Sheketha R. Hauser1,2*
Robert A. Waeiss1,2
Gerald A. Deehan Jr.3Eric A. Engleman1,2Richard L. Bell1,2Zachary A. Rodd1,2- 1Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
- 2Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
- 3Department of Psychology, East Tennessee State University, Johnson City, TN, United States
Adolescence through young adulthood is a unique period of neuronal development and maturation. Numerous agents can alter this process, resulting in long-term neurological and biological consequences. In the clinical literature, it is frequently reported that adolescent alcohol consumption increases the propensity to develop addictions, including alcohol use disorder (AUD), during adulthood. A general limitation of both clinical and human pre-clinical adolescent alcohol research is the high rate of co-using/abusing more than one drug during adolescence, such as co-using/abusing alcohol with nicotine. A primary goal of basic research is elucidating neuroadaptations produced by adolescent alcohol exposure/consumption that promote alcohol and other drug self-administration in adulthood. The long-term goal is to develop pharmacotherapeutics for the prevention or amelioration of these neuroadaptations. This review will focus on studies that have examined the effects of adolescent alcohol and nicotine exposure on adult alcohol consumption, the hypersensitivity of the mesolimbic dopaminergic system, and enhanced responses not only to alcohol but also to nicotine during adulthood. Again, the long-term goal is to identify potential cholinergic agents to prevent or ameliorate the consequences of, peri-adolescent alcohol abuse.
Human research examining adolescent alcohol consumption
Adolescence is a period in which humans begin to use illicit and age-restricted drugs. Although adolescent drinking has decreased from 2002 to 2021, there is still a high prevalence of adolescent alcohol drinking in the United States [1]. This includes 58% of 12th graders reporting the use of alcohol within the past year and 28% of which engaged in binge drinking within the previous 2 weeks (i.e., >5 or more consecutive drinks per drinking episode) [2, 3]. Binge drinking is defined by the National Institute on Alcohol Abuse and Alcoholism as 4+/5+ drinks for women/men per occasion respectively (achieving blood alcohol concentrations (BACs) of 0.08 g/dL = 80 mg/dL) [4]. Binge drinking is exaggerated in US young adults since the average binge episode consists of 9.5 drinks/occasion [5, 6].
A recent trend in adolescent/young adult drinking is that the initiation of binge drinking has become progressively earlier, and a sharp increase in the overall rate of binge drinking during the transition from late adolescent/young adulthood into adulthood [7]. Moreover, there has been a focus on studying the effects of high-intensity and extreme-intensity binge drinking in adolescents [8–10]. A longitudinal study comparing US alcohol consumption from 2005 to 2015 indicated consistent levels of binge drinking in 18 year-olds (approximately 20%) [11]. There were also significant rates of high- (approximately 10%) and extreme-intensity (approximately 5%) binge drinking among these US 18 year-olds [11]. In young adults, recent data have indicated that roughly 30% report binge drinking, 11% report high-intensity binge drinking, and 5% report extreme-intensity binge drinking [11].
Alcohol consumption during adolescence is associated with several deleterious consequences. For example, adolescents and young adults display, relative to their adult counterparts, heavier drinking bouts, arrests for driving with ability impaired, and an increased number of arrests for driving while impaired, and an increased rate of alcohol dependence during adulthood significantly associated with the age of the first alcohol drink and the number of binge alcohol drinking episodes during adolescence [12, 13]. The adolescent brain appears to be more susceptible to the effects of binge alcohol consumption than the adult brain [14, 15], and neuroadaptations produced by adolescent alcohol drinking are thought to underlie an increased rate of alcohol misuse in adults suffering from AUDs [16].
Epidemiological studies indicate that individuals who initiate alcohol use before age 15 are 1.3–1.6 times more likely to suffer from an AUD [17]. Additionally, having a family history that is positive [positive (FHP)] for an AUD combined with the initiation of alcohol consumption during adolescence dramatically increases the risk of adult alcohol dependence [18, 19]. A family history of alcoholism also significantly increases observed alterations in white matter integrity (fractional anisotropy) of adolescent binge-drinking subjects [19]. Overall, the clinical evidence consistently indicates that alterations in the central nervous system (CNS) produced by adolescent alcohol consumption are enhanced in individuals with a family history of alcoholism.
A major caveat concerning the interpretation of clinical data on the influence of adolescent alcohol consumption on adult alcohol consumption and the development of an AUD, was the difficulty of adult subjects in recalling their alcohol consumption during adolescence. Given long-term alcohol use and misuse can dramatically affect memory and recall, the accuracy of such first-person accounts have been called into question [20]. However, several recent longitudinal studies have provided clinical support that adolescent alcohol consumption increases the likelihood of adult alcohol consumption or AUD. In a Swedish military conscript study, young adults consuming high-intensity levels of alcohol (8.6 g/day) displayed an increase in alcohol consumption during later adulthood and developed higher rates of developing an AUD [21]. Specifically, the total consumed dose of alcohol during young adulthood increased the future risk for developing an AUD, but a pattern of heavy episodic drinking (high-intensity drinking) significantly increased the later risks for developing an AUD and cirrhosis of the liver [21]. A parallel longitudinal study examining Norwegian and Australian adolescents [22] reported that adolescent alcohol drinking was associated with an increase in adult alcohol consumption and the rate for developing an AUD. Furthermore, the study indicated that interfering with early adolescent alcohol consumption has a protective effect on drinking patterns during late adolescence and adulthood [22]. Overall, recent longitudinal studies have replicated the initial longitudinal study’s findings on the deleterious effect of adolescent alcohol consumption on the rate of AUD during adulthood [23–25].
Adolescent and adult alcohol consumption in rodents
The effect of voluntary alcohol consumption during adolescence on adult alcohol consumption
Pre-clinical studies use rodent models to investigate the effect of adolescent alcohol (ethanol) exposure on subsequent neurobiological alterations that contribute to observed changes in behavior related to alcohol drinking in adulthood. The animals are typically exposed to alcohol between early adolescence to late adolescence–emerging adulthood (i.e., postnatal day (PND) 28–65; Table 1), which corresponds with 13–25 years of age in humans [14, 26, 27].
TABLE 1. Rat and human ages.
Overall, the field has developed several paradigms to assess rodent drinking, expose animals to binge-like levels of ethanol intake, and/or establish the level of motivation to self-administer ethanol (i.e., operant responding/behavior to obtain alcohol). In typical voluntary free-choice models, animals are allowed access to 2- or 3- bottles with a choice between ethanol or water, or multiple solutions, and animals can freely consume fluid over a 24 h period. Using a slightly different approach, an intermittent drinking paradigm involves alternating periods of access to alcohol with periods of imposed abstinence to establish binge-like intake in outbred rodents [28]. Studies measuring voluntary ethanol consumption in adolescent non-selected (outbred) rats have produced variable findings. There have been reports that voluntary ethanol drinking during adolescence (PND 28 or PND 31) and continued into adulthood (PND 69–70 or PND 71) had no effect on adult ethanol consumption [29, 30]. On the other hand, Amodeo et al. [31] found that adolescent animals (PND 26–59) exposed to an intermittent voluntary ethanol paradigm, during a period of social isolation, exhibited an increase in operant “appetitive” but not “consummatory” behavior related to ethanol intake during adulthood. Interestingly, after separating the adolescent rats into low (average of 0.29 g/kg/30 min exposure) and high (average of 0.65 g/kg) voluntary ethanol consumption during adolescence, there was a significant increase in adult consumption of ethanol in the ‘high’ adolescent ethanol drinkers [31].
Adulteration of an ethanol solution using a sweetener (i.e., sucrose or saccharin) enhanced voluntary ethanol consumption during adolescence (PND 29–54; PND 28–42, respectively) [32, 33] and produced biologically relevant blood ethanol concentrations (BEC) as well as enhanced consumption of the same sweetened ethanol solution in adult non-selected rats, respectively. However, this is not always the case. Gilpin et al. [34] reported that operant voluntary binge ethanol consumption in adolescence (PND 28–42) resulted in pharmacologically relevant binge blood ethanol concentrations BAC levels (≥80 mg/dL); however, operant voluntary binge ethanol consumption in adolescence did not alter adult operant self-administration of sweetened ethanol solution or unsweetened ethanol solution in male Wistar rats.
Adolescent voluntary drinking studies using mice have also reported mixed findings on subsequent adult ethanol drinking. An early study using C57BL/6J mice found that adolescent ethanol consumption (beginning at weaning: 3 weeks of age; PND∼21) was associated with increased ethanol consumption in adulthood [35]. Nevertheless, voluntary ethanol consumption starting at 5 weeks of age (PND 35) in BALB/cByJ mice also exhibited a greater ethanol preference in adulthood [36]. In contrast, other studies did not observe the same increase in adult consumption following adolescent ethanol exposure (starting at ∼PND 21 or ∼PND 35) in C57BL/6J [37].
Studies utilizing the murine model have demonstrated that “intermittent-type access to ethanol during adolescence can produce pharmacologically relevant BECs and facilitate adult ethanol intake, but the findings seem to be strain dependent [38, 39]. For example, utilizing the scheduled high ethanol consumption (SHAC) [40] binge procedure produces adolescent BECs of >80 mg/dL in male and female C57BL/6J mice [38]. Moreover, these authors reported that adolescent females were more vulnerable to, i.e., displayed more of, this effect than males [38]. Researchers using the drinking-in-the-dark (DID) binge drinking model, where animals have access to ethanol for 2 or 4 h and 3 or 4 h into the dark cycle, have also reported that adolescent ethanol exposure (PND 28–42) in C57BL/6J, mice produced significantly higher ethanol consumption in adulthood, a finding that was not observed DBA/2J mouse strain [41]. Adult ethanol consumption was also enhanced in C57BL/6J mice following adolescent access [PND 28–36 to low concentration of ethanol (5%; 20 mg/dL BEC) during a modified DID exposure, whereas adolescent DID ethanol consumption (20%, 20 mg/dL BEC)] in DBA/2J did not alter ethanol consumption in adulthood [42]. These findings would suggest that, while the DID paradigm can produce binge-like ethanol intake in adolescent animals, genetic background likely plays a role as well. That is, genetic factors that have established the C57BL/6J mouse line as a high ethanol-drinking model, likely contributed to the observed increase in ethanol intake in adulthood as the effect was present even when adolescent animals were exposed to low concentrations (non-binge levels: BEC <80 mg/dL) [42].
