Compensatory neuroadaptation to binge drinking: Human evidence for allostasis.

Animal studies have established that acute alcohol increases neural inhibition and that frequent intoxication episodes elicit neuroadaptive changes in the excitatory/inhibitory neurotransmission balance. To compensate for the depressant effects of alcohol, neural hyperexcitability develops in alcohol use disorder and is manifested through withdrawal symptoms. It is unclear, however, whether neuroadaptive changes can be observed in young, emerging adults at lower levels of consumption in the absence of withdrawal symptoms. Here, we used an anatomically constrained magnetoencephalography method to assess cortical excitability in two independent sets of experiments. We measured early visual activity (1) in social drinkers during alcohol intoxication versus placebo conditions and (2) in parallel cohorts of sober binge drinkers (BDs) and light drinkers (LDs). Acute alcohol intoxication attenuated early sensory activity in the visual cortex in social drinkers, confirming its inhibitory effects on neurotransmission. In contrast, sober BDs showed greater neural responsivity compared with a matched group of LDs. A positive correlation between alcohol consumption and neural activity in BDs is indicative of cortical hyperexcitability associated with hazardous drinking. Furthermore, neural responsivity was positively correlated with alcohol intake in social drinkers whose drinking did not reach binge levels. This study provides novel evidence of compensatory imbalance reflected in the downregulation of inhibitory and upregulation of excitatory signaling associated with binge drinking in young, emerging adults. By contrasting acute effects and a history of BD, these results support the mechanistic model of allostasis. Direct neural measures are sensitive to synaptic currents and could serve as biomarkers of neuroadaptation.

Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework.

The development of alcohol use disorder (AUD) involves binge or heavy drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three heuristic stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.

Susceptibility Variations in Air Pollution Health Effects: Incorporating Neuroendocrine Activation.

Diverse host factors/phenotypes may exacerbate or diminish biological responses induced by air pollutant exposure. We lack an understanding of biological indicators of environmental exposures that culminate in a physiological response versus those that lead to adversity. Variations in response phenotype might arise centrally and/or at the local tissue level. In addition to genetic differences, the current evidence supports the roles of preexisting cardiopulmonary diseases, diabetes, diet, adverse prenatal environments, neurobehavioral disorders, childhood infections, microbiome, sex, and psychosocial stressors in modifying the susceptibility to air pollutant exposures. Animal models of human diseases, obesity, nutritional inadequacies, and neurobehavioral conditions have been compared with healthy controls to understand the causes of variations in susceptibility. Although psychosocial stressors have been associated with increased susceptibility to air pollutant effects, the contribution of neuroendocrine stress pathways in mediating these effects is just emerging. The new findings of neuroendocrine activation leading to systemic metabolic and immunological effects of air pollutants, and the potential contribution to allostatic load, emphasize the consideration of these mechanisms into susceptibility. Variations in susceptibility to air pollution health effects are likely to underlie host genetic and physiological conditions in concert with disrupted neuroendocrine circuitry that alters physiological stability under the influence of stressors.

Compared to non-drinkers, individuals who drink alcohol have a more favorable multisystem physiologic risk score as measured by allostatic load.

AIMS: Alcohol use is associated with both positive and negative effects on individual cardiovascular risk factors, depending upon which risk factor is assessed. The present analysis uses a summative multisystem index of biologic risk, known as allostatic load (AL), to evaluate whether the overall balance of alcohol-associated positive and negative cardiovascular risk factors may be favorable or unfavorable. METHODS: This analysis included 1255 adults from the Midlife in the United States (MIDUS) biomarker substudy. Participants, average age 54.5 (±11) years, were divided into 6 alcohol-use categories based on self-reported drinking habits. Current non-drinkers were classified as lifelong abstainers and former light drinkers, former moderate drinkers, or former heavy drinkers. Current alcohol users were classified as light, moderate, or heavy drinkers. A total AL score was calculated using 24 biomarkers grouped into 7 physiologic systems including cardiovascular, inflammation, glucose metabolism, lipid metabolism, sympathetic and parasympathetic nervous systems, and the hypothalamic-pituitary-adrenal axis. Mixed-effects regression models were fit to determine the relationship between alcohol use categories and AL with controls for covariates that may influence the relationship between alcohol use and AL. RESULTS: 468 (37.6%) individuals were current non-drinkers while 776 (62.4%) were current drinkers. In adjusted mixed-effects regression models, all 3 groups of current drinkers had significantly lower average AL scores than the lifelong abstainer/former light drinker group (light: -0.23, 95% CI -0.40, -0.07, p < 0.01; moderate: -0.20, 95% CI -0.38, -0.02, p < 0.05; heavy: -0.30, 95% CI -0.57, -0.04, p < 0.05), while the average AL scores of former moderate and former heavy drinkers did not differ from the lifelong abstainer/former light drinker group. CONCLUSIONS: Current alcohol use is associated cross-sectionally with a favorable multisystem physiologic score known to be associated with better long-term health outcomes, providing evidence in support of long-term health benefits related to alcohol consumption.

