Locus Coeruleus Noradrenergic Modulation of Diurnal Corticosterone, Stress Reactivity, and Cardiovascular Homeostasis in Male Rats.

Introduction: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response.

Methods: Male rats, on day 0, were treated intraperitoneally with either DSP4 (50 mg/kg body weight) (DSP), an LC-NA specific neurotoxin, or normal saline (SAL).

In vivo dialysis setup with a loop injection valve facilitates retrodialysis studies.

Introduction: Retrodialysis, as used in neuropharmacological research, is a technique for in vivo delivery of neuroactive agents with concurrent monitoring of their effects on cellular activity with a separation between certain degree of spatial and temporal resolution. Typically, this is accomplished either by the use of a liquid-switch requiring multiple pumps, or by exchange of flow tubing requiring stopping and restarting dialysis. In the present study, we describe the use of a medium pressure injection valve for retrodialysis that overcomes these problems.

Neuroendocrine homeostasis after vagus nerve stimulation in rats.

Background: The vagus nerve is important in maintaining HPA axis and sympatho-adrenal system (SAS) homeostasis, however little is known about the effect of vagus nerve stimulation (VNS), as used therapeutically, on these functions. Accordingly, the effect of VNS on plasma indices of HPA axis (ACTH, corticosterone), and SAS (norepinephrine, epinephrine) function were evaluated in rats.

Methods: Male rats, on day-0 (D0), underwent surgeries for implantation of catheters into the right jugular vein and programmable (VNP) or non-programmable (VND) neurocybernetic devices encircling the left cervical vagus.

Persistent anxiolytic affects after chronic administration of the CRF₁ receptor antagonist R121919 in rats.

Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF₁ receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF₁ receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained.

The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal.

Rationale: Corticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine.

Ketamine-xylazine-acepromazine anesthesia and postoperative recovery in rats.

We evaluated the effect of ketamine-xylazine-acepromazine anesthesia (31.25, 6.25, and 1.

Combined pre- and postnatal environmental enrichment programs the HPA axis differentially in male and female rats.

Experimental environmental enrichment (EE) is usually applied in adulthood or immediately after weaning, with robust effects on physiology and behaviour. To investigate the effects of EE earlier in life, female rats were maintained under moderate enrichment during pregnancy and, together with their pups, during lactation until weaning. A separate group of dams housed under standard conditions during pregnancy and lactation served as controls.

Early life experience alters behavior during social defeat: focus on serotonergic systems.

Early life experience can have prolonged effects on neuroendocrine, autonomic, and behavioral responses to stress. The objective of this study was to investigate the effects of early life experience on behavior during social defeat, as well as on associated functional cellular responses in serotonergic and non-serotonergic neurons within the dorsal raphe nucleus, a structure which plays an important role in modulation of stress-related physiology and behavior. Male Long Evans rat pups were exposed to either normal animal facility rearing or 15 min or 180 min of maternal separation from postnatal days 2-14.

Chronic maternal stress inhibits the capacity to up-regulate placental 11beta-hydroxysteroid dehydrogenase type 2 activity.

This study investigated the effects of acute and chronic restraint stress during the third week of pregnancy on placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in rats. Acute exposure to stress on gestational day 20 immediately up-regulated placental 11beta-HSD2 activity by 160%, while chronic stress from day 14 to day 19 of pregnancy did not significantly alter basal 11beta-HSD2 activity. However, the latter reduced the capacity to up-regulate placental 11beta-HSD2 activity in the face of an acute stressor by 90%.

Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring.

In a series of studies on the long-term consequences of neonatal rearing, we compared hypothalamic and extrahypothalamic central corticotropin-releasing factor (CRF) systems in male rats reared under conditions of animal facility rearing, nonhandling (HMS0), handling with brief maternal separation for 15 min (HMS15), or handling with moderate maternal separation for 180 min (HMS180) daily from postnatal days 2-14. CRF-like immunoreactivity (CRFir) was elevated in lumbar cerebrospinal fluid of adult HMS180 and HMS0 rats relative to the other groups. In the paraventricular nucleus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and locus coeruleus, CRFir and CRF mRNA levels were significantly elevated in HMS0 and HMS180 rats.

