Growth Hormone Secretagogue Receptor (GHSR) Signaling in the Ventral Tegmental Area (VTA) Mediates Feeding Produced by Chronic Social Defeat Stress in Male Mice.

Ghrelin, a hormone secreted by the stomach, binds to the growth hormone secretagogue receptor (GHSR) in various brain regions to produce a number of behavioral effects that include increased feeding motivation. During social defeat stress, ghrelin levels rise in correlation with increased feeding and potentially play a role in attenuating the anxiogenic effects of social defeat. One region implicated in the feeding effects of ghrelin is the ventral tegmental area (VTA), a region implicated in reward seeking behaviors, and linked to social defeat in mice. Here we examined the role of GHSR signaling in the VTA in feeding behavior in mice exposed to social defeat stress. Male C57BL/J6 mice that were socially defeated once daily for 3 weeks ate more, had higher plasma ghrelin level and increased GHSR expression in the VTA compared to non-stressed mice. Socially defeated GHSR KO mice failed to increase their caloric intake in response to this stressor but rescue of GHSR expression in the VTA restored feeding responses. Finally, we pharmacologically blocked VTA GHSR signalling with JMV2959 infused via an indwelling VTA cannula connected to a minipump. Vehicle-treated mice increased their caloric intake during social defeat, but JMV2959-infusions attenuated feeding responses and increased anxiety-like behaviors. The data suggest that GHSR signalling in the VTA is critical for the increases in appetite observed during chronic social defeat stress. Furthermore, these data support the idea that GHSR signaling in the VTA may also have anxiolytic effects, and blocking GHSR in this region may result in an anxiety-like phenotype.

Metabolic, neuroendocrine and behavioral effects of social defeat in male and female mice using the chronic non-discriminatory social defeat stress model.

Stress-related disorders predominately affect females, yet preclinical models of chronic stress exclusively use males especially in models where social stressors are studied. Here, we implemented a 21-day novel social defeat paradigm in which a female and male C57 intruder are simultaneously placed in the cage of a territorial, resident CD-1 male mouse, and the resident proceeds to attack both intruders. Mice were given access to a regular laboratory diet, high in carbohydrates, and a palatable diet, high in fat. Chronic social defeat stress using this paradigm resulted in increased caloric intake in male and female mice, with the effects being more pronounced in females. We observed sex differences in high fat diet intake in response to stress, which was correlated with higher levels of plasma ghrelin observed in female mice but not male mice. Furthermore, females exposed to chronic stress displayed changes in growth hormone secretatogue receptor (ghsr) and neuropeptide-y (npy) expression in the arcuate nucleus of the hypothalamus, potentially increasing ghrelin sensitivity and inducing changes in diet choice and caloric intake. Behavioral results show that females tended to spend more time interacting during the social interaction test, compared to males who displayed higher vigilance towards the stranger mouse. Overall, our results highlight unique neurometabolic alterations in female mice in response to stress that is not present in male mice and may be important for coping with chronic stress and sustaining reproductive function.

Maternal glucose intolerance during pregnancy affects offspring POMC expression and results in adult metabolic alterations in a sex-dependent manner.

Introduction: Gestational diabetes (GDM) is associated with negative outcomes in mothers and their offspring, including greater risks of macrosomia at birth and the development of metabolic disorders. While these outcomes are well-established, the mechanisms by which this increased metabolic vulnerability is conferred on the offspring are comparatively lacking. One proposed mechanism is that maternal glycemic dysregulation alters the development of the hypothalamic regions related to metabolism and energy balance. Methods: To investigate this possibility, in this study, we first examined the effects of STZ-induced maternal glucose intolerance on the offspring on pregnancy day (PD) 19, and, in a second experiment, in early adulthood (postnatal day (PND) 60). Whether effects would be influenced by sex, or exposure of offspring to a high-fat diet was also investigated. The impact of maternal STZ treatment on POMC neuron number in the ARC of offspring at both time points was also examined. Results: As expected, STZ administration on PD 7 decreased maternal glucose tolerance, and increased risk for macrosomia, and loss of pups at birth. Offspring of STZ-treated mothers were also more vulnerable to developing metabolic impairments in adulthood. These were accompanied by sex-specific effects of maternal STZ treatment in the offspring, including fewer POMC neurons in the ARC of female but not male infants in late pregnancy and a higher number of POMC neurons in the ARC of both male and female adult offspring of STZ-treated dams, which was exacerbated in females exposed to a high-fat diet after weaning. Discussion: This work suggests that maternal hyperglycemia induced by STZ treatment, in combination with early-life exposure to an obesogenic diet, leads to adult metabolic alterations that correlate with the increased hypothalamic expression of POMC, showing that maternal glycemic dysregulation can impact the development of hypothalamic circuits regulating energy state with a stronger impact on female offspring.

