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We examined the interaction between early life stress and vulnerability to alcohol in female rats exposed to prenatal restraint stress (PRS rats). First we studied the impact of PRS on ethanol preference during adolescence. PRS slightly increased ethanol preference per se, but abolished the effect of social isolation on ethanol preference. We then...
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... It should be noted that such effects were observed at the ethanol doses that did not induce significant changes in the animal's locomotor activity. Thus, our results are in agreement with previous work demonstrating that prenatal ethanol exposure increases alcohol preference in later life in humans [11] and in rodents [61,62] and confirm that the drug's rewarding properties not associated with the sensitivity to its locomotor stimulation effect [12,63,64]. In our study, rapamycin, the mTORC1 inhibitor, given before ethanol administration during the neonatal period prevented the sensitivity to rewarding effects of ethanol in adulthood. ...
Ethanol exposure during pregnancy alters the mammalian target of rapamycin (mTOR) signaling pathway in the fetal brain. Hence, in adult rats exposed to ethanol during the neonatal period, we investigated the influence of rapamycin, an mTOR Complex 1 (mTORC1) inhibitor, on deficits in spatial memory and reversal learning in the Barnes maze task, as well as the ethanol-induced rewarding effects (1.0 or 1.5 g/kg) using the conditioning place preference (CPP) paradigm. Rapamycin (3 and 10 mg/kg) was given before intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). Spatial memory/reversal learning and rewarding ethanol effect were evaluated in adult (PND60–70) rats. Additionally, the impact of rapamycin pre-treatment on the expression of the GluN2B subunit of NMDA receptor in the brain was assessed in adult rats. Our results show that neonatal ethanol exposure induced deficits in spatial memory and reversal learning in adulthood, but the reversal learning outcome may have been due to spatial learning impairments rather than cognitive flexibility impairments. Furthermore, in adulthood the ethanol treated rats were also more sensitive to the rewarding effect of ethanol than the control group. Rapamycin prevented the neonatal effect of ethanol and normalized the GluN2B down-regulation in the hippocampus and the prefrontal cortex, as well as normalized this subunit’s up-regulation in the striatum of adult rats. Our results suggest that rapamycin and related drugs may hold promise as a preventive therapy for fetal alcohol spectrum disorders.
... A recent review from the Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium indicates that adolescent alcohol exposure generally produces long-lasting changes in anxiety-like activity in adulthood in rodents 9 . Adolescent alcohol exposure has also been linked to alterations in despair/depressive-like behavior in adulthood that may be sex-dependent, but these results are not consistent [10][11][12][13][14][15][16] . The NADIA Consortium notes that these inconsistencies may be due to the alcohol exposure paradigm and that potential differences between sexes have not been systematically addressed 9 . ...
Adolescent alcohol use is one of the strongest predictors for the development of an alcohol use disorder (AUD). Notably, this period of risk coincides with the development of affective disorders, which disproportionately impact and drive problematic drinking behavior in women. Stress is a particularly salient factor that drives relapse during periods of abstinence. Previous work in our lab has shown that adolescent intermittent ethanol vapor (AIE) produces sex-dependent changes in glutamatergic activity in the bed nucleus of the stria terminalis (BNST) and behavioral outcomes following acute restraint stress in adulthood. In females, AIE disrupts group 1 metabotropic glutamate (mGlu1/5) receptor activity and enhances anhedonia-like behavior. The current study site-specifically knocked down mGlu5 receptors in the BNST of male and female Grm5loxp mice, exposed them to AIE, and observed the interaction of AIE and stress on negative affect-like behaviors in adulthood. These negative affect-like behaviors included the novelty-induced hypophagia task following acute restraint stress, open field activity, and contextual fear conditioning. Overall, we replicated our previous findings that AIE enhanced anhedonia-like activity in the novelty-induced hypophagia task in females and fear acquisition in males. The primary effect of BNST-mGlu5 receptor knockdown was that it independently enhanced anhedonia-like activity in females. Correlation analyses revealed that behavior in these paradigms showed poor interdependence. These results indicate that preclinical models of negative affective-like states encompass distinct features that may have independent, clinically relevant mechanisms. Further, modulating mGlu5 receptors is a prospective treatment target for females experiencing anhedonic-like states that make them susceptible to alcohol relapse.