Differential neuroendocrine responses to chronic variable stress in adult Long Evans rats exposed to handling-maternal separation as neonates.

Burgeoning evidence supports a preeminent role for early- and late-life stressors in the development of physio- and psychopathology. Handling-maternal separation (HMS) in neonatal Long Evans hooded rats leads to stable phenotypes ranging from resilient to vulnerable to later stressor exposure. Handling with 180 min of maternal separation yields a phenotype of stress hyper-responsiveness associated with facilitation of regional CRF neurocircuits and glucocorticoid resistance.

Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation.

Background: Maternally separated rats exhibit exaggerated hypothalamic-pituitary-adrenal responses to an acute stressor but normal diurnal trough functioning. We hypothesized that maternally separated rats experience adequate proactive glucocorticoid negative feedback but deficient "reactive" negative feedback, contributing to prolonged hypothalamic-pituitary-adrenal stress responses.

Methods: We measured plasma adrenocorticotropic hormone and corticosterone concentrations following an acute stressor or 6 to 8 hours after dexamethasone administration in adult rats previously exposed to daily handling-maternal separation for 15 minutes (HMS15) or 180 minutes (HMS180) during postnatal days 2 to 14.

Foster litters prevent hypothalamic-pituitary-adrenal axis sensitization mediated by neonatal maternal separation.

Neonatal maternal separation of rat pups has been shown to produce long-term increases in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, elevated levels of hypothalamic corticotropin releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN), and enhanced anxiety-like behavior. These effects appear to be at least partially mediated by subtle disruptions in the quality of maternal-pup interactions. This hypothesis was tested by providing half the dams with foster litters during the maternal separation paradigm, so that in those litters, only the pups and not the dams were experiencing a period of separation.

The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF(1) receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties.

Jugular vein catheterization for repeated blood sampling in the unrestrained conscious rat.

The ability to obtain repeated, low-stress blood samples from adult rats enables the design of complex experiments in which time course information or evaluation of repeated treatments is necessary. Furthermore, it reduces the number of animals necessary to acquire such information and, thus, facilitates compliance with the animal use 3Rs (reduction, refinement and replacement). To this end, a microsurgical technique to collect blood samples from the right atrium through a catheter (cannula) implanted into the right external jugular vein of adult rats is described.

Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment.

Rationale: This study was based on the findings of a high comorbidity among anxiety and depression as well as with alcohol abuse.

Objective: To evaluate first exposure alcohol preference in a rodent model of moderate neonatal maternal separation.

Methods: Rat pups were exposed to either normal animal facility rearing (AFR) or 15 min (HMS15) or 180 min (HMS180) of maternal separation from postnatal days 2-14.

Chronic administration of the selective corticotropin-releasing factor 1 receptor antagonist CP-154,526: behavioral, endocrine and neurochemical effects in the rat.

Corticotropin-releasing factor 1 (CRF(1)) receptor antagonists may represent a novel group of drugs for the pharmacotherapy of depression and/or anxiety disorders. We have investigated the behavioral, endocrine, and neurochemical effects of chronic administration of a selective CRF(1) receptor antagonist, CP-154,526. After 9 to 10 days of treatment with CP-154,526 (3.

Sensitivity to glucocorticoid-mediated fast-feedback regulation of the hypothalamic-pituitary-adrenal axis is dependent upon stressor specific neurocircuitry.

Unlabelled: Fos-protein immunoreactivity (Fos-IR) was used to identify neurocircuits potentially participating in the regulation of hypothalamic-pituitary-adrenal (HPA) axis sensitivity to glucocorticoid-mediated fast-feedback in rats exposed to the physical stressor, hemorrhage, or the psychological stressor, airpuff startle. Marked regional brain differences in the Fos-IR expression were observed in response to these stressors. Specifically, after hemorrhage, nuclear Fos-IR increased in the nucleus of the solitary tract and other brainstem regions known to regulate hemodynamic processes including the supraoptic nucleus, and the magnocellular division of hypothalamic paraventricular nucleus (PVN).

