Electroencefalografía básica para monitores de profundidad anestésica / Basic electroencephalography for anesthesia depth monitors

Resumen: Los monitores de profundidad anestésica permiten guiar el estado hipnótico del paciente durante la anestesia general. Debido a su sencillez, tradicionalmente se han empleado índices de profundidad anestésica, obtenidos a través del procesamiento del electroencefalograma mediante algoritmos matemáticos, para orientar la monitorización del nivel de consciencia. Sus beneficios han sido ampliamente recogidos en la literatura científica; sin embargo, no están exentos de importantes limitaciones. No todos los anestésicos actúan en las mismas dianas moleculares ni dichos índices tienen en cuenta las características propias del paciente (comorbilidades, edades extremas, etcétera). Estas limitaciones podrían reducirse si interpretamos directamente toda la información que nos ofrecen los monitores. Presentamos una revisión que describe los conceptos básicos necesarios para su valoración directa, así como su correlación con los estados de profundidad anestésica del paciente.

Abstract: Anesthesia depth monitors allow to guide the patient's hypnotic state during general anesthesia. Traditionally, anesthetic depth indices have been used due to their simplicity to guide the monitoring of the level of consciousness. They have been obtained by processing the electroencephalogram using mathematical algorithms and their benefits have been widely reported in the scientific literature. However, they are not exempt from important limitations. Neither all anesthetics act on the same molecular targets, nor these mentioned indices take into account the patient's own characteristics (comorbidities, extreme ages, etc.). These limitations could be far reduced if we are able to understand all the information provided by the monitors. We present a review describing the basic concepts necessary for its direct assessment, as well as their correlation with the patient's anesthetic depth states.

Differential Hypothalamic-pituitary-adrenal Response to Stress among Rat Strains: Methodological Considerations and Relevance for Neuropsychiatric Research.

The hormones of the hypothalamic-pituitary-adrenal (HPA) axis, particularly glucocorticoids (GCs), play a critical role in the behavioral and physiological consequences of exposure to stress. For this reason, numerous studies have described differences in HPA function between different rodent strains/lines obtained by genetic selection of certain characteristics not directly related to the HPA axis. These studies have demonstrated a complex and poorly understood relationship between HPA function and certain relevant behavioral characteristics. The present review first remarks important methodological considerations regarding the evaluation and interpretation of resting and stress levels of HPA hormones. Then, it presents works in which differences in HPA function between Lewis and Fischer rats were explored as a model for how to approach other strain comparisons. After that, differences in the HPA axis between classical strain pairs (e.g. High and Low anxiety rats, Roman high- and low-avoidance, Wistar Kyoto versus Spontaneously Hypertensive or other strains, Flinder Sensitive and Flinder Resistant lines) are described. Finally, after discussing the relationship between HPA differences and relevant behavioral traits (anxiety-like and depression-like behavior and coping style), an example for main methodological and interpretative concerns and how to test strain differences is offered.

Influence of Transition-Metal Order on the Reaction Mechanism of LNMO Cathode Spinel: An Operando X-ray Absorption Spectroscopy Study.

An operando dual-edge X-ray absorption spectroscopy on both transition-metal ordered and disordered LiNi0.5Mn1.5O4 during electrochemical delithiation and lithiation was carried out. The large data set was analyzed via a chemometric approach to gain reliable insights into the redox activity and the local structural changes of Ni and Mn throughout the electrochemical charge and discharge reaction. Our findings confirm that redox activity relies predominantly on the Ni2+/4+ redox couple involving a transient Ni3+ phase. Interestingly, a reversible minority contribution of Mn3+/4+ is also evinced in both LNMO materials. While the reaction steps and involved reactants of both ordered and disordered LNMO materials generally coincide, we highlight differences in terms of reaction dynamics as well as in local structural evolution induced by the TM ordering.

Male long-Evans rats: An outbred model of marked hypothalamic-pituitary-adrenal hyperactivity.