Collectively, the literature suggests that under certain conditions, voluntary ethanol consumption during adolescence can produce enhanced ethanol consumption in adulthood. In some cases, alterations in drinking behavior, due to adolescent ethanol exposure, may be mediated by sex-of-animal effect and/or genotype, however, obtaining biologically relevant blood ethanol levels, (BEC >80 mg/dL) appears to be a critical factor. Towner and Varlinskaya [39] reported that one-third of voluntary adolescent ethanol consumption in rodents resulted in a subsequent increase in adult ethanol consumption and that pharmacological levels of ethanol during adolescence may have to be well above a BEC of 80 mg/dL (e.g., 100–200 mg/dL) to increase subsequent adult ethanol consumption. Thus, DID, SHAC, and forced ethanol (e.g., IP, IG, vapor inhalation) procedures in adolescent rodents tend to result in higher BECs and more consistent increases in adult ethanol consumption [39].
Voluntary alcohol consumption during adolescence effects on adult alcohol consumption in alcohol-preferring rodent models
Selective breeding for high ethanol intake has produced multiple rat lines that voluntarily consume pharmacologically relevant levels of ethanol under 24 h free-access drinking conditions [e.g., alcohol-preferring (P) and Alko Alcohol (AA)] [c.f. 43, 44]. Such lines have been utilized as a powerful tool to examine the influence of genetic background contributing to the behavioral and neurobiological components of AUDs.
Alcohol preferring (P) rat line
The P rat line has demonstrated reliable consumption of biologically relevant levels of ethanol from post-natal day (PND) 7 until death) [45]. Twenty-four free-access drinking access during adolescence results in binge-level of ethanol intake (>80 mg%) in P rats [8]. In P rats, voluntary ethanol consumption during adolescence can alter ethanol-related behaviors during adulthood [46–49]. For example, 24 h free-access ethanol drinking during PND 22–71 increased ethanol consumption during ethanol re-exposure in adulthood (PND 99) compared to control animals [47]. Adolescent (PND 28–60) voluntary ethanol consumption in P rats (average intake of 6.3 g/kg/day) has also been shown to increase the rate of acquisition of operant ethanol self-administration during adulthood (PND 90) compared to animals exposed to the same regimen completely in adulthood (PND 137–169; testing started at PND 199) [48, 49]. Ethanol consumption during adolescence produced resistance to extinction, increased the expression of both context- and ethanol primed-induced ethanol seeking, enhanced relapse drinking, and significantly increased breakpoint in adulthood [48, 50]. Moreover, these effects on operant behavior were observed during the second cycle of testing for extinction, seeking, and relapse, suggesting that voluntary adolescent ethanol consumption can produce persistent effects on ethanol-related behaviors well into adulthood [48]. It is also important to mention that these findings were specific to ethanol as a control study using the same paradigm, but exposing animals instead to saccharin during adolescence, did not alter adult saccharin self-administration, saccharin extinction learning, relapse, or breakpoint [50].
Alko, alcohol (AA) rat line
The AA rat line also readily consumes pharmacologically relevant levels of ethanol (5–8 g/kg) in 24 h with BECs as high as 50 mg% [51–53]. A recent report found that voluntary adolescent ethanol consumption (starting at PND 42 and continuing for 6 weeks) in female AA rats did not increase subsequent ethanol drinking in adulthood, and by extension did not increase ethanol preference [54]. Although the AA rats consumed pharmacologically relevant levels of ethanol during adolescence, animals failed to establish binge-like (>80 mg%) BECs, which may have been a reason as to why the authors failed to observe increased ethanol consumption in adulthood [54]. Further, the timing of adolescent exposure (i.e., mid-late adolescence) may have also been another factor. Previous work suggests that early-mid (PND 28–45) adolescent exposure induces more severe neuroadaptations than mid-late ethanol exposure [26, 54]. Regardless, the data supports the notion that, even in alcohol-preferring rat models, attaining high (i.e., binge-like or higher) BECs during adolescence appears to be important for subsequent increases in adult ethanol drinking.
Adolescent intermittent ethanol (AIE) exposure effects adult alcohol consumption
Vapor exposure of alcohol in adolescence
The adolescent intermittent ethanol (AIE) exposure model is an experimenter-administered binge model (e.g., ethanol vapor, intragastric (IG), intraperitoneal (IP) injection), used to produce consistent binge BEC levels in rodents that do not readily consume ethanol [cf., 6]. The BEC levels achieved with AIE are approximately 160 mg% (i.e., 0.16 g/dL) or greater in rats and mice [55–60]. However, studies utilizing AIE exposure have reported mixed findings. High level AIE vapor exposure (PND 28–42) that established BECs in excess of 300 mg% produced an increase in operant responding for (maintenance) and a resistance to extinction of operant self-administration during adulthood (PND 65–90) in Long-Evans [61]. However, utilizing an identical AIE regimen and rat strain, Nentwig et al. [62] failed to observe similar AIE-induced alterations to adult 2-bottle choice voluntary ethanol consumption or operant self-administration behaviors. Studies examining AIE in mice are also mixed. For instance, AIE (PND 28–42) vapor exposure increased ethanol consumption in adult male C57BL/6J mice following short-term abstinence during late adolescence and early adulthood (PND 50–76) and following protracted abstinence (PND 70–97) in adulthood, but did not alter consumption in female mice [63] indicating that potential sex differences may be at play in vulnerability to the effects of AIE vapor exposure.
Systemic administration of alcohol in adolescence
Several studies have utilized the systemic route of administration (i.e., IP injection or IG gavage) of ethanol during adolescence to examine the long-term effects on ethanol drinking in adulthood. Ethanol administered via the IP or IG routes has been shown to produce equivalent ethanol exposure between subjects that is not approximated in consumption/drinking paradigms, and reliable, dose-dependent, BECs. However, much like the research discussed thus far, the findings have been mixed and there seem to be dose- and sex-dependent, as well as age-related variables that underlie the enduring behavioral effects observed using these techniques.
An early study by Gilpin et al. [34] reported that adult animals exhibited a conditioned taste aversion to sweetened solutions and consumed significantly less sweetened and unsweetened ethanol following adolescent ethanol injections (PND 28–42; 2 g/kg/IP) compared to control animals. In contrast, administration of a lower dose of ethanol (1.5 g/kg/IP; PND 30–50) enhanced consumption of a sweetened ethanol solution during limited access testing in female adult rats (PND 65–80), whereas reducing the dose by half (0.75 g/kg/IP) did not [64]. A similar finding was reported using a higher dose of ethanol (3 g/kg/IP; PND 25–38) in that, adult animals (PND 60) exhibited an increase in ethanol consumption, which produced BECs that were not pharmacologically relevant (<30 mg%) [65]. In a similar experiment, ethanol administration of the same dose of ethanol (3 g/kg/IP) during early-mid adolescence (PND 30–43), but not late adolescence (PND 45–58), increased operant self-administration of ethanol as well as ethanol consumption when animals were provided both free and intermittent access ethanol in young adulthood [66].
Varying effects have also been reported in studies utilizing adolescent IG administration of ethanol. Maldonado-Devincci et al. [67] indicated IG administration of 1.5, 3.0, or 5.0 g/kg ethanol in 4 days intervals (PND 28–31, PND 35–38, and PND 43–45) increased ethanol consumption in young adulthood (PND 60–69) in both male and female Sprague-Dawley (SD) rats, an effect more prominent in male compared to female animals. Intermittent IG ethanol exposure (PND 28–48; 2 days on/2 days off) treatment in male and female P rats resulted in increased adult ethanol consumption (PND 90+) during both operant acquisition and relapse drinking conditions [68, 69]. In contrast, repeated gavage (every 8 h for 2 days: 6 treatments total) during adolescence (PND 30–32) decreased ethanol consumption in adulthood in Sprague Dawley rats [70]. The differences in behavioral data between these studies may be due to the gavage procedure, the length of time animals received exposure, and the strain of rats (P vs. SD rats).
Adolescent alcohol consumption and nicotine use–clinical data
Co-use/abuse is common among adolescents and young adults [71, 72]. A limitation of research is the ability to account for co-use/abuse of more than one drug during the window of adolescence and the effect this may have on the development of drug-related issues later in life. Adolescent alcohol drinking has been linked to increased adulthood use of opioids, cannabis, nicotine, and other drugs of abuse [73, 74]. Specifically for nicotine, adolescent binge drinking enhances the likelihood of smoking during adolescence by 88% as well as during adulthood, while individuals who do not binge drink during this period have lower smoking rates during adolescence and adulthood [74, 75]. Moreover, adolescents who use nicotine have higher rates of AUDs than their non-smoking counterparts [75, 76]. Simultaneous alcohol and tobacco use during early adolescence (age: ∼12 years old) promoted an escalation of drug intake during late adolescence and was associated with a higher rate of adult drug addiction, AUD, and co-substance drug addiction [77].
The use of non-combustible nicotine via electronic delivery (i.e., electronic cigarettes [e-cigarettes] or vaping pens) has become a popular alternative to cigarette smoking, especially among adolescents over the last decade [78]. In 2016, 38% of all high school students stated they had tried e-cigarettes, a rate comparable to alcohol usage in the same demographic [79]. Initiation of e-cigarette use during adolescence is associated with a greater prevalence of traditional nicotine use later in life (cf. [6]) and may promote traditional nicotine use in individuals who would not have initiated use otherwise [80]. Adolescents who use e-cigarettes are 6.5 times more likely to consume alcohol (including bouts of binge drinking), compared to those who do not use e-cigarettes [81]. The liquid nicotine solutions for e-cigarettes can contain 92%–104% more nicotine than stated by the manufacturers (cf. [81]). In addition, individuals who “vape” also receive a significant dose of alcohol as the range of alcohol concentration in liquid nicotine solutions ranges from 0.4%–23.5%, with the most popular brands ranging from 10% to 18% [82]. The rate of absorption of alcohol through the “vaping’”route is extremely high, and alcohol metabolites can be detected in individuals actively “vaping” [82]. With “hacked” e-cigarette systems, the rate of alcohol, acetaldehyde, and aldehyde intake can increase in magnitude, and reach detectable levels within the brain without reaching detectable levels in the periphery [83]. Replicate findings have indicated that alcohol and nicotine co-use/abuse during adolescence enhances adult drug dependency compared to the consumption of only alcohol or nicotine during adolescence (cf. [84]).
Modeling adolescent alcohol consumption and nicotine use–pre-clinical data
For several years, rodent experiments have sought to model ethanol/nicotine use/co-use during the developmental period of adolescence in the clinical population to determine the behavioral and neurobiological effects of these compounds that contribute to drug addiction both during adolescence and later in life. Several techniques have been used to investigate the effects of adolescent nicotine exposure on ethanol reward in adolescence and adulthood, such as oral nicotine access, injections (IP and subcutaneous: SC), intravenous (IV) self-administration, and nicotine vapor exposure. Overall, the findings are mixed as some rodent studies have demonstrated that adolescent nicotine exposure can increase ethanol consumption, while other studies report no effect. The discrepancy between studies seems to be related to when in adolescence (i.e., early, mid, or late) the animals are exposed to nicotine as well as the species used (mouse versus rat). For instance, oral nicotine exposure (200 μg/mL/22 h) during early-mid adolescence (∼PND 35–44) increases binge-like ethanol consumption and BECs in mid adolescence (∼PND 45–48) in female C57BL/6J mice [85, 86]. Oral nicotine consumption (30 μg/mL) using the DID model during late adolescence (PND 42–56) did not affect subsequent binge-like ethanol consumption in early adulthood in male C57BL/6J mice (PND 56–78) [87]. Repeated systemic administration of nicotine (0.4 mg/IP) during adolescence (PND 28–PND 42) induced long-lasting increases in adult ethanol self-administration, while adult (PND 60–74) nicotine administration did not alter subsequent adult ethanol self-administration in male Long-Evans rats [88].