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A ß-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.

Ghrelin and the Control of Energy Balance in Females.

Ghrelin is considered one of the most potent orexigenic peptide hormones and one that promotes homeostatic and hedonic food intake. Research on ghrelin, however, has been conducted predominantly in males and particularly in male rodents. In female mammals the control of energy metabolism is complex and it involves the interaction between ovarian hormones like estrogen and progesterone, and metabolic hormones. In females, the role that ghrelin plays in promoting feeding and how this is impacted by ovarian hormones is not well understood. Basal ghrelin levels are higher in females than in males, and ghrelin sensitivity changes across the estrus cycle. Yet, responses to ghrelin are lower in female and seem dependent on circulating levels of ovarian hormones. In this review we discuss the role that ghrelin plays in regulating homeostatic and hedonic food intake in females, and how the effects of ghrelin interact with those of ovarian hormones to regulate feeding and energy balance.

Examining Risk Factors in the Cannabis-Suicide Link: Considering Trauma and Impulsivity among University Students.

Cannabis is a commonly used substance among university students that may have several negative health repercussions, including suicidal ideation (SI) and suicide attempts (SA). The factors that contribute to or help explain this relation remain uncertain. Earlier negative experiences, especially trauma encountered during early life, have been associated with the development of psychopathology upon later stressor encounters. In the current study, we examined the associations between SI and SA with problematic cannabis use among young adults and the role of earlier trauma experiences and trait impulsiveness in understanding this link. Among university students (N = 539), problematic cannabis use was moderately related to lifetime and past-12-months suicidal ideation and attempts. Impulsiveness mediated the relationship between problematic cannabis use and lifetime SI and SA. Moreover, previous life trauma moderated the relationship between problematic cannabis use and SA, such that the association between problematic cannabis use and SA was stronger among those who experienced high levels of trauma. These findings highlight behavioral and environmental factors that could predict suicide ideation and attempts among young cannabis users. Accordingly, trait impulsiveness and early trauma experiences should be considered, alongside problematic cannabis use, in suicide-risk detection and prevention strategies among young adults.

Energetic demands of lactation produce an increase in the expression of growth hormone secretagogue receptor in the hypothalamus and ventral tegmental area of the rat despite a reduction in circulating ghrelin.

Lactating rats show changes in the secretion of hormones and brain signals that promote hyperphagia and facilitate the production of milk. Little is known, however, about the role of ghrelin in the mechanisms sustaining lactational hyperphagia. Here, we used Wistar female rats that underwent surgery to sever the galactophores to prevent milk delivery (GC rats) and decrease the energetic drain of milk delivery. We compared plasma acyl-ghrelin concentrations and growth hormone secretagogue receptor (GHSR) mRNA expression in different brain regions of GC rats with those of sham operated lactating and nonlactating rats. Additional lactating and nonlactating rats were implanted with cannulae aimed at the lateral ventricles and were used to compare feeding responses to central ghrelin or GHSR antagonist infusions to those of nonlactating rats receiving similar infusions on day 14-16 postpartum (pp). Results show lower plasma acyl-ghrelin concentrations on day 15 pp sham operated lactating rats compared to GC or nonlactating rats. These changes occur in association with increased GHSR mRNA expression in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA) of sham operated lactating rats. Despite lactational hyperphagia, infusions of ghrelin (0.25 or 1 µg) resulted in similar increases in food intake in lactating and nonlactating rats. In addition, infusions of the GHSR antagonist JMV3002 (4 µg in 1 µl of vehicle) produced greater suppression of food intake in lactating rats than in nonlactating rats. These data suggest that, despite lower plasma ghrelin, the energetic drain of lactation increases sensitivity to the orexigenic effects of ghrelin in brain regions important for food intake and energy balance, and these events are associated with lactational hyperphagia.

HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow-Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability.

Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow-derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice.

Chronic exposure to high circulating glucocorticoid or ghrelin concentrations increases food intake, weight gain and adiposity, suggesting that ghrelin could contribute to the metabolic effects of chronic glucocorticoids. In male mice, however, blocking ghrelin receptor (GHSR) signaling increased the weight gain and adiposity induced by chronic corticosterone (CORT), rather than attenuating them. In the current study, we investigated the role of GHSR signaling in the metabolic effects of chronic exposure to high circulating CORT in female mice. To do this, female WT and GHSR KO mice were treated with either CORT in a 1% ethanol (EtOH) solution or 1% EtOH alone in their drinking water for 32 days (n = 5-8/group). Body weight, food, and water intake as well as vaginal cyclicity were assessed daily. As expected, CORT treatment-induced significant increases in body weight, food intake, adiposity and also impaired glucose tolerance. In contrast to results observed in male mice, WT and GHSR KO female mice did not differ on any of these parameters. Neither plasma levels of ghrelin, LEAP-2, the endogenous GHSR antagonist produced by the liver, nor their ratio were altered by chronic glucocorticoid exposure. In addition, CORT treatment disrupted vaginal cyclicity, produced a reduction in sucrose consumption and increased locomotor activity regardless of genotype. Chronic CORT also decreased exploration in WT but not GHSR KO mice. Collectively, these data suggest that most metabolic, endocrine, reproductive and behavioral effects of chronic CORT exposure are independent of GHSR signaling in female mice.

Coping With the COVID-19 Pandemic: Examining Gender Differences in Stress and Mental Health Among University Students.

The COVID-19 pandemic has imposed a wide variety of unprecedented challenges, many of which appear to be disproportionately affecting the mental health and well-being of young adults. While there is evidence to suggest university students experience high rates of mental health disorders, less is known about the specific impacts of the COVID-19 pandemic on student mental health and how they are coping with this stress. To address this gap, we conducted an online study among undergraduate students (n = 366) to examine the impact of the COVID-19 pandemic on academics, social isolation, and mental health, as well as the extent to which they have been implementing a variety of coping strategies. The pandemic had a more pronounced negative effect on female students' academics, social isolation, stress and mental health compared to male counterparts. Moreover, for females, frequent use of social media as a coping mechanism was associated with greater perceived negative impacts on their academic performance and stress levels, compared to males. However, frequent social media use related to similar negative mental health effects for both males and females. While male and female students both reported using substances to cope, for males the use of cannabis was associated with greater negative impacts on academic outcomes, stress and mental health compared to females. These findings highlight the need for adequate student support services across the post-secondary sector, and point to the importance of gender informed interventions to address the impacts of the COVID-19 pandemic.

Contribution of growth hormone secretagogue receptor (GHSR) signaling in the ventral tegmental area (VTA) to the regulation of social motivation in male mice.

Most psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.

Metabolic effects of ghrelin delivery into the hypothalamic ventral premammilary nucleus of male mice.

Ghrelin is a 28 amino acid peptide hormone that targets the brain to promote feeding and adiposity. The ghrowth hormone secretagogue receptor 1a (GHSR1a) is expressed within many hypothalamic nuclei, including the ventral premammillary nucleus (PMV), but the role of GHSR1a signaling in this region is unknown. In order to investigate whether GHSR1a signaling within the PMV modulates energy balance, we implanted osmotic minipumps connected to cannulae that were implanted intracranially and aiming at the PMV. The cannulae delivered either saline or ghrelin (10 µg/day at a flow rate of 0.11µL/h for 28 days) into the PMV of adult male C57BLJ6 mice. We found that chronic infusion of ghrelin into the PMV increased weight gain, promoted the oxidation of carbohydrates as a fuel source and resulted in hyperglycemia, without affecting food intake, or body fat. This suggests that ghrelin signaling in the PMV contributes to the modulation of metabolic fuel utilization and glucose homeostasis.