Allostatic load is associated with psychotic symptoms and decreases with antipsychotic treatment in patients with schizophrenia and first-episode psychosis.

Current pathophysiological models of schizophrenia suggest that stress contributes to the etiology and trajectory of the disorder. We investigated if allostatic load (AL), an integrative index of neuroendocrine, immune and metabolic dysregulation in response to chronic stress, is elevated in patients with schizophrenia (SCZ) and first-episode psychosis (FEP) and related to psychotic symptoms and social and occupational functioning. Additionally, we assessed the temporal dynamics of AL in response to treatment with second-generation antipsychotics. AL, psychotic symptoms and psychosocial functioning were assessed in a longitudinal design in patients with SCZ (n = 28), FEP (n = 28), and healthy controls (n = 53) at baseline and 6 and 12 weeks after commencement of antipsychotic therapy. AL at baseline was higher in patients with SCZ and FEP relative to controls, but not different between patients with SCZ and FEP. Adjusting for age and smoking, we found that positive symptoms were positively correlated with AL and psychosocial functioning was negatively correlated with AL at trend level. Linear mixed model analysis demonstrated that AL decreased after treatment was commenced in patients with SCZ and FEP between the baseline assessment and the 6 and 12-week follow-up. AL was not predictive of treatment response or symptomatic remission. Our data provide evidence for cumulative physiological dysregulation in patients with SCZ and FEP that is linked to the experience of current positive psychotic symptoms. AL could be a useful tool to monitor biological signatures related to chronic stress and unhealthy behaviors in schizophrenia.

Eurycoma Longifolia as a potential adoptogen of male sexual health: a systematic review on clinical studies.

Eurycoma longifolia (EL) has been well recognized as a booster of male sexual health. Over the past few decades, numerous in vivo animal studies and human clinical trials have been conducted across the globe to explore the promising role of EL in managing various male sexual disorders, which include erectile dysfunction, male infertility, low libido, and downregulated testosterone levels. The aim of the present review is to analyze and summarize the literature on human clinical trials which revealed the clinical significance and therapeutic feasibility of EL in improving male sexual health. This systematic review is focused on the following databases: Medline, Wiley Online Library, BioMed Central, Hindawi, Web of Knowledge, PubMed Central and Google Scholar, using search terms such as "Eurycoma longifolia", "EL", "Tongkat Ali", "male sexual health", "sexual infertility", "erectile dysfunction", "male libido", and "testosterone levels". Notably, only human clinical studies published between 2000 and 2014 were selected and thoroughly reviewed for relevant citations. Out of 150 articles, 11 met the inclusion criteria. The majority of articles included were randomized placebo-controlled trials, multiple cohort studies, or pilot trials. All these studies demonstrated considerable effects of EL on male sexual health disorders. Among them, 7 studies revealed remarkable association between the use of EL and the efficacy in the treatment of male sexual disorders, and remaining 4 studies failed to demonstrate sufficient effects on male sexual health. In summary, there is convincing evidence for the prominence of EL in improving the male sexual health. The review also substantiates the use of current methodology in the development of novel and more rationale natural herbal medicines for the management of male sexual disorders.

Lead exposure is related to hypercortisolemic profiles and allostatic load in Brazilian older adults.

