[Overview of acute and chronic stress responses]. / Le stress dans tous ses états.

The psychobiological concept of stress built up over the years since the 1930s. The understanding of the neurobiological mechanisms involved has progressed remarkably during the past years. This article provides an overview of the recent data opposing acute and chronic stress. The former is an adaptative response of the organism to cope with the fluctuations of the environment and thereby is essential for survival. By contrast, chronic stress is deleterious and leads to various disease states in vulnerable individuals. Its adverse effects on the brain and the body result from a dysregulation of the stress system with various origins and mechanisms which we will discuss in this review.

Flaws of drug instrumentalization.

The adaptive use of drugs, or "drug instrumentalization," is presented as a reality that the scientific literature has largely ignored. In this commentary, we demonstrate why this concept has limited value from the standpoint of nosology, why it should not be viewed as "adaptive," and why it has dangerous implications for policy and public health efforts.

Paradoxical effect of severe dietary restriction on Long-Evans rat life span.

It has been firmly established that the longevity of 20- to 60%-calorie-restricted rodents, with malnutrition (essential nutrients deficiency) being avoided, is increased when compared to ad libitum fed rodents. However, the effects on life span of severe dietary restriction (i. e. malnutrition), with limited weight loss, remained unknown. The purpose of this 4-year study was to investigate the effects on longevity of a severe form of dietary restriction, with limited and controlled weight loss. To this end, a group of male Long-Evans rats severely dietary restricted (SDR group), with a weight loss throughout the experiment

Age-dependent effect of prenatal stress on hippocampal cell proliferation in female rats.

Stressors occurring during pregnancy can alter the developmental trajectory of offspring and lead to, among other deleterious effects, cognitive deficits and hyperactivity of the hypothalamo-pituitary-adrenal axis. A recent feature of the prenatal stress (PS) model is its reported influence on structural plasticity in hippocampal formation, which sustains both cognitive functions and stress responsiveness. Indeed, we and others have previously reported that males exposed to stress in utero are characterized by a decrease in hippocampal cell proliferation, and consequently neurogenesis, from adolescence to senescence. Recent studies in females submitted to PS have reported conflicting results, ranging from no effect to a decrease in cell proliferation. We hypothesized that changes in cell proliferation in PS female rats are age dependent. To address this issue, we examined the impact of PS on hippocampal cell proliferation in juvenile, young, middle-aged and old females. As hypothesized, we found an age-dependent effect of PS in female rats as cell proliferation was significantly decreased only when animals reached senescence, a time when adrenal gland weight also increased. These data suggest that the deleterious effects of PS on hippocampal cell proliferation in females are either specific to senescence or masked during adulthood by protective factors.

Plasticity of reward neurocircuitry and the 'dark side' of drug addiction.

Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a 'dark side'--a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction.

[Neurosciences in Bordeaux]. / Chronique historique Les Neurosciences à Bordeaux.

The Bordeaux Neuroscience Institute brings together all the disciplines that constitute the clinical and experimental neurosciences. Outside of the Paris region, the Institute represents the largest community of researchers working on the nervous system. The aim of this brief historical piece is to describe how neuroscientists in Bordeaux are the heirs to a long neuropsychiatric tradition established by pioneers of national and international renown. This tradition has been maintained, without interruption, through many generations. The careers and scientific work of these great neurologists and psychiatrists are briefly evoked, and particularly those of A. Pitres, E. Régis and E. Azam in the 19th century; and, in the 20th century, J. Abadie, H. Verger and R. Cruchet. The determining influence of P Delmas-Marsalet (1898-1977), Professor of Neuropsychiatry, on the development of modern neurosciences in Bordeaux is recalled through his work, his teachings, and his numerous students.

Historical approach and evolution of the stress concept: a personal account.