Chronic continuous nicotine exposure (subcutaneous 21 day time-release pellets) during adolescence (PND 35–56) did not increase ethanol intake in SD rats during young adulthood (PND 53 -PND 74) [89]. Peripheral administration of nicotine (0.4 mg/kg/IP) administered in early adolescence (PND 28–32), prior to ethanol operant training, and then re-administered 2 h after ethanol training session during early-late adolescence (PND 33–56) did not alter self-administration or motivation (i.e., breakpoint) of sweetened ethanol [90]. Recently, Ruffolo et al. [91] examined the effects of vaporized JUUL e-cigarette mint flavored 5% nicotine e-liquid pods on adult ethanol consumption. Their findings indicated that adolescent nicotine vapor exposure (PND 30–46), voluntary ethanol consumption alone, and combination with nicotine exposure (i.e., nicotine vapor exposure, followed by voluntary ethanol consumption) did not alter ethanol intake or preference in adult SD [91]. IG adolescent ethanol exposure (PND 30–32; every 8 h for 2 days: 6 treatments total) also failed to alter ethanol and nicotine co-use during adulthood in SD rats [70].
However, several studies have indicated that co-exposure to ethanol and nicotine during adolescence results in distinct behavioral and neurochemical effects in adulthood that are not observed following adolescent exposure to ethanol or nicotine alone [92–94]. The effects of simultaneous exposure to ethanol and nicotine during adolescence have been reported to increase memory/learning deficits and enhance anxiety-like and drug-seeking behaviors in mice [93, 95, 96]. A recent study demonstrated that simultaneous IV self-administration of ethanol + nicotine during adolescence (PND 32–41) enhances ethanol reinforcement and intake in late adolescence and emerging adulthood in male rats (PND 48–65) [97]. A similar effect was not observed in male nor female rats when the same exposure and testing regimen occurred solely in adulthood (PND 90–99) [97]. Conversely, some studies have indicated that ethanol/nicotine co-exposure during adolescence (PND 30–45) results in certain adult alterations that parallel single drug exposure [98]. Taken together, these pre-clinical studies provide evidence that the effect of adolescent nicotine exposure or adolescent co-exposure to ethanol and nicotine on behavior is fairly complex, and further studies will be needed to determine how exposure, alone or in combination, during this developmental window affects use/abuse liability later in life.
The effect of alcohol during adolescence on dopamine function
The mesocorticolimbic (MCL) dopaminergic (DAnergic) system is involved in processing the rewarding effects of natural reinforcers and drugs of abuse, and it undergoes significant developmental changes during adolescence [14]. For example, during mid-to-late adolescence, DA neurons in the ventral tegmental (VTA), that project to the nucleus accumbens (Acb), are firing at their highest rate, suggesting a pattern of DA overproduction and increased DA receptor expression throughout the circuit, which declines in adulthood [65, 99, 100]. Philpot et al. [101] provided further evidence that basal DA levels in Acb increased through developmental stages of preadolescent (PND 25; lowest DA levels), early adolescent (PND 35), and late adolescent (PND 45; highest DA levels) with a decline in young adulthood (PND 60).
Drugs of abuse effects on DA release are typically observed in the Acb. The Acb is divided into 2 distinct anatomical and functional structures (i.e., shell [AcbSh] and the core [AcbC]), and each plays a different role in reward and motivation. Reports have demonstrated that ethanol, nicotine, and other drugs of abuse preferentially increase DA release in AcbSh compared to AcbC [102]. Moreover, AcbSh receives more DA projections from the VTA than the AcbC [103]. The AcbSh plays a critical role in the reinforcing effects of rewards and spatial/contextual drug-seeking behavior, while AcbC is involved in the motivation to seek rewards and mediating cue-induced drug-seeking behavior [104].
The effects of adolescent ethanol exposure on DA release have been examined in both the AcbSh and AcbC. A consistent finding in the pre-clinical literature is that ethanol exposure during adolescence produces a persistent hyper-dopaminergic state, and this is observed in the AcbSh [65, 105–108]. Pascual et al. [65] reported that basal extracellular DA levels in the AcbSh, following AIE injections (3 g/kg/IP) in adolescence (exposure: PND 25–38; DA collection: PND 41) were higher than if the animals were animals pre-treated with ethanol during adulthood. Moreover, adolescent AIE exposure resulted in a higher expression of D1 and D2 receptors in adolescents compared to adult-exposed animals lending support to previous studies [65]. In a subsequent study, 4 days of repeated administration of low to moderate ethanol (0.5, 1.0, or 2.0 g/kg/IP) with the test days on PND 25 (preadolescent), PND 35 (early adolescent), and PND 45 (late adolescent) increased DA levels in the Acb in all the stages of adolescence [101]. However, the ethanol’s peak effects on DA decreased during pre-adolescence and early adolescence, following a challenge dose of ethanol, but was not altered in late adolescence or young adulthood [101]. These findings indicated that PND 35 and 45 appear to be a key developmental transition periods to the neuroadaptation of effects of repeated ethanol exposure [101]. In contrast to [65], this study found that young adulthood (PND 60) ethanol exposure also increases DA levels in Acb [101]. This difference between studies may be due to different ethanol exposure methods and doses of ethanol.
In another study, moderate ethanol exposure (1 g/kg, every other day) in adolescents (PND 30–50) reduced DA release in the AcbC following a challenge dose during adulthood, with the reduction becoming less robust as the abstinence period (7, 14, 49 days) between adolescent exposure and challenged ethanol dose test increased [109]. The authors finding suggested ethanol exposure starting during early adolescence, not during adulthood (PND 60–80), resulted in a decline in the responsiveness of DAnergic neurons in the AcbC to ethanol [109]. Collectively, these studies demonstrate adolescent ethanol exposure induces age-dependent effects on the MCL DAnergic system that may contribute to the increased risk of AUDs in adulthood.
Ethanol administration in adolescence has also been shown to increase basal DA levels in the AcbSh during adulthood [105, 106]. Injections of ethanol (0.75 g/kg/IP) for 21 consecutive days during adolescence (PND 30–50) produced a persistent increase in basal DA in the shell region of the Acb during adulthood (PND 70) compared to saline pre-treatment [106]. Further, the observed increase in DA was likely due to increases in efflux as there were no changes in DA reuptake [106]. In P rats, 24 h continuous voluntary ethanol consumption from PND 30 to PND 60 produced a prolonged increase (i.e., 2 h long) in the extracellular DA levels and increased DA uptake in Acb following ethanol challenge (2.5 g/kg/IP) in adulthood compared with saline-challenge [105]. The observed differences in the AIE induced increase in DA uptake between studies are possibly due to the use of different rat strains (P rats vs. SD). Research has found that P rats have an abnormal innate DA profile with lower DA and DA metabolites than their control, the non-preferring (NP) rats, which contributes to P rats' high ethanol drinking behavior [110].
The VTA is a heterogeneous structure. Intracranial self-administration studies, which elucidate specific neuroanatomical sites that support drug self-administration, have shown that posterior VTA (pVTA), but not the anterior VTA (aVTA), is a neuroanatomical site mediating the reinforcing actions of drug reinforcement (i.e., ethanol, cocaine, nicotine, delta9 tetrahydrocannabinol [111–115]). Furthermore, the reinforcing effects of pVTA require the activation of DAnergic neurons [116, 117]. Adolescent ethanol exposure has been shown to sensitize DA neurons in the pVTA as challenge doses of ethanol more readily enhance DA levels in adulthood [107, 108]. For example, P rats provided free access to ethanol during adolescence (PND 30–60), and Wistar exposed to an AIE regimen (PND 28–48), exhibited a leftward and upward shift of the dose-response curve when receiving microinjections of ethanol directly into the pVTA during adulthood. Together, these findings provide some evidence that ethanol exposure during adolescence may produce a hyper-dopaminergic system of ethanol that may, in part, underlie the biological basis for enhanced adult ethanol consumption.
The effect of alcohol and nicotine on dopamine function
Ethanol and nicotine share some common mechanisms of action. For example, the reinforcing effects of nicotine are modulated via stimulation of nicotinic acetylcholine receptors (nAChR) receptors within the VTA [118, 119], and ethanol reinforcing effects are partially modulated by nAChR receptors [120–122]. For example, the antagonism of nAChR with mecamylamine, a non-selective nAChR antagonist, can reduce ethanol intake [123, 124] and nicotine-stimulated ethanol drinking [125, 126]. A limited number of pre-clinical studies have focused on the manner in which neuroadaptations that occur due to ethanol exposure during adolescence contribute to the co-use/abuse of drugs later in life. Recently, Waeiss et al. [127] observed that voluntary adolescent ethanol consumption (PND 30–60) increases the sensitivity (leftward shift in the dose-response curve) to the effects of nicotine within the MCL reward circuit (pVTA nicotine microinjection, DA release in AcbSh; 125). To date, however, the majority of studies have featured adult animals.
Combined peripheral injections of ethanol and nicotine, as well as a combined administration of low doses of ethanol peripherally and nicotine centrally (into VTA), have been shown to have an addictive effect on DA release in AcbSh of adult male Wistar rats [128, 129]. In adult P rats, acute exposure to ethanol and additional drugs (nicotine, cocaine, etc) results in unique, synergistic, or additive effects in various brain structures (e.g. [130, 131]). Chronic simultaneous ethanol and nicotine co-use results in unique adaptations in discrete brain regions that enhance drug reward in adult P rats [132, 133]. For example, microinjections of pharmacologically relevant doses of ethanol or nicotine directly into the pVTA induce DA release in the AcbSh [134]. Co-administration of subthreshold concentrations of ethanol and nicotine combined into the pVTA increases DA and glutamate release in the AcbSh, whereas the same subthreshold concentrations of each drug microinjected alone does not [130]. Furthermore, microinjections of ethanol + nicotine (but not ethanol or nicotine alone) into the pVTA altered the sensitivity of ethanol in the AcbSh and the expression of brain derived neurotrophic factor (BDNF) in the AcbSh (weeks following pVTA microinjections) [127]. Overall, the data indicate that co-administration of ethanol + nicotine differentially activates the mesolimbic DA system, which is not observed following the administration of the compounds individually.
