Opportunities for risk-taking during play alters cognitive performance and prefrontal inhibitory signalling in rats of both sexes.

Social play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered prefrontal cortex (PFC) synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.

CaMKIIa+ neurons in the bed nucleus of the stria terminalis modulate pace of natural reward seeking depending on internal state.

This study aims to investigate the underlying neurobiological mechanisms that regulate natural reward seeking behaviors, specifically in the context of sexual behavior and sucrose self-administration. The role of CaMKIIa+ neurons in the bed nucleus of the stria terminalis (BNST) was explored using chemogenetic silencing and -stimulation. Additionally, the study examined how these effects interacted with the internal state of the animals. Through detailed behavioral analysis, it was demonstrated that CaMKIIa+ neurons in the BNST play a significant role in the regulation of both sexual behavior and sucrose self-administration. Although the behavioral outcome measures differed between the two behaviors, the regulatory role of the CaMKIIa+ neurons in the BNST was found to converge on the modulation of the pacing of engagement in these behaviors in male rats. Moreover, our study confirmed that the internal physiological state of the animal affects how the BNST modulates these behaviors. These findings suggest that different types of natural rewards may recruit a similar brain circuitry to regulate the display of motivated behaviors. Overall, this research provides valuable insights into the neural mechanisms underlying natural reward seeking and sheds light on the interconnected nature of reward-related behaviors in male rats.

Alcohol cue reactivity in the brain: Age-related differences in the role of social processes in addiction in male drinkers.

Social attunement (SA)-the tendency to harmonize behavior with the social environment-has been proposed to drive the escalation of alcohol use in adolescence, while reducing use in adulthood. Little is known about how heightened social sensitivity in adolescence may interact with neural alcohol cue reactivity-a marker of alcohol use disorder-and its relationship to alcohol use severity over time. The aims of this study were to test whether (1) adolescents and adults differ in social alcohol cue reactivity in the nucleus accumbens, anterior cingulate cortex, and right medial prefrontal cortex (mPFC), and (2) age moderates the relationship between social alcohol cue reactivity and social attunement, measures of drinking at baseline, and changes in drinking over time. A sample of male adolescents (16-18 years) and adults (29-35 years) completed an fMRI social alcohol cue-exposure task at baseline and an online follow-up two to three years later. No main effects of age or drinking measures were observed in social alcohol cue reactivity. However, age significantly moderated associations of social alcohol cue reactivity in the mPFC and additional regions from exploratory whole-brain analyses with SA, with a positive association in adolescents and negative association in adults. Significant age interactions emerged only for SA in predicting drinking over time. Adolescents with higher SA scores escalated drinking, while adults with higher SA scores reduced drinking. These findings warrant further research on SA as a risk and protective factor and suggest that social processes influence cue reactivity differentially in male adolescents and adults.

Acquiring Financial Support for Children's Sports Participation: Co-Creating a Socially Safe Environment for Parents from Low-Income Families.

Despite the many benefits of club-organized sports participation for children, sports participation is lower among children from low-income families than among those from middle- or high-income families. Social safety experienced by parents from low-income families is an important facilitator for parents to request financial support for their children's sports participation. Therefore, the first aim of this study was to better understand parental social (un)safety in the context of acquiring financial support for children's sports participation and how to create a safe social environment for low-income parents to request and receive this financial support. The second aim was to describe the co-creation process, which was organized to contribute to social safety solutions. To reach these goals, we applied a participatory action research method in the form of four co-creation sessions with professionals and an expert-by-experience, as well as a group interview with parents from low-income families. The data analysis included a thematic analysis of the qualitative data. The results showed that from the perspective of parents, social safety encompassed various aspects such as understandable information, procedures based on trust, and efficient referral processes. Sport clubs were identified as the primary source of information for parents. Regarding the co-creation process, the study found that stakeholders tended to overestimate parental social safety levels. Although the stakeholders enjoyed and learned from the sessions, differences in prior knowledge and a lack of a shared perspective on the purpose of the sessions made it challenging to collaboratively create solutions. The study's recommendations include strategies for increasing parental social safety and facilitating more effective co-creation processes. The findings of this study can be used to inform the development of interventions that contribute to a social environment in which parents from low-income families feel safe to request and receive financial support for their children's sports participation.

A cross-sectional study on gaming intensity and social vulnerability in adolescents that have a chronic condition.