Rat and mouse strains differ in behavioral and physiological characteristics, and such differences can contribute to explain discrepant results between laboratories and better select the most appropriate strain for a particular purpose. Differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis are particularly important given the pivotal role of this system in determining consequences of exposure to stressors. In this regard, Long-Evans (LE) rats are widely used in stress research, but there is no specific study aiming at thoroughly characterizing HPA activity in LE versus other extensively used strains. In a first experiment, LE showed higher resting ACTH and corticosterone levels only at certain points of the circadian rhythm, but much greater ACTH responsiveness to stressors (novel environment and forced swim) than Sprague-Dawley (SD) rats. Accordingly, enhanced corticotropin-releasing hormone (CRH) expression in the paraventricular nucleus of the hypothalamus and reduced expression of glucocorticoid receptors were observed in the hippocampal formation. Additionally, they are hyperactive in novel environments, and prone to adopt passive-like behavior when compared to SD rats. Supporting that altered HPA function has a marked physiological impact, we observed in another set of animals much lower thymus weight in LE than SD rats. Finally, to demonstrate that LE rats are likely to have higher HPA responsiveness to stressors than most strains, we studied resting and stress levels of HPA hormones in LE versus Wistar and Fischer rats, the latter considered an example of high HPA responsiveness. Again, LE showed higher resting and stress levels of ACTH than both Wistar and Fischer rats. As ACTH responsiveness to stressors in LE rats is stronger than that previously reported when comparing other rat strains and they are commercially available, they could be an appropriate model for studying the behavioral and physiological implications of a hyper-active HPA axis under normal and pathological conditions.

Acute exposure of rats to a severe stressor alters the circadian pattern of corticosterone and sensitizes to a novel stressor: Relationship to pre-stress individual differences in resting corticosterone levels.

Traumatic events have been proposed to be associated with hypo-activity of the hypothalamic-pituitary-adrenal (HPA) axis, but data in animal models exposed to severe stressors are controversial and have important methodological concerns. Individual differences in resting or stress levels of corticosterone might explain some of the inconsistencies. We then studied this issue in male rats exposed to 2 h immobilization on boards (IMO), a severe stressor. Thirty-six rats were blood sampled under resting conditions four times a day on three non-consecutive days. Then, they were assigned to control (n = 14) or IMO (n = 22) to study the HPA response to IMO, the stressor-induced alterations in the circadian pattern of corticosterone (CPCORT), and the behavioral and HPA responsiveness to an open-field. Individual differences in pre-IMO resting corticosterone were inconsistent, but averaging data markedly improved consistency. The CPCORT was markedly altered on day 1 post-IMO (higher trough and lower peak levels), less altered on day 3 and apparently normal on day 7. Importantly, when rats were classified in low and high resting corticosterone groups (LCORT and HCORT, respectively), on the basis of the area under the curve (AUC) of the averaged pre-IMO data, AUC differences between LCORT and HCORT groups were maintained in controls but disappeared in IMO rats during the post-IMO week. Open-field hypo-activity and corticosterone sensitization were similar in LCORT and HCORT groups nine days after IMO. A single IMO exposure causes long-lasting HPA alterations, some of them dependent on pre-stress resting corticosterone levels, with no evidence for post-IMO resting corticosterone hypo-activity.

Reversión de sobrepeso y obesidad en población infantil de Vilafranca del Penedès: Programa ACTIVA'T (2012) / Reversion of overweight and obesity in Vilafranca del Penedès child population: ACTIVA'T Program (2012)