Potential pharmacotherapies to mitigate the effects of binge-like ethanol consumption during adolescence as it pertains to adult ethanol consumption
One of the primary goals of the pre-clinical adolescent ethanol research, is to develop useful strategies and/or pharmacotherapeutic treatments that are capable of counteracting the deleterious effects of binge-like ethanol consumption/exposure during adolescence and the subsequent increase in adult ethanol/drug use/abuse that may eventually be utilized to treat the clinical population. So far, the majority of research has focused on describing the biological consequences of adolescent ethanol exposure and there have been limited attempts to assess potential pharmacological interventions to counteract the behavioral and neurobiological consequences of adolescent binge-like ethanol exposure. Simply put, there are two approaches to counter the deleterious effects of binge-like ethanol exposure: reversal or prevention with the majority of effort focused on the latter. The few studies that have focused on “reversing” the effects of adolescent ethanol consumption/exposure have ‘focused on “correcting” the biological alterations produced by exposure to ethanol during the adolescent window.
Alterations in the central cholinergic system are implicated in nicotine and ethanol abuse [6, 135]. There are two classifications of cholinergic receptors: nicotinic and muscarinic. Nicotinic acetylcholine receptors (nAChRs) consist of 11 neuronal subunits, which are divided into 8 alpha subunits (α2-α7, α9-α10) and 3 beta subunits (β2-β4). Adolescent ethanol consumption/exposure has been reported to upregulate α7 nicotinic receptors, which are usually homomeric, during adulthood [127, 136]. Evidence also suggests that adolescent ethanol or nicotine exposure alone can lead to subsequent cholinergic dysfunction [6, 15, 137]. For example, choline acetyltransferase (ChAT), a cholinergic marker that is responsible for the biosynthesis of the neurotransmitter acetylcholine, is reduced in several brain regions following adolescent ethanol or adolescent nicotine exposure [6, 15, 137].
Varenicline
This has led to an investigation of the effect of cholinergic compounds on adolescent ethanol exposure induced cholinergic deficits that persist well into adulthood [15, 137]. The FDA-approved smoking cessation aid Varenicline (i.e., Chantix), an α4β2 nAChR partial agonist, has a slower onset and longer duration on DA release compared to nicotine na d can block nicotine’s effect on DA release [138]. Varenicline has been reported to reduce ethanol consumption in adolescent C57BL/6J mice, after four 2 day DID sessions at PND 32–33, 36–37, 39–40, and 43–44, with Varenicline administered on the second of these 2 day sessions 30 min prior to ethanol access [139].
Cholinesterase inhibitors
The FDA-approved cholinesterase inhibitors Donepezil and Galantamine administered during peri-adolescence to emerging adulthood (PND 69–72; PND 57–72) can reverse AIE (PND 30–48; PND 25–54) induced alteration or deficits (e.g., reversing AIE decreases in dendritic spine density or the persistent losses of cholinergic neuron markers) observed during adulthood in the hippocampus (i.e., learning and memory) and basal forebrain (i.e., behavioral control, attention, and other executive functions) [59, 137, 140]. Moreover, Galantamine administered during AIE exposure (PND 25–54) prevented the AIE induced deficits in the basal forebrain [137]. Interestingly, although Donepezil and Galantamine are both cholinesterase inhibitors, findings have demonstrated that Galantamine, but not Donepezil, increases the firing activity of DAnergic cells in the VTA [141]. Galantamine effect on DA through its allosteric potentiation of nAChRs [141]. Therefore, some of Galantamine’s blocking and reversing effects of AIE may partly be through the DAnergic system.
Galantamine effects also appear to involve the α7 nAChR mediating presynaptic facilitation of glutamate release [141]. In addition, the neuroprotective effects of Donepezil are mediated through α7 nAChR [142, 143]. Glutamatergic projections to MCL are involved in the development of drug-seeking and drug-taking behavior [144]. Moreover, excessive glutamate can induce excitotoxicity and loss of neurons [145]. The α7 nAChRs have a lower affinity for nicotine and are located presynaptically on glutamatergic terminals [146]. Thus, it is suggested that activation of α7 nAChR enhances glutamatergic excitatory drive and may promote DA release after the α4β2 receptors are desensitized [146]. Thus mediating the long-term effects of chronic nicotine exposure [147].
α7 nAChR negative and positive allosteric modulator (NAM and PAM)
Administration of an α7 nAChR negative allosteric modulator (NAM) dehydronorketamine (DHNK) 2 hours before AIE exposure (PND 28–48) prevented the increase of ethanol consumption during acquisition and relapse drinking during adulthood in both male and female P rats [68]. A subsequent study reported that SB-277011-A, an α7 nAChR NAM and a D3 antagonist, could also suppress ethanol consumption during acquisition and relapse drinking in female P rats [69, 148]. In contrast, to α7 nAChR NAMs, activation of the α7 nAChR during adolescence appears to have the opposite effect on ethanol consumption in adulthood. Intermittent adolescent treatment (PND 29, 30, 33, 35, 36, and 37) with the α7 nAChR agonist AR-17779 increased the amount of ethanol consumed during acquisition and relapse during adulthood (PND 90+) in both male and female P rats [68]. Furthermore, co-infusion of α7 nAChR agonist + ethanol into pVTA increased extracellular DA release in AcbSh to a significantly greater extent than either treatment alone in male Wistar rats [69]. In addition, administration of α7 nAChR positive allosteric modulator (PAM) PNU- 120596 followed by low-dose ethanol (gavage, 2 mg/kg) in adolescents (PND 28–48) increased operant beer acquisition, extinction, and relapse drinking in adulthood in female Wistar rats [69]. However, PNU +2 mg/kg ethanol treatment during adolescence did not affect 24-h free-choice ethanol drinking of adult male Wistar rats [69].
Interestingly, AIE (PND 28–48) and peri-adolescent (PND 30–50) ethanol consumption did not alter glutamate release [108] or glutamate transporters [147] in Acb, respectively. However, adolescent nicotine consumption and ethanol + nicotine intake reduced glutamate transporter-1 (GLT-1), which reuptakes 90% of glutamate [145]. Therefore, further research is warranted to determine mechanisms that the α7 nAChR involvement with the glutamatergic system.
Bupropion, Lobeline, and Cytisine
Other nicotinic cholinergic compounds have also been shown to have some effectiveness in reducing ethanol consumption in pre-clinical studies. For example, Bupropion is FDA-approved for smoking cessation as well as depression and seasonal affective disorders. It is an antagonist for α3β2, α4β2, and α7 nAChRs, with Bupropion being ∼50 and 12 times more effective in blocking α3β2 and α4β2 than α7nAChRs [149]. Bupropion is also a dual norepinephrine and DA reuptake inhibitor (cf., [149]). Bupropion effects on ethanol intake have varied with no effects on limited access (2 h) to ethanol in P rats [150] to reducing DID ethanol (2 h) intake in C57BL/J mice [151].
Lobeline is a non-selective antagonist nAChRs that can inhibit nicotine and ethanol DA release [152]. Lobeline also inhibits DA and vesicular monoamine transporters. Cytisine is partial agonist for α4β2 nAChR and a full agonist at β4 and α7 nAChR. Nicotine- and ethanol-induced extracellular DA release can be reduced by Cytisine [cf., 154]. Both compounds have been reported to reduce ethanol consumption in high-alcohol drinking models (i.e., C57BL/6J mice and high alcohol drinking line 2 rats [152–154]) as well as reduce ethanol-induced DA release [155]. However, no research has examined whether Bupropion, Lobeline, or Cytisine would effectively block or reverse the behavioral and neurobiological changes observed in adulthood following adolescent ethanol or ethanol+ nicotine exposure.
Collectively, these studies provide evidence that treatments targeting the nicotinic cholinergic system may represent viable pharmacotherapeutic compounds to ‘reverse’ the effects of adolescent ethanol exposure on ethanol-related neuropathology and drinking behaviors observed during adulthood. Moreover, it will be interesting to extend this line of research to investigate other nicotinic cholinergic compounds as well as examine the utility of these compounds to reverse the additive effects of adolescent ethanol + nicotine exposure on ethanol and/or co-use/abuse in adulthood.
Conclusion
Pre-clinical and clinical research has indicated that adolescent alcohol and/or nicotine consumption/exposure can promote alcohol consumption during adulthood. The likelihood of observing this effect in pre-clinical research is increased if adolescent rats are exposed to biologically relevant levels of ethanol, with appropriate drinking protocols in adulthood, which produce pharmacologically relevant levels of ethanol intake. Recent experiments have indicated potential pharmacological targets that can reverse or prevent some of the persistent deleterious behavioral and neurobiological changes observed during adulthood following adolescent ethanol consumption/exposure. However, there is still a need to elucidate the mechanism and neural substrates that may contribute to the effectiveness of these cholinergic compounds. Pre-clinical research needs to be conducted to determine if the FDA-approved Donepezil, Galantamine, and Bupropion can attenuate adolescent alcohol and/or nicotine consumption/exposure ability to increase the risk of alcohol consumption during adulthood. Moreover, further research is still warranted to better understand adolescent co-use/abuse effects during adulthood, with a goal of developing novel efficacious pharmacotherapies to treat AUDs and co-use/abuse.
Author contributions
SH drafted the manuscript. SH, RW, GD, EE, RB, and ZR provided a critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.
Funding
The researchers were supported by NIAAA grants AA07611, AA07462, AA10721, AA20908, AA019366, AA013522, AA029788, and NIDA grant DA054335.
Conflict of interest
ZR, SH, RW, and RB have applied for a provisional patent titled ‘Use of Alpha-7 Nicotinic Receptor Negative Allosteric Modulators reduce the deleterious effects of adolescent alcohol consumption during adulthood’ with the US and EU patent office.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. National Institute of Alcohol Abuse and Alcoholism. Underage drinking in the United States (ages 12 to 20) (2023). Available at: https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics/underage-drinking-united-states-ages-12-20 (Accessed October 10, 2023).
2. Johnston, LD, O’Malley, PM, Bachman, JG, and Schulenberg, JE. Monitoring the future national survey results on drug use, 1975-2004 secondary school students (NIH Publication No. 04-5507). Bethesda, MD: National Institute on Drug Abuse (2004).
3. Miech, RA, Johnston, LD, O’Malley, PM, Bachman, JG, and Schulenberg, JE. Monitoring the Future national survey results on drug use, 1975-2015: volume I, secondary school students. Michigan: Institute for Social Research, The University of Michigan (2016).
4. Hauser, SR, Rodd, ZA, Deehan, GA, Liang, T, Rahman, S, Bell, RL, et al. Effects of adolescent substance use disorders on central cholinergic function. Int Rev Neurobiol (2021) 160:175–221. doi:10.1016/bs.irn.2021.07.008
5. National Institute on Alcohol Abuse and Alcoholism (NIAAA). NIAAA Council approves definition of binge drinking. NIAAA Newsletter (2004). Available at: https://pubs.niaaa.nih.gov/publications/Newsletter/winter2004/Newsletter_Number3.pdf (Accessed October 10, 2023).