As a matter of research or as a process, stress remains one of the most cited construct in biomedical literature; a medline survey accounts for more than 210,000 citations since 1970. It is difficult to define. It is frequently used in a vague manner, including undifferently the agent, the process, and the response. The concept is multidimensional and composite, including emotion and arousal. Stress has an implicit: it implies alteration of a theoretical balance or equilibrium within physiological systems, and it seems to characterize a process leading to disease. Large individual differences exist in the way to react to a stressor. Psychological and cognitive determinants are central for the course of the process. The homeostasis concept is not useful anymore and has been replaced by the more accurate and flexible concept of allostasis. The physiological hormonal and neural bases of this process are now identified. New perspectives identify stressors, chronic or not, to be a source of vulnerabilities through epigenetic mechanisms and a series of biobehavioral disorders characteristic of our modern civilizations. The evolution of the concept is not linear. It has been enriched by recent neurobiological-neuroendocrinological discoveries and also by behavioral-cognitive sciences.

Drug addiction: pathways to the disease and pathophysiological perspectives.

Drug addiction is a medical condition, a chronic relapsing disease. As in other domains of experimental medicine, appropriate experimental investigations are needed in order to better understand the disease. However, to understand the diverse facets of drug effects and of the underlying pathophysiology it is necessary to keep in mind the complexity of the psychopathological processes. The main symptoms that characterize addiction correspond to expressions of dysfunctions within specific circuits and regions. Pathways to addiction are numerous and comorbidity and in the real world poly-drug use are common. Some of these aspects will be examined as well as the role of life events and stress. Theoretical considerations will be proposed [see also: Koob, G.F., & Le Moal, M.. 2005a. Neurobiology of Addiction. Elsevier. 570 pp] to account for the stages of the disease from impulse control disorder to compulsive disorders, for affective dynamics and for the relations between the symptoms and pathophysiology.

Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis.

BACKGROUND: Prenatal stress constitutes a developmental risk factor for later psychopathology. The behavioral disorders are sustained by neurobiological alterations including long-term reduction of hippocampal neurogenesis; its deregulation has been involved in cognitive impairments, mood disorders and addiction. A major goal is to define periods in development and strategies for intervening to prevent the effects of early stressful events. We investigated the ability of a postnatal infantile stimulation to prevent prenatal stress-induced alteration in hippocampal neurogenesis. METHODS: The influence of postnatal handling on prenatal stress-induced changes in hippocampal neurogenesis was examined in 4 and 26 month-old male rats. Three distinct phases of the neurogenesis were studied: proliferation, survival and neuronal differentiation. RESULTS: Prenatal stress reduced hippocampal cell proliferation all throughout life. Furthermore, the survival rate of newborn cells, the number of immature neurons and the number of differentiated new neurons were reduced in young and old prenatally-stressed rats. All those deleterious effects were counteracted by neonatal handling. CONCLUSIONS: These data show that finer aspects of brain shaping can be rewired by environmental influences occurring at sensitive phase of development. They also suggest that infantile stimulation may reverse the appearance of behavioral disorders induced by early life stress.

Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes.

RATIONALE: The neurosteroids pregnenolone sulfate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3alpha,5alpha THPROG) have been implicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory. OBJECTIVE: To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems. METHODS: We carried out keyword searches in "Medline" to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents. RESULTS: Peripheral and central administrations of PREGS, DHEAS, and 3alpha,5alpha THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneurons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting reports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions. CONCLUSIONS: The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments.

Preexposure during or following adolescence differently affects nicotine-rewarding properties in adult rats.

RATIONALE: Many people come in contact with psychoactive drugs, yet not all of them become addicts. Epidemiology shows that a late approach with cigarette smoking is associated with a lower probability to develop nicotine dependence. Exposure to nicotine during periadolescence, but not similar exposure in the postadolescent period, increases nicotine self-administration in rats, but underlying mechanisms remain poorly understood. OBJECTIVE: We investigated whether exposure to nicotine during or after adolescence would alter rewarding properties of the same drug at adulthood, as assessed by place conditioning. MATERIALS AND METHODS: Periadolescent (PND 34-43) or postadolescent (PND 60-69) rats were injected with saline or nicotine (0.4 mg kg(-1)) for 10 days. The rats received three pairings with saline and three pairings with nicotine (0, 0.3, or 0.6 mg kg(-1)) 5 weeks after pretreatment. The rats were then tested for place conditioning in a drug-free state. RESULTS: Upon first exposure to the apparatus, animals pretreated with nicotine during adolescence showed elevated novelty-induced activation. The 0.3 (but not the 0.6) mg kg(-1) dose failed to produce both ongoing locomotor sensitization and place conditioning in animals pretreated with nicotine following adolescence. This suggests a rightward shift in the dose-response curve, namely, a reduced efficacy of nicotine. Conversely, the same dose was effective in saline-pretreated controls and noteworthy in rats pretreated during adolescence. CONCLUSION: Exposure following the adolescent period might diminish the risk to develop nicotine dependence. As for human implications, findings are consistent with a reduced vulnerability to nicotine addiction in people who start smoking late in their life.