Lead levels (Pb) have been linked to both hyper- and hypo-reactivity of hypothalamic-pituitary-adrenal axis (HPA) axis to acute stress in animals and humans. Similarly, allostatic load (AL), the 'wear and tear' of chronic stress, is associated with inadequate HPA axis activity. We examined whether Pb levels would be associated with altered diurnal cortisol profile, as a primary mediator of AL, during aging. Pb levels were measured from blood samples (BPb) of 126 Brazilian individuals (105 women), between 50 and 82 years old. Six neuroendocrine, metabolic, and anthropometric biomarkers were analyzed and values were transformed into an AL index using clinical reference cut-offs. Salivary samples were collected at home over 2 days at awakening, 30-min after waking, afternoon, and evening periods to determine cortisol levels. A multiple linear regression model showed a positive association between BPb as the independent continuous variable and cortisol awakening response (R2=0.128; B=0.791; p=0.005) and overall cortisol concentration (R2=0.266; B=0.889; p<0.001) as the outcomes. Repeated measures ANOVA showed that individuals with high BPb levels showed higher cortisol at 30min after awakening (p=0.003), and in the afternoon (p=0.002) than those with low BPb values. Regarding AL, regression model showed that BPb was positively associated with AL index (R2=0.100; B=0.204; p=0.032). Correlation analyzes with individual biomarkers showed that BPb was positively correlated with HDL cholesterol (p=0.02) and negatively correlated with DHEA-S (p=0.049). These findings suggest that Pb exposure, even at levels below the reference blood lead level for adults recommended by the National Institute for Occupational Safety and Health and by the Center for Disease Control and Prevention, may contribute to AL and dysregulated cortisol functioning in older adults. Considering these findings were based on cross-sectional data future research is needed to confirm our exploratory results.

The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort.

The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at ∼164 Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes.

Evaluating the Effects of Coping Style on Allostatic Load, by Sex: The Jackson Heart Study, 2000-2004.

The objective of this study was to examine the cross-sectional association between coping styles and allostatic load among African American adults in the Jackson Heart Study (2000-2004). Coping styles were assessed using the Coping Strategies Inventory-Short Form; allostatic load was measured by using 9 biomarkers standardized into z-scores. Sex-stratified multivariable linear regressions indicated that females who used disengagement coping styles had significantly higher allostatic load scores (ß = 0.016; 95% CI, 0.001-0.032); no such associations were found in males. Future longitudinal investigations should examine why disengagement coping style is linked to increased allostatic load to better inform effective interventions and reduce health disparities among African American women.

Free fatty acid availability is closely related to myocardial lipid storage and cardiac function in hypoglycemia counterregulation.

Hypoglycemia, a major side effect of intensive glucose-lowering therapy, was recently linked to increased cardiovascular risk in patients with diabetes. Whether increased circulating free fatty acids (FFA) owing to catecholamine-induced lipolysis affect myocardial energy metabolism and thus link hypoglycemia to cardiac vulnerability is unclear. Therefore, this study investigated the impact of hypoglycemia counterregulation (± inhibition of lipolysis) on myocardial lipid content (MYCL) and left ventricular function in healthy subjects. Nine healthy men were studied in randomized order: 1) insulin/hypoglycemia test (IHT; ins+/aci-), 2) IHT during inhibition of adipose tissue lipolysis by acipimox (ins+/aci+), 3) normoglycemia with acipimox (ins-/aci+), and 4) normoglycemia with placebo (ins-/aci-). MYCL and cardiac function were assessed by employing magnetic resonance spectroscopy/imaging at baseline and at 2 and 6 h. In response to acute hypoglycemia, plasma FFA (P<0.0001) and ejection fraction (EF; from 63.2±5.5 to 69.6±6.3%, P=0.0001) increased significantly and were tightly correlated with each other (r=0.68, P=0.0002); this response was completely blunted by inhibition of adipose tissue lipolysis. In the presence of normoglycemia, inhibition of lipolysis was associated with a drop in EF (from 59.2±5.5 to 53.9±6.9%,P=0.005) and a significant decrease in plasma FFA, triglycerides, and MYCL (by 48.5%, P=0.0001). The present data indicate that an intact interorgan cross-talk between adipose tissue and the heart is a prerequisite for catecholamine-mediated myocardial contractility and preservation of myocardial lipid stores in response to acute hypoglycemia.

Allostatic load amplifies the effect of blood lead levels on elevated blood pressure among middle-aged U.S. adults: a cross-sectional study.

