward-learning behaviors in adulthood.
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