Background: Adolescents growing up with a chronic condition might experience more social vulnerabilities compared to their healthy peers as an indirect result of their conditions. This can lead to a relatedness need frustration for these adolescents. Consequently, they might spend more time playing video games compared to their peers. Research shows that both social vulnerability and gaming intensity are predictors for problematic gaming. Therefore, we investigated if social vulnerability and gaming intensity are more pronounced in adolescents that have a chronic condition compared to the general population; and if these levels reflect the levels of a clinical group being treated for Internet Gaming Disorder (IGD). Methods: Data on peer problems and gaming intensity were compared from three separate samples: a national representative sample of adolescents, a clinical sample of adolescents that are undergoing treatment for IGD, and a sample of adolescents diagnosed with a chronic condition. Results: No differences were found on either peer problems or gaming intensity between the group of adolescents that have chronic conditions and the national representative group. The group with chronic conditions scored significantly lower on gaming intensity than the clinical group. No significant differences were found between these groups on peer problems. We repeated the analyses for boys only. Similar results were found for the group with chronic conditions compared to the national representative group. The group with chronic conditions now scored significantly lower on both peer problems and gaming intensity than the clinical group. Conclusion: Adolescents growing up with a chronic condition appear similar in their gaming intensity and peer problems compared to their healthy peers.

The impact of age on olfactory alcohol cue-reactivity: A functional magnetic resonance imaging study in adolescent and adult male drinkers.

BACKGROUND: Adolescence is marked not only by rapid surges in the prevalence of alcohol use disorders (AUDs) but also by remarkable recovery rates, as most adolescent-onset AUDs naturally resolve over time. Little is known about the differential vulnerability of adolescents and adults. Therefore, this study aimed to unravel the moderating role of age by comparing neural alcohol cue-reactivity, an important AUD biomarker, between low-to-high beer-drinking adolescent (n = 50, 16 to 18 years), and adult (n = 51, 30 to 35 years) males matched on drinking severity. METHODS: Associations between beer odor-induced brain activity and AUD diagnosis, severity of alcohol use-related problems, recent alcohol use, binge-drinking frequency, and task-induced craving were investigated across and between age groups in regions of interest thought to be central in alcohol cue-reactivity: the medial prefrontal cortex, anterior cingulate cortex, and striatal subregions (nucleus accumbens and caudate putamen). These analyses were complemented by exploratory whole-brain analyses. RESULTS: Pre-task beer craving increased pre-to-post task in adolescents only. Individual differences in alcohol use, binge drinking, and craving did not relate to beer odor-induced activity. Although region-of-interest analyses did not reach significance, whole-brain analyses showed that adolescents with AUD, compared with adolescents without AUD and adults with AUD, had higher beer odor-induced activity in a large mesocorticolimbic cluster encompassing the right caudate, nucleus accumbens, orbitofrontal cortex, and the olfactory sulcus. Activity in the right caudate and putamen was positively associated with the severity of alcohol use-related problems in adolescents but negatively associated in adults. CONCLUSION: These findings suggest a differential role of alcohol cue-reactivity in adolescents compared with adults with AUD and highlight the need for further studies investigating the role of age in the fundamental processes underlying the development of and recovery from of AUD.

Age-dependent effects of tobacco smoke and nicotine on cognition and the brain: A systematic review of the human and animal literature comparing adolescents and adults.

Cigarette smoking is often initiated during adolescence and an earlier age of onset is associated with worse health outcomes later in life. Paradoxically, the transition towards adulthood also marks the potential for recovery, as the majority of adolescents are able to quit smoking when adulthood emerges. This systematic review aimed to evaluate the evidence from both human and animal studies for the differential impact of adolescent versus adult repeated and long-term tobacco and nicotine exposure on cognitive and brain outcomes. The limited human studies and more extensive yet heterogeneous animal studies, provide preliminary evidence of heightened fear learning, anxiety-related behaviour, reward processing, nicotinic acetylcholinergic receptors expression, dopamine expression and serotonin functioning after adolescent compared to adult exposure. Effects of nicotine or tobacco use on impulsivity were comparable across age groups. These findings provide novel insights into the mechanisms underlying adolescents' vulnerability to tobacco and nicotine. Future research is needed to translate animal to human findings, with a focus on directly linking a broader spectrum of brain and behavioural outcomes.

Age-related differences in the effect of chronic alcohol on cognition and the brain: a systematic review.