6. Naimi, TS, Nelson, DE, and Brewer, RD. The intensity of binge alcohol consumption among US adults. Amj Prev Med (2010) 38:201–7. doi:10.1016/j.amepre.2009.09.039
7. Jager, J, Keyes, KM, and Schulenberg, JE. Historical variation in young adult binge drinking trajectories and its link to historical variation in social roles and minimum legal drinking age. Dev Psych (2015) 51:962–74. doi:10.1037/dev0000022
8. Bell, RL, Rodd, ZA, Engleman, EA, Toalston, JE, and McBride, WJ. Scheduled access alcohol drinking by alcohol-preferring (P) and high-alcohol-drinking (HAD) rats: modeling adolescent and adult binge-like drinking. Alcohol (2014) 48:225–34. doi:10.1016/j.alcohol.2013.10.004
9. Patrick, ME, and Terry-McElrath, YM. High-intensity drinking by underage young adults in the United States. Addictions (2016) 112:82–93. doi:10.1111/add.13556
10. Terry-McElrath, YM, and Patrick, ME. Intoxication and binge and high-intensity drinking among US young adults in their mid-20s. Subst Abus (2016) 37:597–605. doi:10.1080/08897077.2016.1178681
11. Patrick, ME, Terry-McElrath, YM, Miech, RA, Schulenberg, JE, O’Malley, PM, and Johnston, LD. Age-specific prevalence of binge and high-intensity drinking among US young adults: changes from 2005 to 2015. Alcohol Clin Exp Res (2017) 41:1319–28. doi:10.1111/acer.13413
12. Chou, SP, and Pickering, RP. Early onset of drinking as a risk factor for lifetime alcohol-related problems. Br J Addict (1992) 87:1199–204. doi:10.1111/j.1360-0443.1992.tb02008.x
13. Hingson, RW, Heeren, T, and Edwards, EM. Age at drinking onset, alcohol dependence, and their relation to drug use and dependence, driving under the influence of drugs and motor-vehicle crash involvement because of drugs. J Stud Alcohol Drugs (2008) 69:192–201. doi:10.15288/jsad.2008.69.192
14. Spear, LP. Effects of adolescent alcohol consumption on the brain and behaviour. Nat Rev Neursci (2018) 19:197–214. doi:10.1038/nrn.2018.10
15. Crews, FT, Robinson, DL, Chandler, LJ, Ehlers, CL, Mulholland, PJ, Pandey, SC, et al. Mechanisms of persistent neurobiological changes following adolescent alcohol exposure: NADIA consortium findings. Alcohol Clin Exp Res (2019) 43:1806–22. doi:10.1111/acer.14154
16. Bates, ME, and Labouvie, EW. Adolescent risk factors and the prediction of persistent alcohol and drug use into adulthood. Alcohol Clin Exp Res (1997) 21:944–50. doi:10.1111/j.1530-0277.1997.tb03863.x
17. Dawson, DA, Goldstein, RB, Chou, SP, Ruan, WJ, and Grant, BF. Age at first drink and the first incidence of adult-onset DSM-IV alcohol use disorders. Alcohol Clin Exp Res (2008) 32:2149–60. doi:10.1111/j.1530-0277.2008.00806.x
18. Agrawal, A, Sartor, CE, Lynskey, MT, Grant, JD, Pergadia, ML, Grucza, R, et al. Evidence for an interaction between age at first drink and genetic influences on DSM-IV alcohol dependence symptoms. Alcohol Clin Exp Res (2009) 33:2047–56. doi:10.1111/j.1530-0277.2009.01044.x
19. Jacobus, J, McQueeny, T, Bava, D, Schweinsburg Bc< Frank, LR, Yang, TT, Tapert, SF, et al. White matter integrity in adolescents with histories of marijuana use and binge drinking. Neurotoxicol teratol (2009) 31:349–55. doi:10.1016/j.ntt.2009.07.006
20. Bachman, JG, Johnston, LD, O'Malley, PM, Schulenberg, JE, and Miech, RA. The monitoring the future project after four decades and procedures (Monitoring the Future Occasional Paper No. 82). Ann Arbor MI: Institute for Social Research, University of Michigan (2015).
21. Hagstrom, H, and Andreasson, A. Is teenage heavy drinking more hazardous than we thought. Expert Rev Gastroenterol Hepatol (2019) 13:603–5. doi:10.1080/17474124.2019.1608819
22. Enstad, F, Evans-Whipp, T, Kjeldsen, A, Toumbourou, JW, and von Soest, T. Predicting hazardous drinking in late adolescence/young adulthood from early and excessive adolescent drinking - a longitudinal cross-national study of Norwegian and Australian adolescents. BMC Public Health (2019) 19:790. doi:10.1186/s12889-019-7099-0
23. Grant, BF, and Dawson, DA. Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: results from the national longitudinal alcohol epidemiologic survey. J Subst Abus (1997) 9:103–10. doi:10.1016/s0899-3289(97)90009-2
24. Sher, KJ, Grekin, ER, and Williams, NA. The development of alcohol use disorders. Annu Rev Clin Psychol (2005) 1:493–523. doi:10.1146/annurev.clinpsy.1.102803.144107
25. Brown, SA, McGue, M, Maggs, J, Schulenberg, J, Hingson, R, Swartzwelder, S, et al. A developmental perspective on alcohol and youths 16 to 20 years of age. Pediatrics (2008) 121(Suppl. 4):S290–310. doi:10.1542/peds.2007-2243D
26. Spear, LP. Adolescent alcohol exposure: are there separable vulnerable periods within adolescence? Physio Behav (2015) 148:122–30. doi:10.1016/j.physbeh.2015.01.027
27. Spear, LP, and Swartzwelder, HS. Adolescent alcohol exposure and persistence of adolescent-typical phenotypes into adulthood: a mini-review. Neurosci Biobehav Rev (2014) 45:1–8. doi:10.1016/j.neubiorev.2014.04.012
28. Carnicella, S, Ron, D, and Barak, S. Intermittent ethanol access schedule in rats as a pre-clinical model of alcohol abuse. Alcohol (2014) 48:243–52. doi:10.1016/j.alcohol.2014.01.006
29. Siegmund, S, Vengeliene, V, Singer, MV, and Spanagel, R. Influence of age at drinking onset on long-term ethanol self-administration with deprivation and stress phases. Alcohol Clin Exp Res (2005) 29:1139–45. doi:10.1097/01.alc.0000171928.40418.46
30. Vetter, CS, Doremus-Fitzwater, TL, and Spear, LP. Time course of elevated ethanol intake in adolescent relative to adult rats under continuous, voluntary access conditions. Alcohol Clin Exp Res (2007) 31:1159–68. doi:10.1111/j.1530-0277.2007.00417.x
31. Amodeo, LR, Kneiber, D, Will, DN, and Ehlers, CL. Alcohol drinking during adolescence increases consumptive responses to alcohol in adulthood in wistar rats. Alcohol (2017) 59:43–51. doi:10.1016/j.alcohol.2016.12.002
32. Walker, BM, and Ehlers, CL. Appetitive motivational experience during adolescence results in enhanced alcohol consumption during adulthood. Behav Neurosci (2009) 123:926–35. doi:10.1037/a0016002
33. Broadwater, M, Varlinskaya, EI, and Spear, LP. Effects of voluntary access to sweetened ethanol during adolescence on intake in adulthood. Alcohol Clin Exp Res (2013) 37:1048–55. doi:10.1111/acer.12049
34. Gilpin, NW, Karanikas, CA, and Richardson, HN. Adolescent binge drinking leads to changes in alcohol drinking, anxiety, and amygdalar corticotropin releasing factor cells in adulthood in male rats. PLoS One (2012) 7:e31466. doi:10.1371/journal.pone.0031466
35. Ho, A, Chin, AJ, and Dole, VP. Early experience and the consumption of alcohol by adult C57BL/6J mice. Alcohol (1989) 6:511–5. doi:10.1016/0741-8329(89)90060-8
36. Blizard, DA, Vandenbergh, DJ, Jefferson, AL, Chatlos, CD, Vogler, GP, and McClearn, GE. Effects of periadolescent ethanol exposure on alcohol preference in two BALB substrains. Alcohol (2004) 34:177–85. doi:10.1016/j.alcohol.2004.08.007
37. Hefner, K, and Holmes, A. An investigation of the behavioral actions of ethanol across adolescence in mice. Psychopharmacology (Berl) (2007) 191:311–22. doi:10.1007/s00213-006-0646-2
38. Strong, MN, Yoneyama, N, Fretwell, AM, Snelling, C, Tanchuck, MA, and Finn, DA. “Binge” drinking experience in adolescent mice shows sex differences and elevated ethanol intake in adulthood. Horm Behav (2010) 58:82–90. doi:10.1016/j.yhbeh.2009.10.008
39. Towner, TT, and Varlinskaya, EI. Adolescent ethanol exposure: anxiety-like behavioral alterations, ethanol intake, and sensitivity. Front Behav Neurosci (2020) 14:45. doi:10.3389/fnbeh.2020.00045
40. Finn, DA, Belknap, JK, Cronise, K, Yoneyama, N, Murillo, A, and Crabbe, JC. A procedure to produce high alcohol intake in mice. Psychopharmacology (Berl) (2005) 178(4):471–80. doi:10.1007/s00213-004-2039-8
41. Moore, EM, Mariani, JN, Linsenbardt, DN, Melon, LC, and Boehm, SL. Adolescent C57BL/6J (but not DBA/2J) mice consume greater amounts of limited-access ethanol compared to adults and display continued elevated ethanol intake into adulthood. Alcohol Clin Exp Res (2010) 34:734–42. doi:10.1111/j.1530-0277.2009.01143.x
42. Wolstenholme, JT, Younis, RM, Toma, W, and Damaj, MI. Adolescent low-dose ethanol drinking in the dark increases ethanol intake later in life in C57BL/6J, but not DBA/2J mice. Alcohol (2020) 89:85–91. doi:10.1016/j.alcohol.2020.08.005
43. Bell, RL, Franklin, KM, Hauser, SR, and Zhou, FC. Introduction to the special issue "Pharmacotherapies for the treatment of alcohol abuse and dependence" and a summary of patents targeting other neurotransmitter systems. Recent Pat CNS Drug Discov (2012) 7:93–112. doi:10.2174/157488912800673155