BACKGROUND: Scientists and regulators have sought to understand whether and how physiologic dysregulation due to chronic stress exposure may enhance vulnerability to the adverse health effects of toxicant exposures. We conducted a cross-sectional study to determine whether allostatic load (AL), a composite measure of physiologic response to chronic exposure to stress, amplifies the effect of lead exposure on blood pressure among middle-aged adults. METHODS: We analyzed associations between blood lead levels and blood pressure in a nationally representative sample of 8,194 U.S. adults (aged 40-65 years) participating in the National Health and Nutritional Examination Survey, 1999--2008. Outcomes were elevated systolic (≥ 140 mm Hg) and diastolic (≥ 90 mm Hg) blood pressure. AL was defined as the aggregate score of seven components, reflecting dysregulation of the cardiovascular, inflammatory, and endocrine systems. RESULTS: Logistic regression models showed a linear dose-response relationship for quintiles of blood lead and elevated systolic blood pressure in the high AL group (p = 0.03) but not the low AL group (p = 0.24). Similarly, the relationship between lead exposure and elevated diastolic blood pressure was stronger among the high AL group than the low AL group. Within the high AL group, the fourth and fifth quintiles had significantly elevated odds of elevated blood pressure compared to lowest quintile [OR = 1.92, (95% CI, 1.07, 3.47) and OR =2.28 (95% CI, 1.33, 3.91), respectively]. In the low AL group, none of the quintile effects were significantly different than the referent group although there was evidence of a linear trend (p =0.03). The lead by AL interaction term was not statistically significant for either systolic or diastolic blood pressure models. CONCLUSIONS: Results suggest that higher AL may amplify the adverse effects of lead on blood pressure. Future research should assess the implications of cumulative exposures to environmental and social stressors for regulatory decision-making.

Evidence for involvement of central vasopressin V1b and V2 receptors in stress-induced baroreflex desensitization.

BACKGROUND AND PURPOSE: It is well recognized that vasopressin modulates the neurogenic control of the circulation. Here, we report the central mechanisms by which vasopressin modulates cardiovascular response to stress induced by immobilization. EXPERIMENTAL APPROACH: Experiments were performed in conscious male Wistar rats equipped with radiotelemetric device for continuous measurement of haemodynamic parameters: systolic and diastolic BP and heart rate (HR). The functioning of the spontaneous baro-receptor reflex (BRR) was evaluated using the sequence method and the following parameters were evaluated: BRR sensitivity (BRS) and BRR effectiveness index (BEI). KEY RESULTS: Under baseline physiological conditions intracerebroventricular injection of 100 and 500 ng of selective non-peptide V1a or V1b or V2 receptor antagonist did not modify BP, HR and BRR. Rats exposed to 15 min long stress by immobilization exhibited increase of BP, HR, reduction of BRS and no change in BEI. Pretreatment of rats with V1a receptor antagonist did not modulate the BP, HR, BRS and BEI response to stress. Pretreatment of rats with V1b receptor and V2 receptor antagonist, at both doses, prevented BRR desensitization and tachycardia, but failed to modulate stress-induced hypertension. CONCLUSIONS AND IMPLICATIONS: Vasopressin by the stimulation of central V1b- and V2-like receptors mediates stress-induced tachycardia and BRR desensitization. If these mechanisms are involved, BRR desensitization in heart failure and hypertension associated with poor outcome, they could be considered as novel targets for cardiovascular drug development.

Glial cell line-derived neurotrophic factor reverses alcohol-induced allostasis of the mesolimbic dopaminergic system: implications for alcohol reward and seeking.

We previously showed that infusion of glial cell line-derived neurotrophic factor (GDNF) into the ventral tegmental area (VTA) rapidly reduces alcohol intake and relapse (Carnicella et al., 2008, 2009a), and increases dopamine (DA) levels in the nucleus accumbens (NAc) of alcohol-naive rats (Wang et al., 2010). Withdrawal from excessive alcohol intake is associated with a reduction in NAc DA levels, whereas drug-induced increases in NAc DA levels are associated with reward. We therefore tested whether GDNF in the VTA reverses alcohol withdrawal-associated DA deficiency and/or possesses rewarding properties. Rats were trained for 7 weeks to consume high levels of alcohol (5.47 ± 0.37 g/kg/24 h) in intermittent access to 20% alcohol in a two-bottle choice procedure. Using in vivo microdialysis, we show that 24 h withdrawal from alcohol causes a substantial reduction in NAc DA overflow, which was reversed by intra-VTA GDNF infusion. Using conditioned place preference (CPP) paradigm, we observed that GDNF on its own does not induce CPP, suggesting that the growth factor is not rewarding. However, GDNF blocked acquisition and expression of alcohol-CPP. In addition, GDNF induced a downward shift in the dose-response curve for operant self-administration of alcohol, further suggesting that GDNF suppresses, rather than substitutes for, the reinforcing effects of alcohol. Our findings suggest that GDNF reduces alcohol-drinking behaviors by reversing an alcohol-induced allostatic DA deficiency in the mesolimbic system. In addition, as it lacks abuse liability, the study further highlights GDNF as a promising target for treatment of alcohol use/abuse disorders.