Adolescence is an important developmental period associated with increased risk for excessive alcohol use, but also high rates of recovery from alcohol use-related problems, suggesting potential resilience to long-term effects compared to adults. The aim of this systematic review is to evaluate the current evidence for a moderating role of age on the impact of chronic alcohol exposure on the brain and cognition. We searched Medline, PsycInfo, and Cochrane Library databases up to February 3, 2021. All human and animal studies that directly tested whether the relationship between chronic alcohol exposure and neurocognitive outcomes differs between adolescents and adults were included. Study characteristics and results of age-related analyses were extracted into reference tables and results were separately narratively synthesized for each cognitive and brain-related outcome. The evidence strength for age-related differences varies across outcomes. Human evidence is largely missing, but animal research provides limited but consistent evidence of heightened adolescent sensitivity to chronic alcohol's effects on several outcomes, including conditioned aversion, dopaminergic transmission in reward-related regions, neurodegeneration, and neurogenesis. At the same time, there is limited evidence for adolescent resilience to chronic alcohol-induced impairments in the domain of cognitive flexibility, warranting future studies investigating the potential mechanisms underlying adolescent risk and resilience to the effects of alcohol. The available evidence from mostly animal studies indicates adolescents are both more vulnerable and potentially more resilient to chronic alcohol effects on specific brain and cognitive outcomes. More human research directly comparing adolescents and adults is needed despite the methodological constraints. Parallel translational animal models can aid in the causal interpretation of observed effects. To improve their translational value, future animal studies should aim to use voluntary self-administration paradigms and incorporate individual differences and environmental context to better model human drinking behavior.

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol.

RATIONALE: Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT+/+ (regular functioning), SERT+/- (50% transporter reduction) and SERT-/- (complete reduction). OBJECTIVES: We investigated sex and genotype differences in ethanol consumption in SERT knock-out Wistar rats (F0) followed by studying behaviour in the offspring (F1) of the male drinkers to assess effects of paternal alcohol consumption. METHODS: An intermittent access two-bottle choice paradigm (IA2BC) was used to yield ethanol drinking behaviour in F0 adolescent Wistar rats. The highest drinking males were mated to alcohol-naive females and their offspring were compared with controls. Drinking behaviour (IA2BC) and ethanol-induced motor coordination effects (via rotarod) were measured in the F1s. RESULTS: F0 drinking saw no SERT genotype differences in males. However, females consumed higher volumes of ethanol compared to males, with SERT-/- females showing the highest intake. A clearer genotype effect was seen in the F1 animals, with reduction in SERT activity leading to enhanced ethanol intake in both sexes. Importantly, paternal exposure to ethanol significantly reduced the ethanol induced motor side effects in offspring, independent of sex and genotype. CONCLUSIONS: These indicate a difference in the way genetic factors may act across sexes and suggest the involvement of epigenetic mechanisms in the intergenerational effects of alcohol.

Increased elasticity of sucrose demand during hyperdopaminergic states in rats.

RATIONALE: Deficits in cost-benefit decision-making are a core feature of several psychiatric disorders, including substance addiction, eating disorders and bipolar disorder. Mesocorticolimbic dopamine signalling has been implicated in various processes related to cognition and reward, but its precise role in reward valuation and cost-benefit trade-off decisions remains incompletely understood. OBJECTIVES: We assessed the role of mesocorticolimbic dopamine signalling in the relationship between price and consumption of sucrose, to better understand its role in cost-benefit decisions. METHODS: Dopamine neurons in the ventral tegmental area (VTA) were chemogenetically activated in rats, and a behavioural economics approach was used to quantify the relationship between price and consumption of sucrose. Motivation for sucrose was also assessed under a progressive ratio (PR) schedule of reinforcement. To further gauge the role of dopamine in cost-benefit trade-offs for sucrose, the effects of treatment with D-amphetamine and the dopamine receptor antagonist alpha-flupentixol were assessed. RESULTS: Chemogenetic activation of VTA dopamine neurons increased demand elasticity, while responding for sucrose under a PR schedule of reinforcement was augmented upon stimulation of VTA dopamine neurons. Treatment with amphetamine partially replicated the effects of chemogenetic dopamine neuron activation, whereas treatment with alpha-flupentixol reduced free consumption of sucrose and had mixed effects on demand elasticity. CONCLUSIONS: Stimulation of mesocorticolimbic dopaminergic neurotransmission altered cost-benefit trade-offs in a complex manner. It reduced the essential value of palatable food, increased incentive motivation and left free consumption unaltered. Together, these findings imply that mesocorticolimbic dopamine signalling differentially influences distinct components of cost expenditure processes aimed at obtaining rewards.

On the interrelation between alcohol addiction-like behaviors in rats.