Ghrelin infused into the dorsomedial hypothalamus of male mice increases food intake and adiposity.

Ghrelin is a 28 amino acid peptide hormone that targets the brain to promote feeding and adiposity. The ghrelin receptor, the GHSR1a, is expressed within most hypothalamic nuclei, including the DMH, but the role of GHSR1a in this region on energy balance is unknown. In order to investigate whether GHSR1a within the DMH modulate energy balance, we implanted osmotic minipumps filled with saline, ghrelin, or the GHSR1a antagonist JMV2959, and connected it to a cannula aimed unilaterally at the DMH of adult male C57BLJ6 mice and assessed their metabolic profile. We found that chronic infusion of ghrelin in the DMH promoted an increase in caloric intake as well as a decrease in energy expenditure. This translated to an overall increase in weight gain, primarily in the form of adipose tissue in ghrelin treated animals. Further, chronic ghrelin unilateral infusion into the DMH slowed glucose clearance. These results suggest that GHSR in the DMH significantly contribute to the metabolic effects produced by ghrelin.

Ghrelin Receptor Signaling Is Not Required for Glucocorticoid-Induced Obesity in Male Mice.

Chronically elevated levels of glucocorticoids increase food intake, weight gain, and adiposity. Similarly, ghrelin, a gut-secreted hormone, is also associated with weight gain, adiposity, and increased feeding. Here we sought to determine if corticosterone-induced metabolic and behavioral changes require functional ghrelin receptors (GHSR). To do this, we treated male C57BL mice with chronic corticosterone (CORT) mixed in their drinking water for 28 days. Half of these mice received the GHSR antagonist JMV2959 via osmotic minipumps while treated with CORT. In a second experiment, we gave the same CORT protocol to mice with a targeted mutation to the GHSR or their wild-type littermates. As expected, CORT treatment increased food intake, weight gain, and adiposity, but contrary to expectations, mice treated with a GHSR receptor antagonist or GHSR knockout (KO) mice did not show attenuated food intake, weight gain, or adiposity in response to CORT. Similarly, the effects of CORT on the liver were the same or more pronounced in GHSR antagonist-treated and GHSR KO mice. Treatment with JMV2959 did attenuate the effects of chronic CORT on glycemic regulation as determined by the glucose tolerance test. Finally, disruption of GHSR signaling resulted in behavioral responses associated with social withdrawal, potentially due to neuroprotective effects of GHSR activation. In all, we propose that blocking GHSR signaling helps to moderate glucose concentrations when CORT levels are high, but blocking GHSR signaling does not prevent increased food intake, weight gain, or increased adiposity produced by chronic CORT.

Ghrelin Signaling: GOAT and GHS-R1a Take a LEAP in Complexity.

Ghrelin and the growth hormone secretagogue receptor 1a (GHS-R1a) are important targets for disorders related to energy balance and metabolic regulation. Pharmacological control of ghrelin signaling is a promising avenue to address health issues involving appetite, weight gain, obesity, and related metabolic disorders, and may be an option for patients suffering from wasting conditions like cachexia. In this review, we summarize recent developments in the biochemistry of ghrelin and GHS-R1a signaling. These include unravelling the enzymatic transformations that generate active ghrelin and the discovery of multiple proteins that interact with ghrelin and GHS-R1a to regulate signaling. Furthermore, we propose that harnessing these processes will lead to highly selective treatments to address obesity, diabetes, and other metabolism-linked disorders.

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages.

Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production. We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral vs. inflammatory immune responses.

Stress and obesity: The ghrelin connection.