Long-term behavioral effects of repetitive pain in neonatal rat pups.

Human preterm neonates are subjected to repetitive pain during neonatal intensive care. We hypothesized that exposure to repetitive neonatal pain may cause permanent or long-term changes because of the developmental plasticity of the immature brain. Neonatal rat pups were stimulated one, two, or four times each day from P0 to P7 with either needle prick (noxious groups N1, N2, N4) or cotton tip rub (tactile groups T1, T2, T4).

Patterns of Fos-Immunoreactivity in the CNS Induced by Repeated Hemorrhage in Conscious Rats: Correlations with Pituitary-Adrenal Axis Activity.

While the present understanding of pituitary-adrenal function predicts attenuation of responses to a repeated stressor, experimental observations often show occurrence of potentiation rather than inhibition. The role of the CNS in this phenomenon was investigated in rats sustaining either a single (S-HEM) or a double episode (R-HEM) of hemorrhage. For S-HEM, blood was withdrawn over 3min and retransfused at 10min; for R-HEM, the stimulus was repeated at 90 min.

Reduced noradrenergic tone to the hypothalamic paraventricular nucleus contributes to the stress hyporesponsiveness of lactation.

Lactation in mammals is accompanied by a marked decrease in stress responsiveness that we previously attributed, in part, to a reduction in noradrenergic (NA) innervation of hypothalamic paraventricular nucleus (PVN) neurons controlling neuroendocrine stress responses. In the present study, we compared in-vivo PVN catecholamine secretion by microdialysis between nonlactating and lactating females and tested the effects of NA alpha-1 and alpha-2 receptor antagonists (corynanthine and idazoxan, respectively) on the acute stress response of lactating and virgin female rats. To determine if PVN alpha-adrenoreceptor density, affinity, or synthesis, changes as a function of lactation, we performed receptor autoradiography, Scatchard analysis and in situ hybridization of alpha-adrenoreceptors.

Endocrine and behavioral effects of airpuff-startle in rats.

Adult male rats chronically implanted with cannulae in the jugular vein were used to characterize the endocrine and behavioral consequences of airpuff-startle. In the first series of experiments, resting animals subjected to three blocks of airpuff (blocks of three airpuffs each with each block separated by 1 min) showed a 10-fold increase in plasma adrenocorticotropin (ACTH) and corticosterone levels, indicating a significant but moderate activation of the hypothalamo-pituitary-adrenal (HPA) axis when compared with the untreated controls (n = 5 each). In the second series of experiments, monitoring of anxiety-related behavior in the defensive withdrawal paradigm revealed a significant increase in anxiety induced by airpuff-startle application compared with the untreated controls (n = 10 each).

Clozapine-induced EEG abnormalities and clinical response to clozapine.

The authors hypothesized that patients who develop gross EEG abnormalities during clozapine treatment would have a less favorable outcome than patients who did not develop abnormal EEGs. The clinical EEGs and the Brief Psychiatric Rating Scale (BPRS) scores of 12 patients with schizophrenia and 4 patients with schizoaffective disorder were compared before and during treatment with clozapine. Eight patients developed significant EEG abnormalities on clozapine; 1 showed worsening of an abnormal pre-clozapine EEG; none of these subjects had clinical seizures.

Age-related alterations of hypothalamic-pituitary-adrenal axis function in male Fischer 344 rats.

Aging is frequently associated with changes in physiological and cognitive processes. Among these changes is a distinct dysregulation of the hypothalamic-pituitary-adrenal axis. In the current experiments, aspects of hypothalamic-pituitary-adrenal axis function were compared in young (3- to 4-month-old) and aged (21- to 24-month-old) Fisher 344/N male rats.