Stress, alcohol and drug interaction: an update of human research.

A challenging question that continues unanswered in the field of addiction is why some individuals are more vulnerable to substance use disorders than others. Numerous risk factors for alcohol and other drugs of abuse, including exposure to various forms of stress, have been identified in clinical studies. However, the neurobiological mechanisms that underlie this relationship remain unclear. Critical neurotransmitters, hormones and neurobiological sites have been recognized, which may provide the substrates that convey individual differences in vulnerability to addiction. With the advent of more sophisticated measures of brain function in humans, such as functional imaging technology, the mechanisms and neural pathways involved in the interactions between drugs of abuse, the mesocorticolimbic dopamine system and stress systems are beginning to be characterized. This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from occasional drug use to drug dependence. We also review factors that contribute to different levels of hormonal/brain stress activation, which has implications for understanding individual vulnerability to drug dependence. Ultimately, these efforts may improve our chances of designing treatment strategies that target addiction at the core of the disorder.

Dorsal raphe nuclei integrate allostatic information evoked by depletion-induced sodium ingestion.

Structures of the lamina terminalis (LT) sense and integrate information reflecting the state of body water and sodium content. Output from the LT projects into a neural network that regulates body fluid balance. Serotonin (5-HT) and the dorsal raphe nuclei (DRN) have been implicated in the inhibitory control of salt intake (i.e., sodium appetite). Signals arriving from the LT evoked by fluid depletion-induced sodium ingestion interact with this inhibitory serotonergic system. We investigated the role of neurons along the LT that directly project to the DRN. We analyzed the pattern of immunoreactivity (ir) of LT cells double-labeled for Fos (a marker of neural activity) and Fluorogold (FG; a retrograde tracer) following sodium depletion-induced sodium intake. Seven days after injection of FG into the DRN, sodium appetite was induced by furosemide injection and overnight access to only a low sodium diet (Furo-LSD) and distilled water. Twenty-four hours later, access to 0.3 M NaCl was given to depleted or sham-depleted rats and sodium intake was measured over the following 60 min. Ninety minutes after the termination of the intake test, the animals were perfused and their brains were processed for immunohistochemical detection of Fos and FG. Compared to sham-depleted animals there was a significantly greater number of Fos-/FG-ir double-labeled cells in the subfornical organ, the organum vasculosum of the lamina terminalis and the median preoptic nucleus in rats that ingested NaCl. Projections from the LT cells may contribute to inhibitory mechanisms involving 5-HT neurons in the DRN that limit the intake of sodium and prevent excess volume expansion.

Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats.

RATIONALE: Nitrous oxide (N(2)O) can initially lower core temperature (T (core)), but hypothermic tolerance develops with chronic administration. Therefore, one or both of T (core)'s controlling determinants, heat production (HP) and heat loss (HL), must adapt across repeated N(2)O administrations. Simultaneous measurements of HP, HL, and T (core) during chronic N(2)O administrations will elucidate this adaptive process and constitute a rigorous model for studying the systems-level dynamics of tolerance in both mature and young animals. This approach is justified by the need to better understand the increased vulnerability to addiction associated with adolescent drug use. OBJECTIVES: The objective of the study was to measure HL and HP across repeated steady-state administrations of 60% N(2)O in young and mature rats. MATERIALS AND METHODS: Synchronous measurements of HP (indirect calorimetry), HL (direct calorimetry), and T (core) (telemetry) were obtained during 60% N(2)O administrations in adolescent (28-45 days, n = 11) and mature rats (>90 days, n = 8). Rats received five 90-min drug exposures (every other day). RESULTS: Compared to mature rats, adolescents initially exhibited greater hypothermia, but acquired tolerance more rapidly and actually developed hyperthermia during the fifth administration. In both groups, N(2)O consistently increased HL, but progressive increases of intrasessional HP over repeated administrations prevented hypothermia and subsequently promoted hyperthermia in adolescent rats. CONCLUSIONS: Adolescent rats hyper-adapt to N(2)O hypothermia. Increases of intrasessional HP across N(2)O administrations explained both tolerance to N(2)O hypothermia and the unexpected hyperthermia observed in adolescents. These findings raise the possibility that the increased vulnerability to addiction associated with adolescent drug use involves a hyper-adaptive tolerance mechanism.