Ghrelin is a hormone associated with feeding and energy balance. Not surprisingly, this hormone is secreted in response to acute stressors and it is chronically elevated after exposure to chronic stress in tandem with a number of metabolic changes aimed at attaining homeostatic balance. In the present review, we propose that ghrelin plays a key role in these stress-induced homeostatic processes. Ghrelin targets the hypothalamus and brain stem nuclei that are part of the sympathetic nervous system to increase appetite and energy expenditure and promote the use of carbohydrates as a source of fuel at the same time as sparing fat. Ghrelin also targets mesolimbic brain regions such as the ventral segmental area and the hippocampus to modulate reward processes, to protect against damage associated with chronic stress, as well as to potentially increase resilience to stress. In all, these data support the notion that ghrelin, similar to corticosterone, is a critical metabolic hormone that is essential for the stress response.

Hungry to gamble? Ghrelin as a predictor of persistent gambling in the face of loss.

Ghrelin, a peptide hormone associated with appetite, is also linked to increased reward seeking behaviors, including food, sex, and drug seeking behaviors through the stimulation of the mesolimbic dopaminergic system. Moreover, plasma ghrelin concentrations are increased by cues that predict rewards, suggesting that cues could facilitate cravings and ultimately relapse. In this project we examined the effects of an overnight fast, a manipulation known to increase ghrelin concentrations, on gambling behaviors. We also examined if cues associated with gambling would also increase ghrelin and, if so, we examined if these increases were associated with gambling behavior. One hundred and one (37 females) participants were asked to fast overnight or after breakfast and then asked to complete food and gambling craving questionnaires. Participants were then presented with gambling cues (a casino like environment in the lab) or a control cue (a cubicle with a computer). After the cue, subjects filled gambling craving questionnaires, and were allowed to gamble. Following 25 practice spins, the slot machines were fixed so that all subsequent spins were losses, and the number of spins in spite of losses were quantified. Blood samples were collected throughout the experiment. Results showed that the gambling cues significantly increased ghrelin concentrations particularly in fasted individuals, and that ghrelin concentrations 20 min after the cue were the best predictor for gambling persistence in the face of continued loss (p < 0.05). Our results suggest that cues that predict the opportunity to gamble have an acute effect on ghrelin concentrations that is facilitated by fasting, and that ghrelin concentrations are a significant predictor of gambling persistence.

Palatable Food Dampens the Long-Term Behavioral and Endocrine Effects of Juvenile Stressor Exposure but May Also Provoke Metabolic Syndrome in Rats.

The juvenile period is marked by a reorganization and growth of important brain regions including structures associating with reward seeking behaviors such as the nucleus accumbens (NA) and prefrontal cortex (PFC). These changes are impacted by stressors during the juvenile period and may lead to a predisposition to stress induced psychopathology and abnormal development of brain reward systems. Like in humans, adult rodents engage certain coping mechanisms such as increases in the consumption of calorie-rich palatable foods to reduce stress, but this behavior can lead to obesity and metabolic disorders. In this study, we examined whether stressors during the juvenile period led to increased caloric intake when a palatable diet was accessible, and whether this diet attenuated adult stress responses. In addition, we examined if the stress buffering effects produced by the palatable diet were also accompanied by an offset propensity towards obesity, and by alterations in mRNA expression of dopamine (DA) receptors in the NA and PFC in adulthood. To this end, juvenile male Wistar rats underwent episodic stressor exposure (forced swim, elevated platform stress and restraint) on postnatal days (PD) 27-29 and received access to regular chow or daily limited access to a palatable diet until adulthood. At the age of 2 months, rats were tested on a social interaction test that screens for anxiety-like behaviors and their endocrine responses to an acute stressor. Animals were sacrificed, and their brains processed to detect differences in DA receptor subtype expression in the PFC and NA using qPCR. Results showed that rats that were stressed during the juvenile period displayed higher social anxiety and a sensitized corticosterone response as adults and these effects were attenuated by access to the palatable diet. Nevertheless, rats that experienced juvenile stress and consumed a palatable diet showed greater adiposity in adulthood. Interestingly, the same group displayed greater mRNA expression of DA receptors at the NA. This suggests that access to a palatable diet mitigates the behavioral and endocrine effects of juvenile stressor exposure in adulthood, but at the cost of metabolic imbalances and a sensitized dopaminergic system.