44. Loi, B, Colombo, G, Maccioni, P, Carai, MA, Franconi, F, and Gessa, GL. High alcohol intake in female Sardinian alcohol-preferring rats. Alcohol (2014) 48:345–51. doi:10.1016/j.alcohol.2014.01.001
45. Johnson, TB, and Goodlett, CR. Selective and enduring deficits in spatial learning after limited neonatal binge alcohol exposure in male rats. Alcohol Clin Exp Res (2002) 26:83–93. doi:10.1111/j.1530-0277.2002.tb02435.x
46. Salimov, RM, McBride, WJ, McKinzie, DL, Lumeng, L, and Li, TK. Effects of ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol (1996) 13:297–300. doi:10.1016/0741-8329(95)02060-8
47. McKinzie, DL, Nowak, KL, Yorger, L, McBride, WJ, Murphy, JM, Lumeng, L, et al. The alcohol deprivation effect in the alcohol-preferring P rat under free-drinking and operant access conditions. Alcohol Clin Exp Res (1998) 22:1170–6. doi:10.1111/j.1530-0277.1998.tb03718.x
48. Rodd-Henricks, ZA, Bell, RL, Kuc, KA, Murphy, JM, McBride, WJ, Lumeng, L, et al. Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: I. Periadolescent exposure. Alcohol Clin Exp Res (2002) 26:1632–41. doi:10.1097/01.ALC.0000036301.36192.BC
49. Rodd-Henricks, ZA, Bell, RL, Kuc, KA, Murphy, JM, McBride, WJ, Lumeng, L, et al. Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: II. Adult exposure. Alcohol Clin Exp Res (2002) 26:1642–52. doi:10.1097/01.ALC.0000036302.73712.9D
50. Toalston, JE, Deehan, GA, Hauser, SR, Engleman, EA, Bell, RL, Murphy, JM, et al. The reinforcing properties of ethanol are quantitatively enhanced in adulthood by peri-adolescent ethanol, but not saccharin, consumption in female alcohol-preferring (P) rats. Alcohol (2015) 49:513–8. doi:10.1016/j.alcohol.2015.04.007
51. Päivärinta, P, and Korpi, ER. Voluntary ethanol drinking increases locomotor activity in alcohol-preferring AA rats. Pharmacol Biochem Behav (1993) 44:127–32. doi:10.1016/0091-3057(93)90289-6
52. Nurmi, M, Kiianmaa, K, and Sinclair, JD. Brain ethanol levels after voluntary ethanol drinking in AA and Wistar rats. Alcohol (1999) 19:113–8. doi:10.1016/s0741-8329(99)00022-1
53. Bell, RL, Hauser, SR, Liang, T, Sari, Y, Maldonado-Devincci, A, and Rodd, ZA. Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology (2017) 122:201–43. doi:10.1016/j.neuropharm.2017.02.004
54. Mugantseva, E, Hyytiä, P, and Latvala, A. Voluntary adolescent-onset alcohol drinking fails to influence alcohol consumption or anxiety-like behaviour in adulthood in female alcohol-preferring rats. Alcohol Alcohol (2022) 57:396–403. doi:10.1093/alcalc/agab063
55. Ehlers, CL, Criado, JR, Wills, DN, Liu, W, and Crews, FT. Periadolescent ethanol exposure reduces adult forebrain ChAT+IR neurons: correlation with behavioral pathology. Neuroscience (2011) 199:333–45. doi:10.1016/j.neuroscience.2011.10.011
56. Coleman, LG, He, J, Lee, J, Styner, M, and Crews, FT. Adolescent binge drinking alters adult brain neurotransmitter gene expression, behavior, brain regional volumes, and neurochemistry in mice. Alcohol Clin Exp Res (2011) 35:671–88. doi:10.1111/j.1530-0277.2010.01385.x
57. Pandey, SC, Sakharkar, AJ, Tang, L, and Zhang, H. Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood. Neurobiol Dis (2015) 82:607–19. doi:10.1016/j.nbd.2015.03.019
58. Wolstenholme, JT, Mahmood, T, Harris, GM, Abbas, S, and Miles, MF. Intermittent ethanol during adolescence leads to lasting behavioral changes in adulthood and alters gene expression and histone methylation in the PFC. Front Mol Neurosci (2017) 10:307. doi:10.3389/fnmol.2017.00307
59. Mulholland, PJ, Teppen, TL, Miller, KM, Seton, HG, Pandey, SC, and Swartwelder, HS. Donepezil reverses dendritic spine morphology adaptations and Fmr1 epigenetic modifications in hippocampus of adult rats after adolescent alcohol exposure. Alcohol Clin Exp Res (2018) 42:706–17. doi:10.1111/acer.13599
60. Vetreno, RP, and Crews, FT. Adolescent binge ethanol-induced loss of basal forebrain cholinergic neurons and neuroimmune activation are prevented by exercise and indomethacin. PLoS One (2018) 13:e0204500. doi:10.1371/journal.pone.0204500
61. Gass, JT, Glen, WB, McGonigal, JT, Trantham-Davidson, H, Lopez, MF, Randall, PK, et al. Adolescent alcohol exposure reduces behavioral flexibility, promotes disinhibition, and increases resistance to extinction of ethanol self-administration in adulthood. Neuropsychopharmacology (2014) 39:2570–83. doi:10.1038/npp.2014.109
62. Nentwig, TB, Starr, EM, Chandler, LJ, and Glover, EJ. Absence of compulsive drinking phenotype in adult male rats exposed to ethanol in a binge-like pattern during adolescence. Alcohol (2019) 79:93–103. doi:10.1016/j.alcohol.2019.01.006
63. Maldonado-Devincci, AM, Makdisi, JG, Hill, AM, Waters, RC, Hall, NI, Shobande, MJ, et al. Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice. J Neurosci Res (2022) 100:1560–72. doi:10.1002/jnr.24814
64. Maldonado-Devincci, AM, and Kirstein, CL. Chronic ethanol exposure during adolescence increases voluntary ethanol consumption in adulthood in female sprague dawley rats. Brain Sci (2020) 10:900. doi:10.3390/brainsci10120900
65. Pascual, M, Boix, J, Felipo, V, and Guerri, C. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem (2009) 108:920–31. doi:10.1111/j.1471-4159.2008.05835.x
66. Alaux-Cantin, S, Warnault, V, Legastelois, R, Botia, B, Pierrefiche, O, Vilpoux, C, et al. Alcohol intoxications during adolescence increase motivation for alcohol in adult rats and induce neuroadaptations in the nucleus accumbens. Neuropharmacology (2013) 67:521–31. doi:10.1016/j.neuropharm.2012.12.007
67. Maldonado-Devincci, AM, Ailpour, KK, Michael, LA, and Kirstein, CL. Repeated binge ethanol administration during adolescence enhances voluntary sweetened ethanol intake in young adulthood in male and female rats. Pharmacol Biochem Behav (2010) 96:476–87. doi:10.1016/j.pbb.2010.07.008
68. Rodd, ZA, Hauser, SR, Swartzwelder, HS, Waeiss, RA, Lahiri, DK, and Bell, RL. Regulation of the deleterious effects of binge-like exposure to alcohol during adolescence by α7 nicotinic acetylcholine receptor agents: prevention by pretreatment with a α7 negative allosteric modulator and emulation by a α7 agonist in alcohol-preferring (P) male and female rats. Psychopharmacology (2020) 237:2601–11. doi:10.1007/s00213-020-05557-1
69. Rodd, ZA, Swartzwelder, HS, Waeiss, RA, Soloviov, SO, Lahiri, DK, Engleman, EA, et al. Negative and positive allosteric modulators of the α7 nicotinic acetylcholine receptor regulates the ability of adolescent binge alcohol exposure to enhance adult alcohol consumption. Front Behav Neurosci (2023) 16:954319. doi:10.3389/fnbeh.2022.954319
70. Chandler, CM, Hamid, U, Maggio, SE, Peng, H, Pauly, JR, Beckmann, J, et al. Effects of adolescent alcohol exposure via oral gavage on adult alcohol drinking and co-use of alcohol and nicotine in Sprague Dawley rats. Drug Alcohol Depend (2022) 232:109298. doi:10.1016/j.drugalcdep.2022.109298
71. Tomczyk, S, Isensee, B, and Hanewinkel, R. Latent classes of polysubstance use among adolescents-a systematic review. Drug Alcohol Depend (2016) 160:12–29. doi:10.1016/j.drugalcdep.2015.11.035
72. Merrin, GJ, Thompson, K, and Leadbeater, BJ. Transitions in the use of multiple substances from adolescence to young adulthood. Drug Alcohol Depend (2018) 189:147–53. doi:10.1016/j.drugalcdep.2018.05.015
73. Anthony, JC, and Petronis, KR. Early-onset drug use and risk of later drug problems. Drug Alcohol Depend (1995) 40:9–15. doi:10.1016/0376-8716(95)01194-3
74. Best, D, Rawaf, S, Rowley, J, Floyd, K, Manning, V, and Strang, J. Drinking and smoking as concurrent predictors of illicit drug use and positive drug attitudes in adolescents. Drug and Alcohol Dependence (2000) 60:319–21. doi:10.1016/s0376-8716(00)00113-7
75. Bobo, JK, and Husten, C. Sociocultural influences on smoking and drinking. Alcohol Res Health (2000) 24:225–32.
76. Grucza, RA, and Bierut, LJ. Cigarette smoking and the risk for alcohol use disorders among adolescent drinkers. Alcohol Clin Exp Res (2006) 30:2046–54. doi:10.1111/j.1530-0277.2006.00255.x
77. Griffin, KW, Lowe, SR, Botvin, C, and Acevedo, BP. Patterns of adolescent tobacco and alcohol use as predictors of illicit and prescription drug abuse in minority young adults. J Prev Interv Community (2019) 47:228–42. doi:10.1080/10852352.2019.1603672
78. Sapru, S, Vardhan, M, Li, Q, Guo, Y, Li, X, and Saxena, D. E-cigarettes use in the United States: reasons for use, perceptions, and effects on health. BMC Public Health (2020) 20:1518. doi:10.1186/s12889-020-09572-x
79. Center for Disease Control. National youth tobacco survey (NYTS). Atlanta, Georgia: US Department of Health and Human Services, CDC (2016). Avaliable at: https://www.cdc.gov/tobacco/data_statistics/surveys/nyts/.