Objetivo: Describir los resultados sobre el estado nutricional de niños/as de 8 a 14 años con sobrepeso u obesidad y poco activos/as, antes y después de una intervención nutricional con promoción de la actividad física (Programa ACTIVA'T). Método: Estudio antes-después en población infantil (8-14 años) de Vilafranca del Penedès (Barcelona) con sobrepeso u obesidad y poco activos, aleatorizados en grupo control (n = 51, 47,1% niñas, intervención nutricional y actividad física ≤3h/sem) y en grupo ACTIVA'T (n = 45, 37,8% niñas, intervención nutricional y actividad física ≥5h/sem). Se determinaron el índice de masa corporal, el índice cintura/altura y la calidad de la dieta mediante el test KIDMED al inicio y al final del estudio. Durante la intervención, cada participante estuvo acompañado/a por un familiar (padre o madre) que realizó las mismas actividades que los/las niños/as. Resultados: Las recomendaciones dietéticas han cambiado positivamente los hábitos del grupo ACTIVA'T y del grupo control. La reversión en la prevalencia de sobrepeso y obesidad ha sido del 93,8% y el 58,6%, respectivamente, en el grupo ACTIVA'T, frente al 25,0% y el 35,8% en el grupo control. La obesidad abdominal se redujo del 42,2% al 17,8% en el grupo ACTIVA'T y del 47,1% al 27,5% en el grupo control. Conclusiones: El programa de educación nutricional y promoción de la actividad física ACTIVA'T mejora la calidad de la dieta y revierte la prevalencia de sobrepeso y obesidad en la población infantil poco activa

Objective: To assess a 6-month nutritional and physical activity intervention program on the nutritional status of overweight or obese and not very active 8-14 years old children by means of a controlled pre-post design (ACTIVA'T program). Method: Pre-post study in 8-14 years old overweight or obese and low active children from Vilafranca del Penedès (Barcelona, Spain) randomized in control group (n = 51, 47.1% girls, nutritional intervention and ≤3h/wk physical activity) and ACTIVA'T group (n = 45, 37.8% girls, nutritional and physical activity ≥5h/wk intervention). Body mass index, waist/height index, and diet quality by means of KIDMED test at the beginning and at the end of the program were assessed. During the intervention, each participant was accompanied by a relative (father or mother) who performed the same activities as the children. Results: Dietary recommendations have positively changed the habits of both ACTIVA'T and control group. The reversion in the prevalence of overweight and obesity was 93.8% and 58.6%, respectively, in the ACTIVA'T group, compared to 25.0% and 35.8% in the control group. Abdominal obesity was decreased from 42.2% to 17.8% in the ACTIVA'T group and from 47.1% to 27.5% in the control group. Conclusions: The program ACTIVA'T (nutritional education and physical activity promotion) improves the quality of diet and reverses the prevalence of overweight and obesity in the underactive child population

Controllability affects endocrine response of adolescent male rats to stress as well as impulsivity and behavioral flexibility during adulthood.

Exposure to stress during adolescence exerts a long-term impact on behavior and might contribute to the development of several neuropsychiatric disorders. In adults, control over stress has been found to protect from the negative consequences of stress, but the influence of controllability at early ages has not been extensively studied. Here, we evaluated in a rodent model the effects of repeated exposure in adolescent male rats to controllable versus uncontrollable foot-shock stress (CST or UST, respectively). Rats were assigned to three groups: non-stress (stress-naïve), CST (exposed to 8 sessions of a two-way shuttle active avoidance task over a period of 22 days) and UST (receiving the same amount of shocks as CST, regardless of their actual behavior). During adulthood, different cohorts were tested in several tasks evaluating inhibitory control and cognitive flexibility: 5-choice serial reaction time, delay-discounting, gambling test and probabilistic reversal learning. Results showed that the hypothalamic-pituitary-adrenal response to the first shock session was similar in CST and UST animals, but the response to the 8th session was lower in CST animals. In adulthood, the UST animals presented impaired motor (but not cognitive) impulsivity and more perseverative behavior. The behavioral effects of UST were associated with increased number of D2 dopamine receptors in dorsomedial striatum, but not in other striatal regions. In summary, UST exposure during adolescence induced long-term impairments in impulsivity and compulsivity, whereas CST had only minor effects. These data support a critical role of stress uncontrollability on the long-lasting consequences of stress, as a risk factor for mental illnesses.

[Reversion of overweight and obesity in Vilafranca del Penedès child population: ACTIVA'T Program (2012)]. / Reversión de sobrepeso y obesidad en población infantil de Vilafranca del Penedès: Programa ACTIVA'T (2012).