RATIONALE: Alcohol use disorder (AUD) is a complex, heterogeneous disorder that only occurs in a minority of alcohol users. Various behavioral constructs, including excessive intake, habit formation, motivation for alcohol and resistance to punishment have been implicated in AUD, but their interrelatedness is unclear. OBJECTIVE: The aim of this study was therefore to explore the relation between these AUD-associated behavioral constructs in rats. We hypothesised that a subpopulation of animals could be identified that, based on these measures, display consistent AUD-like behavior. METHODS: Lister Hooded rats (n = 47) were characterised for alcohol consumption, habit formation, motivation for alcohol and quinine-adulterated alcohol consumption. The interrelation between these measures was evaluated through correlation and cluster analyses. In addition, addiction severity scores were computed using different combinations of the behavioral measures, to assess the consistency of the AUD-like subpopulation. RESULTS: We found that the data was uniformly distributed, as there was no significant tendency of the behavioral measures to cluster in the dataset. On the basis of multiple ranked addiction severity scores, five animals (~ 11%) were classified as displaying AUD-like behavior. The composition of the remaining subpopulation of animals with the highest addiction severity score (9 rats; ~ 19%) varied, depending on the combination of measures included. CONCLUSION: Consistent AUD-like behavior was detected in a small proportion of alcohol drinking rats. Alcohol consumption, habit formation, motivation for alcohol and punishment resistance contribute in varying degrees to the AUD-like phenotype across the population. These findings emphasise the importance of considering the heterogeneity of AUD-like behavior.

Psychosocial functioning in adolescents growing up with chronic disease: The Dutch HBSC study.

Many adolescents worldwide (indirectly) grow up with a chronic disease, which may impact their functioning and wellbeing. The objective of this study is to assess whether adolescents with a (family member with a) chronic disease differ from their healthy counterparts in terms of psychosocial functioning. Data from the Dutch 2013 HBSC-survey were used, including 7168 adolescents (Meanage = 13.7, SD = 1.57, 50.5% female). Participants indicated whether they or one of their family members had a long-term (> 3 months) disease or disability (mental/physical) and were categorized into four groups based on disease presence (none, other, self, both). Psychosocial functioning was assessed in terms of life satisfaction, self-rated health, psychosomatic health, mental health problems, support, substance use, physical exercise, screen time, and school liking. Chronically diseased adolescents (n = 162) reported lower life satisfaction, self-rated and psychosomatic health, more mental health problems, lower peer support, more substance use, and less physical exercise compared to healthy peers. Chronically diseased adolescents who also had a family member with a chronic disease (n = 74) showed comparable outcomes on these life domains, although they did not differ from their healthy peers regarding peer support, substance use, and physical activity. Healthy adolescents with a chronically diseased family member (n = 737) reported significantly lower life satisfaction, self-rated and psychosomatic health, more mental health problems, and less family support compared to healthy peers who grew up in healthy families; however, they reported more positive outcomes than adolescents who had a chronic disease themselves.Conclusion: Having a (family member with a) chronic disease is associated with impaired psychosocial functioning on various life domains. Our findings aid in understanding the psychosocial associates of chronic disease and imply that caregivers should be observant of psychosocial problems among vulnerable adolescents to provide appropriate guidance. What is Known: • Adolescents who grow up with a (family member with a) chronic disease encounter numerous challenges that may be related to poorer developmental outcomes on the long term. What is New: • This study adds a comprehensive overview of the psychosocial functioning of adolescents with a (family member with a) chronic disease, as compared to healthy counterparts that grow up in a healthy family.

The continued need for animals to advance brain research.

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised.

Individual differences in social play behaviour predict alcohol intake and control over alcohol seeking in rats.

RATIONALE: Social play behaviour is a rewarding social activity displayed by young mammals, thought to be important for the development of brain and behaviour. Indeed, disruptions of social play behaviour in rodents have been associated with cognitive deficits and augmented sensitivity to self-administration of substances of abuse, including alcohol, later in life. However, the relation between social development and loss of control over substance use, a key characteristic of substance use disorders including alcohol use disorder (AUD), has not been investigated. Moreover, it remains unknown how inherent differences in playfulness relate to differences in the sensitivity to substance use and AUD. OBJECTIVE: The objective of this study is to determine how individual differences in juvenile social play behaviour predict alcohol intake and loss of control over alcohol seeking. METHODS: Juvenile male Lister hooded rats were characterized for their tendency to engage in social play behaviour. Subsequently, alcohol consumption and conditioned suppression of alcohol seeking were assessed in the tertiles of rats that showed the most and least social play. RESULTS: The rats that engaged most in social play behaviour consumed more alcohol than their less playful counterparts. However, whereas the most playful rats showed intact conditioned suppression of alcohol seeking, the least playful rats showed no such suppression. CONCLUSION: Individual levels of playfulness predict the sensitivity to alcohol-directed behaviour. Highly playful rats are more prone to alcohol intake, yet show greater control over alcohol seeking. These findings increase our understanding of the relationship between social development and vulnerability to AUD.

Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake.

In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.

How the COVID-19 pandemic highlights the necessity of animal research.

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.

Abstinence-dependent dissociable central amygdala microcircuits control drug craving.

We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with activation of CeL-expressing somatostatin (SOM) neurons. Here we determined the causal role of CeL PKCδ and SOM in incubation using short-hairpin RNAs against PKCδ or SOM that we developed and validated. We injected two groups with shPKCδ or shCtrlPKCδ into CeL and trained them to lever press for social interaction (6 d) and then for methamphetamine infusions (12 d). We injected two other groups with shSOM or shCtrlSOM into CeL and trained them to lever press for methamphetamine infusions (12 d). We then assessed relapse to methamphetamine seeking after 1 and 15 abstinence days. Between tests, the rats underwent either social choice-induced abstinence (shPKCδ groups) or homecage forced abstinence (shSOM groups). After test day 15, we assessed PKCδ and SOM, Fos, and double-labeled expression in CeL and central amygdala medial division (CeM). shPKCδ CeL injections decreased Fos in CeL PKCδ-expressing neurons, increased Fos in CeM output neurons, and reversed the inhibitory effect of social choice-induced abstinence on incubated drug seeking on day 15. In contrast, shSOM CeL injections decreased Fos in CeL SOM-expressing neurons, decreased Fos in CeM output neurons, and decreased incubated drug seeking after 15 forced abstinence days. Our results identify dissociable central amygdala mechanisms of abstinence-dependent expression or inhibition of incubation of craving.

Healthy play, better coping: The importance of play for the development of children in health and disease.

Play is of vital importance for the healthy development of children. From a developmental perspective, play offers ample physical, emotional, cognitive, and social benefits. It allows children and adolescents to develop motor skills, experiment with their (social) behavioural repertoire, simulate alternative scenarios, and address the various positive and negative consequences of their behaviour in a safe and engaging context. Children with a chronic or life-threatening disease may face obstacles that negatively impact play and play development, possibly impeding developmental milestones, beyond the actual illness itself. Currently, there is limited understanding of the impact of (1) aberrant or suppressed play and (2) play-related interventions on the development of chronic diseased children. We argue that stimulating play behaviour enhances the adaptability of a child to a (chronic) stressful condition and promotes cognitive, social, emotional and psychomotor functioning, thereby strengthening the basis for their future health. Systematic play research will help to develop interventions for young patients, to better cope with the negative consequences of their illness and stimulate healthy development.

Age-Related Differences in Alcohol Intake and Control Over Alcohol Seeking in Rats.

Alcohol use disorder (AUD) is characterized by excessive and persistent alcohol use, despite adverse consequences. AUD often originates during adolescence, as do other substance use disorders. However, despite periods of excessive alcohol intake, many adolescents reduce their alcohol use by early adulthood. Brain development, social context, personality traits, and genetic makeup are thought to play an important role in these age-dependent fluctuations in alcohol use. However, studies that directly investigate age-related differences in the effects of alcohol exposure on brain and behavior are sparse. Therefore, to better understand the relationship between adolescent alcohol consumption and AUD-like behavior, this study compared the degree of control over alcohol seeking in rats that differed in terms of age of onset of alcohol drinking and in their level of alcohol consumption. We hypothesized that control over alcohol seeking is more prominent in adolescent-onset rats than in adult-onset rats, and that control over alcohol seeking is related to the consumed amount of alcohol. To test this hypothesis, alcohol seeking in the presence of a conditioned aversive stimulus was assessed after 2 months of intermittent alcohol access (IAA) in rats that consumed alcohol from postnatal day 42 (adolescence) or day 77 (adulthood). The rats were subdivided into low (LD), medium (MD), or high (HD) alcohol drinking rats, in order to assess the impact of the extent of alcohol intake on control over alcohol seeking. The adolescent-onset animals consumed slightly, but significantly less alcohol compared to the adult-onset rats. In adult-onset rats, we found that conditioned suppression of alcohol seeking, i.e., reduction of alcohol seeking by presentation of a conditioned aversive stimulus, was most pronounced in LD. By contrast, in the adolescent-onset rats, MD and HD showed increased alcohol seeking compared to LD, which was suppressed by conditioned aversive stimuli. Taken together, these findings reveal a complex relationship between the age of onset and level of alcohol intake with control over alcohol seeking, whereby adolescent rats consume less alcohol than adults. In adult rats, control over alcohol seeking is negatively related to preceding levels of alcohol intake. By contrast, adolescent rats appear to retain control over alcohol seeking, even after a history of high levels of alcohol intake.