... Furthermore, exposure to stress has been tightly linked to addictive behaviors (Chauvet, Lardeux, Goldberg, Jaber, & Solinas, 2009;Piazza et al., 1991). Several studies have shown that exposure to prenatal restraint stress induces an enhanced vulnerability to addiction (Deminière et al., 1992;Morley-Fletcher et al., 2004;Reynaert et al., 2016;Van Waes et al., 2011). A recent study from our group highlighted that exposure of mice to prenatal stress leads to excessive alcohol intake in association with anxiety-like behavior in adulthood (Dong, Guidotti, Zhang, & Pandey, 2018). ...
Chronic exposure to stress throughout lifespan alters brain structure and function, inducing a maladaptive response to environmental stimuli, that can contribute to the development of a pathological phenotype. Studies have shown that hypothalamic-pituitary-adrenal (HPA) axis dysfunction is associated with various neuropsychiatric disorders, including major depressive, alcohol use and post-traumatic stress disorders. Downstream actors of the HPA axis, glucocorticoids are critical mediators of the stress response and exert their function through specific receptors, i.e., the glucocorticoid receptor (GR), highly expressed in stress/reward-integrative pathways. GRs are ligand-activated transcription factors that recruit epigenetic actors to regulate gene expression via DNA methylation, altering chromatin structure and thus shaping the response to stress. The dynamic interplay between stress response and epigenetic modifiers suggest DNA methylation plays a key role in the development of stress surfeit disorders.
... In contrast, other studies have reported that female offspring who experience prenatal stress in late gestation were hypoactive and anxious (Bowman et al., 2004;Zagron and Weinstock, 2006), as evidenced by longer open field entry latencies or by less open arm frequency, central platform frequency, and less open arm duration in the elevated plus maze (Carola et al., 2002). Numerous researchers have reported that PRS in male rats results in prominent hypoactivity and anxiety-like behavior, while female rats are more prone to developing depression-like behavior (Zuena et al., 2008;Morley-Fletcher et al., 2011;Van Waes et al., 2011). Even though the behavioral results reported in other studies seem inconsistent with those from the current study, we note that none of the other studies had the same experimental design. ...
Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress (PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation (days 8–14 and 15–21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light (6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early- and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China (approval No. KMMU2019074) in January 2019.
... In the context of preventing negative-affect-induced relapse, it is necessary to investigate whether mGlu 5 receptor modulation might also rescue enhanced anxiety-like activity that occurs during extensive ethanol abstinence. Similarly, females may be especially sensitive to anxiety during periods of abstinence [11,47], with protracted withdrawal from adolescent alcohol resulting in enhanced anxiety-like and despair behavior [99,102]. These results highlight the need to observe the ability of mGlu 5 receptor modulation to alter anxiety-like activity in males and females during protracted withdrawal from alcohol. ...
Allosteric modulators of metabotropic glutamate 5 receptors (mGlu5 receptors) have been identified as a promising treatment to independently alleviate both negative affective states and ethanol-seeking and intake. However, these conditions are often comorbid and might precipitate one another. Acute and protracted ethanol withdrawal can lead to negative affective states. In turn, these states are primary drivers of alcohol relapse, particularly among women. The current review synthesizes preclinical studies that have observed the role of mGlu5 receptor modulation in negative affective states following ethanol exposure. The primary behavioral assays discussed are ethanol-seeking and intake, development and extinction of ethanol-associated cues and contexts, behavioral despair, and anxiety-like activity. The work done to-date supports mGlu5 receptor modulation as a promising target for mediating negative affective states to reduce ethanol intake or prevent relapse. Limitations in interpreting these data include the lack of models that use alcohol-dependent animals, limited use of adolescent and female subjects, and a lack of comprehensive evaluations of negative affective-like behavior.