Individual differences in cognitive aging: implication of pregnenolone sulfate.

In humans and animals, individual differences in aging of cognitive functions are classically reported. Some old individuals exhibit performances similar to those of young subjects while others are severely impaired. In senescent animals, we have previously demonstrated a significant correlation between the cognitive performance and the cerebral concentration of a neurosteroid, the pregnenolone sulfate (PREG-S). Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, cortex and hippocampus induced by intracerebroventricular (i.c.v.) or intracerebral administrations of PREG-S. Central ACh neurotransmission is known to be involved in the regulation of memory processes and is affected in normal aging and severely altered in human neurodegenerative pathologies like Alzheimer's disease. In the central nervous system, ACh neurotransmission is also involved in the modulation of sleep-wakefulness cycle, and particularly the paradoxical sleep (PS). Relationships between paradoxical sleep and memory are documented in the literature in old animals in which the spatial memory performance positively correlates with the basal amounts of paradoxical sleep. PREG-S infused at the level of ACh cell bodies (nucleus basalis magnocellularis, NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young animals.Finally, aging related cognitive dysfunctions, particularly those observed in Alzheimer's disease, have also been related to alterations of mechanisms underlying cerebral plasticity. Amongst these mechanisms, neurogenesis has been extensively studied recently. Our data demonstrate that PREG-S central infusions dramatically increase neurogenesis, this effect could be related to the negative modulator properties of this steroid at the GABA(A) receptor level. Taken together these data suggest that neurosteroids can influence cognitive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore, our recent data suggest a critical role for neurosteroids in the modulation of cerebral plasticity, mainly on hippocampal neurogenesis.

Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats.

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a "critical" ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.

The glucocorticoid receptor as a potential target to reduce cocaine abuse.

Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose-response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose-dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment.

Nicotine self-administration impairs hippocampal plasticity.

Nicotine, the neuroactive compound responsible for tobacco addiction, is primarily believed to have beneficial effects on the adult brain. However, in heavy smokers, abstinence from nicotine is accompanied by cognitive impairments that suggest adverse effects of nicotine on brain plasticity. For this reason, we studied changes in plasticity-related processes in the dentate gyrus (DG) of the hippocampal formation of animals trained to self-administer nicotine. The DG was chosen because it undergoes profound plastic rearrangements, many of which have been related to memory and learning performances. In this region, we examined the expression of the polysialylated (PSA) forms of neural cell adhesion molecule (NCAM), PSA-NCAM, neurogenesis, and cell death by measuring the number of pyknotic cells. It was found that nicotine self-administration profoundly decreased, in a dose-dependent manner, the expression of PSA-NCAM in the DG; a significant effect was observed at all the doses tested (0.02, 0.04, and 0.08 mg/kg per infusion). Neurogenesis was also decreased in the DG, but a significant effect was observed only for the two highest doses of nicotine. Finally, the same doses that decreased neurogenesis also increased cell death. These results raise an important additional concern for the health consequences of nicotine abuse and open new insight on the possible neural mechanisms of tobacco addiction.

Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis.

Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO-related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S-nitrosocysteine (SNO-cysteine) and showed that anti-NO-cysteine Abs of the IgM isotype are in fact present in the sera of some MS patients (Boullerne et al., 1995). We report here the presence of a seemingly identical Ab response directed against SNO-cysteine in an acute model of MS, experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with the 68-84 peptide of guinea pig myelin basic protein (MBP(68-84)). Serum levels of anti-SNO-cysteine Abs peaked 1 week before the onset of clinical signs and well before the appearance of anti-MBP(68-84) Abs. The anti-SNO-cysteine Ab peak titer correlated with the extent of subsequent CNS demyelination, suggesting a link between Ab level and CNS lesion formation. In relapsing-remitting MS patients, we found elevated anti-SNO-cysteine Ab at times of relapse and normal values in most patients judged to be in remission. Two-thirds of patients with secondary progressive MS had elevated anti-SNO-cysteine Ab levels, including those receiving interferon beta-1b. The data show that a rise in circulating anti-SNO-cysteine Ab levels precedes onset of EAE. Anti-SNO-cysteine Abs are also elevated at times of MS attacks and in progressive disease, suggesting a possible role for these Abs, measurable in blood, as a biological marker for clinical activity.

Sciences of the brain: The long road to scientific maturity and to present-day reductionism.

When examined in a long-term perspective, brain sciences demonstrate certain conceptual consistencies as well as theoretical oppositions that have lasted for centuries, ever since Ancient Greece. The neurosciences have progressed more on the basis of technological than conceptual advances, and the constant recuperation of new techniques from other sciences have led to a continually reductionist view of the brain and its functions. In a different perspective, if not opposite to the reductionism, are the psychological constructs and those that constitute the functional unity of individuals, which are still mysterious. In fact, the gap between these two approaches has never been larger than it is now. This chapter discusses the enduring nature of some of these problems and their recent consequences.

Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies.

Transcutaneous cranial electrical stimulation (TCES) with high frequency (166 kHz) intermittent current (100 Hz: Limoge current) has been used for several years in cardiac, thoracic, abdominal, urological and micro-surgery. The main benefits are a reduced requirement for analgesic drugs, especially opiates, and a long-lasting postoperative analgesia. We have confirmed these clinical observations in rats using the tail-flick latency (TFL) test to measure pain threshold. TCES was not found to modify the pain threshold in drug-free rats, but it potentiated morphine-induced analgesia (systemic injection). To obtain a maximal effect, the stimulation must be initiated 3 h before the drug injection and be maintained throughout the duration of its pharmacological action. TCES potentitation was found to depend on the dose of the drug, the intensity of the current and the polarity of electrodes. These findings were confirmed by blind tests of the efficiency of TCES on several opiate analgesic drugs currently used in human surgery (morphine, fentanyl, alfentanil and dextromoramide). The analgesic effect of these 4 opiates (TFL as % of baseline without or with TCES) were respectively: 174%, 306%; 176%, 336%; 160%, 215%; and 267%, 392%. The results were obtained not only after systemic opiate treatment, but also after intracerebroventricular injection of morphine (10 micrograms; analgesic effect 152%, 207% with TCES) suggesting that TCES potentiation of opiate-induced analgesia is centrally mediated.

Early and later adoptions differently modify mother-pup interactions.

Life events occurring during the perinatal period have strong long-term effects. In rats, prenatal stress, postnatal maternal separations, or adoptions at different periods are known to affect behavior and reactivity to stress in offspring. To determine the role of maternal factors on differential outcome adoptions, the authors investigated interactions between pups and the adopting mothers by assessing both pups' ultrasound emissions and maternal behavior. Early and late adoptions increased mother care at the moment of adoption and during mother-infant reunion after a separation procedure. However, although early adoption induced a decrease in pups' ultrasound emissions in response to a stressful separation, later adoptions enhanced it. Results suggest a sensitive period during which fostering may change pups' and dams' behavior.

Neuroactive steroids: new biomarkers of cognitive aging.

Intensive studies in animals established that neuroactive steroids display neuronal actions and influence behavioral functions. We describe here investigations on the role of neuroactive steroids in learning and memory processes during aging and suggest their role as biomarkers of cognitive aging. Our work demonstrated the role of the steroid pregnenolone (PREG) sulfate as a factor underlying an individual's age-related cognitive decline in animals. As new perspectives of research we argue that knowing whether neuroactive steroids exist as endogenous neuromodulators and modulate physiologically behavioral functions is essential. To this end, a new approach using the sensitive, specific, and accurate quantitative determination of neuroactive steroids by mass spectrometry seems to have potential for examining the role of each steroid in discrete brain areas in learning and memory alterations, as observed during aging.