OBJECTIVE: To assess a 6-month nutritional and physical activity intervention program on the nutritional status of overweight or obese and not very active 8-14 years old children by means of a controlled pre-post design (ACTIVA'T program). METHOD: Pre-post study in 8-14 years old overweight or obese and low active children from Vilafranca del Penedès (Barcelona, Spain) randomized in control group (n = 51, 47.1% girls, nutritional intervention and ≤3h/wk physical activity) and ACTIVA'T group (n = 45, 37.8% girls, nutritional and physical activity ≥5h/wk intervention). Body mass index, waist/height index, and diet quality by means of KIDMED test at the beginning and at the end of the program were assessed. During the intervention, each participant was accompanied by a relative (father or mother) who performed the same activities as the children. RESULTS: Dietary recommendations have positively changed the habits of both ACTIVA'T and control group. The reversion in the prevalence of overweight and obesity was 93.8% and 58.6%, respectively, in the ACTIVA'T group, compared to 25.0% and 35.8% in the control group. Abdominal obesity was decreased from 42.2% to 17.8% in the ACTIVA'T group and from 47.1% to 27.5% in the control group. CONCLUSIONS: The program ACTIVA'T (nutritional education and physical activity promotion) improves the quality of diet and reverses the prevalence of overweight and obesity in the underactive child population.

Early life stress in rats sex-dependently affects remote endocrine rather than behavioral consequences of adult exposure to contextual fear conditioning.

Exposure to electric foot-shocks can induce in rodents contextual fear conditioning, generalization of fear to other contexts and sensitization of the hypothalamic-pituitary-adrenal (HPA) axis to further stressors. All these aspects are relevant for the study of post-traumatic stress disorder. In the present work we evaluated in rats the sex differences and the role of early life stress (ELS) in fear memories, generalization and sensitization. During the first postnatal days subjects were exposed to restriction of nesting material along with exposure to a "substitute" mother. In the adulthood they were exposed to (i) a contextual fear conditioning to evaluate long-term memory and extinction and (ii) to a novel environment to study cognitive fear generalization and HPA axis heterotypic sensitization. ELS did not alter acquisition, expression or extinction of context fear conditioned behavior (freezing) in either sex, but reduced activity in novel environments only in males. Fear conditioning associated hypoactivity in novel environments (cognitive generalization) was greater in males than females but was not specifically affected by ELS. Although overall females showed greater basal and stress-induced levels of ACTH and corticosterone, an interaction between ELS, shock exposure and sex was found regarding HPA hormones. In males, ELS did not affect ACTH response in any situation, whereas in females, ELS reduced both shock-induced sensitization of ACTH and its conditioned response to the shock context. Also, shock-induced sensitization of corticosterone was only observed in males and ELS specifically reduced corticosterone response to stressors in males but not females. In conclusion, ELS seems to have only a minor impact on shock-induced behavioral conditioning, while affecting the unconditioned and conditioned responses of HPA hormones in a sex-dependent manner.

Sex-dependent impact of early-life stress and adult immobilization in the attribution of incentive salience in rats.

Early life stress (ELS) induces long-term effects in later functioning and interacts with further exposure to other stressors in adulthood to shape our responsiveness to reward-related cues. The attribution of incentive salience to food-related cues may be modulated by previous and current exposures to stressors in a sex-dependent manner. We hypothesized from human data that exposure to a traumatic (severe) adult stressor will decrease the attribution of incentive salience to reward-associated cues, especially in females, because these effects are modulated by previous ELS. To study these factors in Long-Evans rats, we used as an ELS model of restriction of nesting material and concurrently evaluated maternal care. In adulthood, the offspring of both sexes were exposed to acute immobilization (IMO), and several days after, a Pavlovian conditioning procedure was used to assess the incentive salience of food-related cues. Some rats developed more attraction to the cue predictive of reward (sign-tracking) and others were attracted to the location of the reward itself, the food-magazine (goal-tracking). Several dopaminergic markers were evaluated by in situ hybridization. The results showed that ELS increased maternal care and decreased body weight gain (only in females). Regarding incentive salience, in absolute control animals, females presented slightly greater sign-tracking behavior than males. Non-ELS male rats exposed to IMO showed a bias towards goal-tracking, whereas in females, IMO produced a bias towards sign-tracking. Animals of both sexes not exposed to IMO displayed an intermediate phenotype. ELS in IMO-treated females was able to reduce sign-tracking and decrease tyrosine hydroxylase expression in the ventral tegmental area and dopamine D1 receptor expression in the accumbens shell. Although the predicted greater decrease in females in sign-tracking after IMO exposure was not corroborated by the data, the results highlight the idea that sex is an important factor in the study of the long-term impact of early and adult stressors.