80. Barrington-Trimis, JL, Urman, R, Leventhal, AM, Gauderman, WJ, Cruz, TB, Gilreath, TD, et al. E-Cigarettes, cigarettes, and the prevalence of adolescent tobacco use. Pediatrics (2016) 138:e20153983. doi:10.1542/peds.2015-3983
81. Rothrock, AN, Andris, H, Swetland, SB, Chavez, V, Isaak, S, Pagane, M, et al. Association of E-cigarettes with adolescent alcohol use and binge drinking-drunkenness: a systematic review and meta-analysis. Am J Drug Alcohol Abuse (2020) 46:684–98. doi:10.1080/00952990.2020.1771723
82. Valentine, GW, Jatlow, PI, Coffman, M, Nadim, H, Gueorguieva, R, and Sofuoglu, M. The effects of alcohol-containing e-cigarettes on young adult smokers. Drug Alcohol Depend (2016) 159:272–6. doi:10.1016/j.drugalcdep.2015.12.011
83. Sleiman, M, Logue, JM, Montesinos, VN, Russell, ML, Litter, MI, Gundel, LA, et al. Emissions from electronic cigarettes: key parameters affecting the release of harmful chemicals. Environ Sci Technol (2016) 50:9644–51. doi:10.1021/acs.est.6b01741
84. Mooney-Leber, SM, and Gould, TJ. The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse. Learn Mem (2018) 25:481–91. doi:10.1101/lm.046672.117
85. Locker, AR, Marks, MJ, Kamens, HM, and Klein, LC. Exposure to nicotine increases nicotinic acetylcholine receptor density in the reward pathway and binge ethanol consumption in C57BL/6J adolescent female mice. Brain Res Bull (2016) 123:13–22. doi:10.1016/j.brainresbull.2015.09.009
86. Silva, CP, Horton, WJ, Caruso, MJ, Sebastian, A, Klein, LC, Albert, I, et al. The influence of adolescent nicotine exposure on ethanol intake and brain gene expression. PLoS One (2018) 13:e0198935. doi:10.1371/journal.pone.0198935
87. DeBaker, MC, Robinson, JM, Moen, JK, Wickman, K, and Lee, AM. Differential patterns of alcohol and nicotine intake: combined alcohol and nicotine binge consumption behaviors in mice. Alcohol (2020) 85:57–64. doi:10.1016/j.alcohol.2019.09.006
88. Thomas, AM, Ostroumov, A, Kimmey, BA, Taormina, MB, Holden, WM, Kim, K, et al. Adolescent nicotine exposure alters GABAA receptor signaling in the ventral tegmental area and increases adult ethanol self-administration. Cell Rep (2018) 23:68–77. doi:10.1016/j.celrep.2018.03.030
89. Smith, AM, Kelly, RB, and Chen, WJ. Chronic continuous nicotine exposure during periadolescence does not increase ethanol intake during adulthood in rats. Alcohol Clin Exp Res (2002) 26:976–9. doi:10.1097/01.ALC.0000021176.13538.55
90. Madayag, AC, Czarnecki, KS, Wangler, LM, and Robinson, DL. Chronic nicotine exposure initiated in adolescence and unpaired to behavioral context fails to enhance sweetened ethanol seeking. Front Behav Neurosci (2017) 11:153. doi:10.3389/fnbeh.2017.00153
91. Ruffolo, J, Frie, JA, Thorpe, HHA, Talhat, MA, and Khokhar, JY. Alcohol and vaporized nicotine Co-exposure during adolescence contribute differentially to sex-specific behavioral effects in adulthood. Nicotine Tob Res (2022) 24:1177–85. doi:10.1093/ntr/ntab250
92. Abreu-Villaca, Y, Nunes, F, do E Queiroz-Gomes, F, Manhae, AC, and Filgueiras, CC. Combined exposure to nicotine and ethanol in adolescent mice DifferentiallyAffects anxiety levels during exposure, short-term, and long-term withdrawal. Neuropsychopharmacology (2008) 33:599–610. doi:10.1038/sj.npp.1301429
93. Abreu-Villaca, Y, Cavina, CC, Ribeiro-Carvalho, A, Correa-Santos, M, Naiff, VF, Filgueiras, CC, et al. Combined exposure to tobacco smoke and ethanol during adolescence leads to short- and long-term modulation of anxiety-like behavior. Drug Alcohol Depend (2013) 133:52–60. doi:10.1016/j.drugalcdep.2013.05.033
94. Abreu-Villaca, Y, Manhães, AC, Krahe, TE, Filgueiras, CC, and Ribeiro-Carvalho, A. Tobacco and alcohol use during adolescence: interactive mechanisms in animal models. Biochem Pharmacol (2017) 144:1–17. doi:10.1016/j.bcp.2017.06.113
95. Abreu-Villaca, Y, de Carvalho Graça, AC, Ribeiro-Carvalho, A, Naiff, VF, Manhães, AC, and Filgueiras, CC. Combined exposure to tobacco smoke and ethanol in adolescent mice elicits memory and learning deficits both during exposure and withdrawal. Nicotine Tob Res (2013) 15:1211–21. doi:10.1093/ntr/nts250
96. Riberio-Carvalho, A, Lima, CS, Nunes-Freitas, AL, Filgueiras, CC, Manhaes, AC, and Abreu-Villaca, Y. Exposure to nicotine and ethanol in adolescent mice: effects on depressive-like behavior during exposure and withdrawal. Behav Brain Res (2011) 221:282–9. doi:10.1016/j.bbr.2011.03.014
97. Larraga, A, Belluzzi, JD, and Leslie, FM. Nicotine increases alcohol intake in adolescent male rats. Front Behav Neurosci (2017) 11:25. doi:10.3389/fnbeh.2017.00025
98. Abreu-Villaca, Y, Guimaraes, VMS, Nunes-Freitas, A, Dutra-Tavares, AC, Manhaes, AC, Filgueiras, CC, et al. Tobacco smoke and ethanol during adolescence: both combined- and single-drug exposures lead to short- and long-term disruption of the serotonergic system in the mouse brain. Brain Res Bull (2019) 146:94–103. doi:10.1016/j.brainresbull.2018.12.007
99. Spear, LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev (2000) 24:417–63. doi:10.1016/s0149-7634(00)00014-2
100. Philpot, R, and Kirstein, C. Developmental differences in the accumbal dopaminergic response to repeated ethanol exposure. Ann N Y Acad Sci (2004) 1021:422–6. doi:10.1196/annals.1308.056
101. Philpot, RM, Wecker, L, and Kirstein, CL. Repeated ethanol exposure during adolescence alters the developmental trajectory of dopaminergic output from the nucleus accumbens septi. Int J Dev Neurosci (2009) 27:805–15. doi:10.1016/j.ijdevneu.2009.08.009
102. Di Chiara, G, and Bassareo, V. Reward system and addiction: what dopamine does and doesn't do. Curr Opin Pharmacol (2007) 7(1):69–76. doi:10.1016/j.coph.2006.11.003
103. Ikemoto, S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens-olfactory tubercle complex. Brain Res Rev (2007) 56:27–78. doi:10.1016/j.brainresrev.2007.05.004
104. Koob, GF, Arends, AA, McCracken, M, and Le Moal, M. Introduction to addiction: addiction, animal models, and theories. Academic Press (2019). p. 125–262.
105. Sahr, AE, Thielen, RJ, Lumeng, L, Li, T-K, and McBride, WJ. Long-lasting alterations of the mesolimbic dopamine system after periadolescent ethanol drinking by alcohol-preferring rats. Alcohol Clin Exp Res (2004) 28:702–11. doi:10.1097/01.alc.0000125344.79677.1c
106. Badanich, KA, Maldonado, AM, and Kirstein, CL. Chronic ethanol exposure during adolescence increases basal dopamine in the nucleus accumbens septi during adulthood. Alcohol Clin Exp Res (2007) 31:895–900. doi:10.1111/j.1530-0277.2007.00370.x
107. Toalston, JE, Deehan, GA, Hauser, SR, Engleman, EA, Bell, RL, Murphy, JM, et al. Reinforcing properties and neurochemical response of ethanol within the posterior ventral tegmental area are enhanced in adulthood by periadolescent ethanol consumption. J Pharmacol Exp Ther (2014) 351:317–26. doi:10.1124/jpet.114.218172
108. Hauser, SR, Mulholland, PJ, Truitt, WA, Waeiss, A, Engleman, EA, Bell, RL, et al. Adolescent intermittent ethanol (AIE) enhances the dopaminergic response to ethanol within the mesolimbic pathway during adulthood: alterations in cholinergic/dopaminergic genes expression in the nucleus accumbens shell. Int J Mol Sci (2021) 22:11733. doi:10.3390/ijms222111733
109. Zandy, SL, Matthews, DB, Tokunaga, S, Miller, A, Blaha, CD, and Mittleman, G. Reduced dopamine release in the nucleus accumbens core of adult rats following adolescent binge alcohol exposure: age and dose-dependent analysis. Psychopharmacology (Berl) (2015) 232:777–84. doi:10.1007/s00213-014-3712-1
110. McBride, WJ, Murphy, JM, Lumeng, L, and Li, TK. Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats. Alcohol (1990) 7:199–205. doi:10.1016/0741-8329(90)90005-w
111. Rodd-Henricks, ZA, McKinzie, DL, Crile, RS, Murphy, JM, and McBride, WJ. Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female wistar rats. Psychopharmacology (Berl) (2000) 149:217–24. doi:10.1007/s002139900347
112. Rodd, ZA, Bell, RL, Melendez, RI, Kuc, KA, Lumeng, L, Li, TK, et al. Comparison of intracranial self-administration of ethanol within the posterior ventral tegmental area between alcohol-preferring and wistar rats. Alcohol Clin Exp Res (2004) 28(8):1212–9. doi:10.1097/01.alc.0000134401.30394.7f
113. Rodd, ZA, Bell, RL, McQueen, VK, Davids, MR, Hsu, CC, Murphy, JM, et al. Chronic ethanol drinking by alcohol-preferring rats increases the sensitivity of the posterior ventral tegmental area to the reinforcing effects of ethanol. Alcohol Clin Exp Res (2005) 29:358–66. doi:10.1097/01.alc.0000156127.30983.9d
114. Ikemoto, S, Qin, M, and Liu, ZH. Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci (2006) 26:723–30. doi:10.1523/JNEUROSCI.4542-05.2006
115. Zangen, A, Solinas, M, Ikemoto, S, Goldberg, SR, and Wise, RA. Two brain sites for cannabinoid reward. J Neurosci (2006) 26:4901–7. doi:10.1523/JNEUROSCI.3554-05.2006
116. Rodd, ZA, Melendez, RI, Bell, RL, Kuc, KA, Zhang, Y, Murphy, JM, et al. Intracranial self-administration of ethanol within the ventral tegmental area of male Wistar rats: evidence for involvement of dopamine neurons. J Neurosci (2004) 24(5):1050–7. doi:10.1523/JNEUROSCI.1319-03.2004
117. Rodd, ZA, Bell, RL, Kuc, KA, Zhang, Y, Murphy, JM, and McBride, WJ. Intracranial self-administration of cocaine within the posterior ventral tegmental area of Wistar rats: evidence for involvement of serotonin-3 receptors and dopamine neurons. J Pharmacol Exp Ther (2005) 313:134–45. doi:10.1124/jpet.104.075952
118. Corrigall, WA, Coen, KM, and Adamson, KL. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res (1994) 653:278–84. doi:10.1016/0006-8993(94)90401-4