... int/maternal_child_adolescent/topics/adolescence/dev/en/). The available research in adolescence mostly has involved social isolation housing (Butler, Carter, & Weiner, 2014;Doremus et al., 2005;Schenk, Gorman, & Amit, 1990;Skelly, Chappell, Carter, & Weiner, 2015;Van Waes et al., 2011). Although often referred to as a social stressor, social isolation housing does not involve the repeated, rapid, and prolonged elevation of corticosterone that usually identifies an event as a stressor and may be better characterized as a severe form of "social malnourishment" (reviewed in McCormick, Green, & Simone, 2017;McCormick et al., 2015;Montagu, 1977). ...
Social instability stress in adolescent rats (SS; postnatal day 30-45, daily 1 hour isolation + new cage partner) alters behavioural responses to psychostimulants, but differences in voluntary consumption of natural and drug rewards is unknown. SS also is associated with an atypical behavioural repertoire, e.g., reduced social interactions. Here, we investigated whether SS rats differ from control (CTL) rats in ethanol (EtOH) or sucrose intake in experiments involving different social contexts: alone, in the presence of an unfamiliar peer, in the presence of its cage partner, or in competition against its cage partner. SS rats drank more EtOH than CTL rats irrespective of social context, although the effects were driven primarily by those tested soon after the test procedure rather than weeks later in adulthood. SS and CTL rats did not differ in sucrose intake, except in adulthood under conditions of competition for limited access (SS > CTL). Adolescent rats drank more sucrose than adults, in keeping with evidence that adolescents are more sensitive to natural rewards than adult animals. Overall, adolescent SS modified the reward value of EtOH and sucrose, perhaps through stress/glucocorticoids modifying the development of the mesocorticolimbic system.
... Rodents with a history of early life adversity display more anxiety-related behavior in the elevated plus maze, reduced feeding in a novel environment and reduced activity in an open field (Wigger and Neumann, 1999;Macrí et al., 2004;Aisa et al., 2007;Pascual and Zamora-León, 2007;Li et al., 2013). Increased depressive-like behavior in the forced swimming test and sucrose intake test are also commonly reported (Morley-Fletcher et al., 2003;Cui et al., 2006;Aisa et al., 2007;Van Waes et al., 2011). In the cognitive domain, maternal separation during the first 3 weeks of life impairs learning of male Wistar rats in the Morris water maze and novel object recognition test (Aisa et al., 2007). ...
Early life adversity has a profound impact on brain development and later life health. Animal models have provided insight how early life stress programs stress responsiveness and might contribute to the development of psychiatric disorders. In the present study, the long-term effects of maternal deprivation on behavioral inhibition and attention were examined in adult male Wistar rats. To this end animals were tested in the 5-choice serial reaction time task (5-choice SRTT). We also explored the potential of a 3-day treatment with the glucocorticoid receptor antagonist mifepristone during early adolescence to normalize putative behavioral effects of early life stress. Deprivation of the mother for 24h on postnatal day (PND) 3 led to a modest but significant increase in premature responses in the 5-choice SRTT, but did not affect measures of attention. Bodyweight was lower in deprived animals from weaning until the start of testing. Early adolescent mifepristone treatment (PND 26-28) did not influence performance on the 5-choice SRTT and did not mitigate the deprivation-related impairment in behavioral inhibition. Our results indicate that maternal deprivation leads to impaired behavioral inhibition, and that mifepristone treatment during early adolescence does not normalize the behavioral changes caused by early life stress.
... Gender is a critical factor in some behavioral phenotypes induced by PRS in rats, with males showing greater susceptibility to emotional behavior in adult life (Valle´e et al., 1997(Valle´e et al., , 1999Zuena et al., 2008), and displaying an increased behavioral response (ultrasonic vocalizations) to social isolation in infancy (Laloux et al., 2012) and reduced social play during adolescence (Morley-Fletcher et al., 2003b). In contrast, no gender effect has been found in the forced swimming test (Morley-Fletcher et al., 2003a, 2004aVan Waes et al., 2011) or the splash test (Marrocco et al., 2014) in PRS rats. Again, it should be highlighted that chronic treatment with antidepressants in adulthood can fully reverse these behavioral abnormalities in PRS rats (Morley-Fletcher et al., 2003a, 2004aMairesse et al., 2013). ...