Long-Lasting Impairment of mGluR5-Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration.

Background: Cocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors, with allosteric modulators showing particular promise. Methods: We evaluated the capacity of group I metabotropic glutamate receptors to induce functional responses in ex vivo striatal slices from rats with (1) acute cocaine self-administration, (2) chronic cocaine self-administration, and (3) 60 days cocaine self-administration withdrawal by Western blot and extracellular recordings of synaptic transmission. Results: We found that striatal group I metabotropic glutamate receptors are the principal mediator of the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine-induced cAMP responsive-element binding protein phosphorylation. Both acute and chronic cocaine self-administration blunted group I metabotropic glutamate receptor effects on cAMP responsive-element binding protein phosphorylation in the striatum, which correlated with the capacity to induce long-term depression, an effect that was maintained 60 days after chronic cocaine self-administration withdrawal. In the nucleus accumbens, the principal brain region mediating the rewarding effects of drugs, chronic cocaine self-administration blunted group I metabotropic glutamate receptor stimulation of extracellular signal-regulated protein kinases 1/2 and cAMP responsive-element binding protein. Interestingly, the group I metabotropic glutamate receptor antagonist/inverse-agonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride, led to a specific increase in cAMP responsive-element binding protein phosphorylation after chronic cocaine self-administration, specifically in the nucleus accumbens, but not in the striatum. Conclusions: Prolonged cocaine self-administration, through withdrawal, leads to a blunting of group I metabotropic glutamate receptor responses in the striatum. In addition, specifically in the accumbens, group I metabotropic glutamate receptor signaling to cAMP responsive-element binding protein shifts from an agonist-induced to an antagonist-induced cAMP responsive-element binding protein phosphorylation.

Long-term moderate treadmill exercise promotes stress-coping strategies in male and female rats.

Recent evidence has revealed the impact of exercise in alleviating anxiety and mood disorders; however, the exercise protocol that exerts such benefit is far from known. The current study was aimed to assess the effects of long-term moderate exercise on behavioural coping strategies (active vs. passive) and Hypothalamic-Pituitary-Adrenal response in rats. Sprague-Dawley male and female rats were exposed to 32-weeks of treadmill exercise and then tested for two-way active avoidance learning (shuttle-box). Two groups were used as controls: a non-handled sedentary group, receiving no manipulation, and a control group exposed to a stationary treadmill. Female rats displayed shorter escape responses and higher number of avoidance responses, reaching criterion for performance earlier than male rats. In both sexes, exercise shortened escape latencies, increased the total number of avoidances and diminished the number of trials needed to reach criterion for performance. Those effects were greater during acquisition in female rats, but remained over the shuttle-box sessions in treadmill trained male rats. In females, exercise did not change ACTH and corticosterone levels after shuttle-box acquisition. Collectively, treadmill exercise improved active coping strategies in a sex-dependent manner. In a broader context, moderate exercise could serve as a therapeutic intervention for anxiety and mood disorders.

Stress-induced sensitization: the hypothalamic-pituitary-adrenal axis and beyond.