119. Nisell, M, Nomikos, GG, and Svensson, TH. Infusion of nicotine in the ventral tegmental area or the nucleus accumbens of the rat differentially affects accumbal dopamine release. Pharmacol Toxicol (1994) 75:348–52. doi:10.1111/j.1600-0773.1994.tb00373.x
120. Blomqvist, O, Ericson, M, Johnson, DH, Engel, JA, and Söderpalm, B. Voluntary ethanol intake in the rat: effects of nicotinic acetylcholine receptor blockade or subchronic nicotine treatment. Eur J Pharmacol (1996) 314:257–67. doi:10.1016/s0014-2999(96)00583-3
121. Ericson, M, Molander, A, Löf, E, Engel, JA, and Söderpalm, B. Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors. Eur J Pharmacol (2003) 467(1-3):85–93. doi:10.1016/s0014-2999(03)01564-4
122. Söderpalm, B, Ericson, M, Olausson, P, Blomqvist, O, and Engel, JA. Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res (2000) 113:85–96. doi:10.1016/s0166-4328(00)00203-5
123. Lê, AD, Corrigall, WA, Harding, JW, Juzytsch, W, and Li, TK. Involvement of nicotinic receptors in alcohol self-administration. Alcohol Clin Exp Res (2000) 24:155–63. doi:10.1111/j.1530-0277.2000.tb04585.x
124. Hendrickson, LM, Zhao-Shea, R, and Tapper, AR. Modulation of ethanol drinking-in- the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice. Psychopharmacology (Berl) (2009) 204:563–72. doi:10.1007/s00213-009-1488-5
125. Sajja, RK, and Rahman, S. Neuronal nicotinic receptor ligands modulate chronic nicotine-induced ethanol consumption in C57BL/6J mice. Pharmacol Biochem Behav (2012) 102:36–43. doi:10.1016/j.pbb.2012.03.017
126. Smith, BR, Horan, JT, Gaskin, S, and Amit, Z. Exposure to nicotine enhances acquisition of ethanol drinking by laboratory rats in a limited access paradigm. Psychopharmacology (Berl) (1999) 142:408–12. doi:10.1007/s002130050906
127. Waeiss, RA, Knight, CP, Carvajal, GB, Bell, RL, Engleman, EA, McBride, WJ, et al. Peri-adolescent alcohol consumption increases sensitivity and dopaminergic response to nicotine during adulthood in female alcohol-preferring (P) rats: alterations to α7 nicotinic acetylcholine receptor expression. Behav Brain Res (2019) 376:112190. doi:10.1016/j.bbr.2019.112190
128. Tizabi, Y, Copeland, RL, Louis, VA, and Taylor, RE. Effects of combined systemic alcohol and central nicotine administration into ventral tegmental area on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res (2002) 26:394–9. doi:10.1111/j.1530-0277.2002.tb02551.x
129. Tizabi, Y, Bai, L, Copeland, RL, and Taylor, RE. Combined effects of systemic alcohol and nicotine on dopamine release in the nucleus accumbens shell. Alcohol Alcohol (2007) 42:413–6. doi:10.1093/alcalc/agm057
130. Waeiss, RA, Knight, CP, Engleman, EA, Hauser, SR, and Rodd, ZA. Co-administration of ethanol and nicotine heightens sensitivity to ethanol reward within the nucleus accumbens (NAc) shell and increasing NAc shell BDNF is sufficient to enhance ethanol reward in naïve wistar rats. J Neurochem (2019) 152:556–69. doi:10.1111/jnc.14914
131. Ding, ZM, Katner, SN, Rodd, ZA, Truitt, W, Hauser, SR, Deehan, GA, et al. Repeated exposure of the posterior ventral tegmental area to nicotine increases the sensitivity of local dopamine neurons to the stimulating effects of ethanol. Alcohol (2012) 46:217–23. doi:10.1016/j.alcohol.2011.11.007
132. Deehan, GA, Hauser, SR, Waeiss, RA, Knight, CP, Toalston, JE, Truitt, WA, et al. Co-administration of ethanol and nicotine: the enduring alterations in the rewarding properties of nicotine and glutamate activity within themesocorticolimbic system of female alcohol-preferring (P) rats. Psychopharmacology (2015) 232:4293–302. doi:10.1007/s00213-015-4056-1
133. Truitt, WA, Hauser, SR, Deehan, GA, Toalston, JE, Wilden, JA, Bell, RL, et al. Ethanol and nicotine interaction within the posterior ventral tegmental area in male and female alcohol-preferring rats: evidence of synergy and differential gene activation in the nucleus accumbens shell. Psychopharmacology (2015) 232:639–49. doi:10.1007/s00213-014-3702-3
134. Deehan, GAJ, Hauser, SR, Getachew, B, Waeiss, RA, Engleman, EA, Knight, CP, et al. Selective breeding for high alcohol consumption and response to nicotine: locomotor activity, dopaminergic in the mesolimbic system and innate genetic differences in male and female alcohol-preferring, non-preferring and replicate lines of high-alcohol drinking and low-alcohol drinking rats. Psychopharmacology (Berl) (2018) 235:2755–69. doi:10.1007/s00213-018-4970-0
135. Bell, RL, Hauser, S, Rodd, ZA, Liang, T, Sari, Y, McClintick, J, et al. A genetic animal model of alcoholism for screening medications to treat addiction. Int Rev Neurobiol (2016) 126:179–261. doi:10.1016/bs.irn.2016.02.017
136. Hauser, SR, Knight, CP, Truitt, WA, Waeiss, RA, Holt, IS, Carvajal, GB, et al. Adolescent intermittent ethanol increases the sensitivity to the reinforcing properties of ethanol and the expression of select cholinergic and dopaminergic genes within the posterior ventral tegmental area. Alcohol Clin Exp Res (2019) 43:1937–48. doi:10.1111/acer.14150
137. Crews, FT, Fisher, R, Deason, C, and Vetreno, RP. Loss of basal forebrain cholinergic neurons following adolescent binge ethanol exposure: recovery with the cholinesterase inhibitor galantamine. Front Behav Neurosci (2021) 15:652494. doi:10.3389/fnbeh.2021.652494
138. Rollema, H, Chambers, LK, Coe, JW, Glowa, J, Hurst, RS, Lebel, LA, et al. Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology (2007) 52:985–94. doi:10.1016/j.neuropharm.2006.10.016
139. Kamens, HM, Silva, C, Peck, C, and Miller, CN. Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice. Brain Res Bull (2018) 138:20–5. doi:10.1016/j.brainresbull.2017.07.020
140. Swartzwelder, HS, Healey, KL, Liu, W, Dubester, K, Miller, KM, and Crews, FT. Changes in neuroimmune and neuronal death markers after adolescent alcohol exposure in rats are reversed by donepezil. Sci Rep (2019) 9:12110. doi:10.1038/s41598-019-47039-1
141. Schilström, B, Ivanov, VB, Wiker, C, and Svensson, TH. Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology (2007) 32:43–53. doi:10.1038/sj.npp.1301087
142. Kihara, T, Shimohama, S, Sawada, H, Honda, K, Nakamizo, T, Shibasaki, H, et al. Alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem (2001) 276:13541–6. doi:10.1074/jbc.M008035200
143. Takada, Y, Yonezawa, A, Kume, T, Katsuki, H, Kaneko, S, Sugimoto, H, et al. Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther (2003) 306(2):772–7. doi:10.1124/jpet.103.050104
144. LaLumiere, RT, and Kalivas, PW. Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci (2008) 28:3170–7. doi:10.1523/JNEUROSCI.5129-07.2008
145. Alasmari, F, Bell, RL, Rao, PSS, Hammad, AM, and Sari, Y. Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats. Pharmacol Biochem Behav (2018) 170:44–55. doi:10.1016/j.pbb.2018.05.006
146. Wills, L, and Kenny, PJ. Addiction-related neuroadaptations following chronic nicotine exposure. J Neurochem (2021) 157:1652–73. doi:10.1111/jnc.15356
147. Besson, M, Granon, S, Mameli-Engvall, M, Cloëz-Tayarani, I, Maubourguet, N, Cormier, A, et al. Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc Natl Acad Sci U S A (2007) 104:8155–60. doi:10.1073/pnas.0702698104
148. Zheng, F, Robertson, AP, Abongwa, M, Yu, EW, and Martin, RJ. The Ascaris suum nicotinic receptor, ACR-16, as a drug target: four novel negative allosteric modulators from virtual screening. Int J Parasitol Drugs Drug Resist (2016) 6:60–73. doi:10.1016/j.ijpddr.2016.02.001
149. Slemmer, JE, Martin, BR, and Damaj, MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther (2000) 295(1):321–7.
150. Nicholson, ER, Dilley, JE, and Froehlich, JC. Co-administration of low-dose naltrexone and bupropion reduces alcohol drinking in alcohol-preferring (P) rats. Alcohol Clin Exp Res (2018) 42:571–7. doi:10.1111/acer.13577
151. Navarro, M, Luhn, KL, Kampov-Polevoy, AB, Garbutt, JC, and Thiele, TE. Bupropion, alone and in combination with naltrexone, blunts binge-like ethanol drinking and intake following chronic intermittent access to ethanol in male C57bl/6J mice. Alcohol Clin Exp Res (2019) 43:783–90. doi:10.1111/acer.13992
152. Sajja, RK, and Rahman, S. Lobeline and Cytisine reduce voluntary ethanol drinking behavior in male C57BL/6J mice. Prog Neuropsychopharmacol Biol Psychiatry (2011) 35:257–64. doi:10.1016/j.pnpbp.2010.11.020
153. Farook, JM, Lewis, B, Gaddis, JG, Littleton, JM, and Barron, S. Lobeline, a nicotinic partial agonist attenuates alcohol consumption and preference in male C57BL/6J mice. Physiol Behav (2009) 97:503–6. doi:10.1016/j.physbeh.2009.02.031
154. Bell, RL, Eiler, BJ, Cook, JB, and Rahman, S. Nicotinic receptor ligands reduce ethanol intake by high alcohol-drinking HAD-2 rats. Alcohol (2009) 43:581–92. doi:10.1016/j.alcohol.2009.09.027
Keywords: adolescence, alcohol, nicotine, cholinergic system, co-abuse
Citation: Hauser SR, Waeiss RA, Deehan GA Jr., Engleman EA, Bell RL and Rodd ZA (2023) Adolescent alcohol and nicotine exposure alters the adult response to alcohol use. Adv. Drug Alcohol Res. 3:11880. doi: 10.3389/adar.2023.11880
Received: 02 August 2023; Accepted: 31 October 2023;
Published: 22 November 2023.
Edited by:
Emmanuel Onaivi, William Paterson University, United StatesReviewed by:
Douglas Matthews, University of Wisconsin–Eau Claire, United StatesShafiqur Rahman, South Dakota State University, United States
Copyright © 2023 Hauser, Waeiss, Deehan, Engleman, Bell and Rodd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sheketha R. Hauser, shhauser@iupui.edu