In mammals, early adverse experiences, including mother-pup interactions, shape the response of an individual to chronic stress or to stress-related diseases during adult life. This has led to the elaboration of the theory of the developmental origins of health and disease (DOHaD), in particular adult diseases such as cardiovascular and metabolic disorders. In addition, in humans, as stated by Massimo Fagioli’s Human Birth Theory, birth is healthy and equal for all individuals, so that mental disorders develop exclusively in the postnatal period because of the quality of the relationship in the first year of life. Thus, this review focuses on the importance of programming during the early developmental period on the manifestation of adult diseases in both animal models and humans. Considering the obvious differences between animals and humans we cannot systematically move from animal models to humans. Consequently, in the first part of this review, we will discuss how animal models can be used to dissect the influence of adverse events occurring during the prenatal and postnatal periods on the developmental trajectories of the offspring, and in the second part, we will discuss the role of postnatal critical periods on the development of mental diseases in humans. Epigenetic mechanisms that cause reversible modifications in gene expression, driving the development of a pathological phenotype in response to a negative early postnatal environment, may lie at the core of this programming, thereby providing potential new therapeutic targets. The concept of the Human Birth Theory leads to a comprehension of the mental illness as a pathology of the human relationship immediately after birth and during the first year of life.
... When social interaction occurred within the same context as self-administration, group-housed rats drank as much or more alcohol as isolated rats (Doremus et al., 2005;Thorsell et al., 2005). Nevertheless, other studies have not supported such a hypothesis (Pisu et al., 2011;Van Waes et al., 2011). ...
... The sex of the rat might also modulate the effects of group access to alcohol. A study by Van Waes et al. (2011) showed that when alcohol was presented in the home cage, female rats that were isolated and tested during adolescence consumed more alcohol than paired female rats. This result contrasts with the studies that used the male rats mentioned above, suggesting that the effect of group housing on alcohol consumption is influenced by sex. ...
Social conditions have been proposed to play a significant role in determining alcohol dependence, but no consensus has been reached regarding the circumstances under which social interaction influences alcohol intake. Studies with animal models that investigate the effects of social conditions on alcohol consumption have reported mixed results. In the present review, we intended to identify procedural variables that may explain differences among experiments. Separately, we analyzed features of isolation and group-housing conditions that might influence the effects of social conditions on alcohol consumption. For each condition, some variables were found to influence alcohol consumption. In isolation studies, variables such as age at isolation, age at alcohol intake, and length of isolation have been shown to alter alcohol intake. Studies that have focused on social interaction showed that such factors as group size, environmental enrichment, and the context of self-administration affect consumption in group-housed rats. The studies reviewed herein indicated that several elements of social conditions-and numerous interactions between them-influence drinking behavior. Systematic evaluations that isolate the effects of each variable are necessary to better understand the effects of the interplay between biological and environmental factors on alcohol consumption. (PsycINFO Database Record
... These and other data not reviewed here Läck et al. 2005;Richardson et al. 2008a;Uhart & Wand 2009) show that effects of chronic EtOH exposure on CRF systems cannot be defined without careful consideration of methodological details. Furthermore, factors such as sex, species and age of stress or EtOH exposure should be considered (Logrip et al. 2013;Przybycien-Szymanska et al. 2010Silva et al. 2009;Van Waes et al. 2011). ...
The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol consumption and ethanol-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including ethanol and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in ethanol drinking and in the effects of chronic or repeated ethanol treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF1) in ethanol-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence, and alter ethanol sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with ethanol drinking, though additional data are needed. These results suggest that CRF1 antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.