Exposure to certain acute and chronic stressors results in an immediate behavioral and physiological response to the situation followed by a period of days when cross-sensitization to further novel stressors is observed. Cross-sensitization affects to different behavioral and physiological systems, more particularly to the hypothalamus-pituitary-adrenal (HPA) axis. It appears that the nature of the initial (triggering) stressor plays a major role, HPA cross-sensitization being more widely observed with systemic or high-intensity emotional stressors. Less important appears to be the nature of the novel (challenging) stressor, although HPA cross-sensitization is better observed with short duration (5-15 min) challenging stressors. In some studies with acute immune stressors, HPA sensitization appears to develop over time (incubation), but most results indicate a strong initial sensitization that progressively declines over the days. Sensitization can affect other physiological system (i.e. plasma catecholamines, brain monoamines), but it is not a general phenomenon. When studied concurrently, behavioral sensitization appears to persist longer than that of the HPA axis, a finding of interest regarding long-term consequences of traumatic stress. In many cases, behavioral and physiological consequences of prior stress can only be observed following imposition of a new stressor, suggesting long-term latent effects of the initial exposure.

Adaptation of the hypothalamus-pituitary-adrenal axis to daily repeated stress does not follow the rules of habituation: A new perspective.

Repeated exposure to a wide range of stressors differing in nature and intensity results in a reduced response of prototypical stress markers (i.e. plasma levels of ACTH and adrenaline) after an acute challenge with the same (homotypic) stressor. This reduction has been considered to be a habituation-like phenomenon. However, direct experimental evidence for this assumption is scarce. In the present work we demonstrate in adult male rats that adaptation of the hypothalamus-pituitary-adrenal (HPA) axis to repeated stress does not follow some of the critical rules of habituation. Briefly, adaptation was stronger and faster with more severe stressors, maximally observed even with a single exposure to severe stressors, extremely long-lasting, negatively related to the interval between the exposures and positively related to the length of daily exposure. We offer a new theoretical view to explain adaptation to daily repeated stress.

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats.

Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23-28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin-releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated-plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors.

Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects.

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits ß-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.

Sex-dependent effects of an early life treatment in rats that increases maternal care: vulnerability or resilience?

Early life stress (ELS) in rodents has profound long-term effects that are partially mediated by changes in maternal care. ELS not only induces "detrimental" effects in adulthood, increasing psychopathology, but also promotes resilience to further stressors. In Long-Evans rats, we evaluated a combination of two procedures as a model of ELS: restriction of bedding during the first post-natal days and exposure to a "substitute" mother. The maternal care of biological and "substitute" mothers was measured. The male and female offspring were evaluated during adulthood in several contexts. Anxiety was measured by the elevated plus-maze (EPM), acoustic startle response (ASR) and forced swim test (FST). In other group of animals, novelty-seeking was measured (activity in an inescapable novel environment, preference for novel environments and exploration of novel objects). Plasmatic ACTH and corticosterone in basal conditions and in response to stress were also measured. Cognitive impulsivity was assessed by a delay-discounting paradigm, and impulsive action, attention and compulsive-like behavior by a five choice serial reaction time task (5CSRTT). ELS decreased pup body weight and increased the care of the biological mother; however, the "substitute" mother did not exhibit overt maltreatment. A mixture of "detrimental" and "beneficial" effects was shown. In the 5CSRTT, attention was impaired in both genders, and in females, ELS increased compulsive-like behavior. Novel object exploration was only increased by ELS in males, but the preference for novel spaces decreased in both genders. Baseline anxiety (EPM and ASR) and recognition memory were not affected. Unexpectedly, ELS decreased the ACTH response to novelty and swim stress and increased active coping in the FST in both genders. Cognitive impulsivity was decreased only in females, but impulsive action was not affected. The enhancement in maternal care may "buffer" the effects of ELS in a context-dependent manner.

Physiological and behavioural consequences of long-term moderate treadmill exercise.

