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

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

Who's laughing? Play, tickling and ultrasonic vocalizations in rats

Social play in rats is a highly rewarding, energetic form of social interaction and important for development of the brain and social skills. The 50 kHz ultrasonic vocalizations (USV) emitted during social play are thought to be an expression of a positive affective state (laughter), which in some situations may also function as communication signals. Heterospecific play, ‘tickling’ by an experimenter, is thought to simulate conspecific play, and has been used to improve welfare and to study the neurobiology of positive affect. Given that tickling evokes substantial amounts of USV, we investigated whether heterospecific play is simulating conspecific play by comparing USV-behaviour associations in both contexts. If the 50 kHz calls are merely an expression of ‘laughter’ then the pattern and type of emission in both contexts should be similar. By contrast, as playing with a conspecific involves a two-way exchange of signalling, the additional demands on communication should lead to a different pattern of calling. While calling was prevalent in both types of play, how the different types of 50 kHz calls are used in the two contexts differed markedly. The findings suggest that while conspecific and heterospecific play are positive experiences, tickling is not the equivalent of conspecific play. This article is part of the theme issue ‘Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience’

Treatment with low doses of nicotine but not alcohol affects social play reward in rats

Social play behaviour is a vigorous, highly rewarding activity inyoung animals. It is thought to facilitate social, cognitive andemotional development, but its underlying neural mechanisms areincompletely understood. Previously, we found that low doses ofalcohol and nicotine enhanced social play behaviour in youngrats. Using place and operant conditioning setups to assess thepleasurable and motivational aspects of social play, weinvestigated how treatment with nicotine and alcohol affectssocial play reward. Nicotine-treatment increased the incentivemotivational properties of social play as well as the expression ofsocial play itself. Moreover, while nicotine by itself evokedconditioned place preference (CPP), it reduced social play-inducedCPP. Alcohol-treatment did not affect the motivation for andexpression of social play, nor did it affect social play-induced CPP.Thefinding that nicotine but not alcohol modulates social playreward increases our understanding of the neural underpinningsof this developmentally important behaviour

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