The benefits of long-term moderate exercise for health are widely accepted in humans, but few animal studies have been undertaken to characterize the effects of such activity on emotionality and responsiveness to stress. The present study describes the effects of long-term moderate forced treadmill training (36 weeks) on exploratory activity, anxiety-like behaviour, and the resting or stress levels of some physiological variables, including pituitary-adrenal (PA) hormones. Five-week-old male Sprague-Dawley rats were trained on the treadmill (TM) for 36 weeks, using a more moderate training (12m/min, 30min/day, 4-5 days/week) than that currently used in the literature. Two groups were used as controls: a non-handled sedentary (SED) group, receiving no manipulation, and a control (CON) group exposed to a stationary treadmill for the same amount of time as the TM group. In accordance with literature data, TM rats showed lower resting levels of glucose, triglycerides and cholesterol than the other two groups. The TM and CON groups both showed higher ambulation than the SED group in some behavioural tests, without evidence for altered anxiety. Resting levels of adrenocorticotropin (ACTH) and corticosterone did not differ among the groups, but a reduced ACTH response to both a novel environment (mild stressor) and an active escape-avoidance task (severe stressor) was observed in TM rats, whereas changes in corticosterone were modest. The results support the view that the physiological consequences of long-term moderate training are beneficial, including reduced PA responsiveness to stress, even though exercise training did not affect anxiety-like behaviour.

What can we know from pituitary-adrenal hormones about the nature and consequences of exposure to emotional stressors?

Exposure to stress induces profound physiological and behavioral changes in the organisms and some of these changes may be important regarding stress-induced pathologies and animal models of psychiatric diseases. Consequences of stress are dependent on the duration of exposure to stressors (acute, chronic), but also of certain characteristics such as intensity, controllability, and predictability. If some biological variables were able to reflect these characteristics, they could be used to predict negative consequences of stress. Among the myriad of physiological changes caused by stress, only a restricted number of variables appears to reflect the intensity of the situation, mainly plasma levels of ACTH and adrenaline. Peripheral hypothalamic-pituitary-adrenal (HPA) hormones (ACTH and corticosterone) are also able to reflect fear conditioning. In contrast, the activation of the HPA axis is not consistently related to anxiety as evaluated by classical tests such as the elevated plus-maze. Similarly, there is no consistent evidence about the sensitivity of the HPA axis to psychological variables such as controllability and predictability, despite the fact that: (a) lack of control over aversive stimuli can induce behavioral alterations not seen in animals which exert control, and (b) animals showed clear preference for predictable versus unpredictable stressful situations. New studies are needed to re-evaluate the relationship between the HPA axis and psychological stress characteristics using ACTH instead of corticosterone and taking advantages of our current knowledge about the regulation of this important stress system.

Sex-dependent effects of maternal deprivation and adolescent cannabinoid treatment on adult rat behaviour.

Early life experiences such as maternal deprivation (MD) exert long-lasting changes in adult behaviour and reactivity to stressors. Adolescent exposure to cannabinoids is a predisposing factor in developing certain psychiatric disorders. Therefore, the combination of the two factors could exacerbate the negative consequences of each factor when evaluated at adulthood. The objective of this study was to investigate the long-term effects of early MD [24 hours at postnatal day (PND) 9] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (0.4 mg/kg, PND 28-42) on diverse behavioural and physiological responses of adult male and female Wistar rats. We tested them in the prepulse inhibition (PPI) of the startle response and analysed their exploratory activity (holeboard) and anxiety (elevated plus maze, EPM). In addition, we evaluated their adrenocortical reactivity in response to stress and plasma leptin levels. Maternal behaviour was measured before and after deprivation. MD induced a transient increase of maternal behaviour on reuniting. In adulthood, maternally deprived males showed anxiolytic-like behaviour (or increased risk-taking behaviour) in the EPM. Adolescent exposure to the cannabinoid agonist induced an impairment of the PPI in females and increased adrenocortical responsiveness to the PPI test in males. Both, MD and adolescent cannabinoid exposure also induced sex-dependent changes in plasma leptin levels and body weights. The present results indicate that early MD and adolescent cannabinoid exposure exerted distinct sex-dependent long-term behavioural and physiological modifications that could predispose to the development of certain neuropsychiatric disorders, though no synergistic effects were found.