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1.
Neuroendocrinology ; 112(8): 763-776, 2022.
Article in English | MEDLINE | ID: mdl-34649254

ABSTRACT

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). On day 10, animals were surgically prepared with jugular vein (hypothalamic-pituitary-adrenal [HPA] axis) or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress (transient hemorrhage [14 mL/kg body weight] or air puff-startle), and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. RESULTS: In DSP rats compared to SAL rats, (1) regional brain norepinephrine was decreased, but there was no change in median eminence or olfactory bulb CRF content; (2) during HPA axis acrophase, the plasma corticosterone response was blunted; (3) after hemorrhage and air puff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; (4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and (5) after hemorrhage, hemodynamics exhibited asynchronous responses. CONCLUSION: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed.


Subject(s)
Corticosterone , Pituitary-Adrenal System , Adrenocorticotropic Hormone , Animals , Body Weight , Corticotropin-Releasing Hormone/metabolism , Homeostasis , Hypothalamo-Hypophyseal System/metabolism , Locus Coeruleus/metabolism , Male , Norepinephrine , Pituitary-Adrenal System/metabolism , Rats
2.
Physiol Rep ; 6(21): e13904, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30426706

ABSTRACT

The mouse has become the most common mammalian animal model used in biomedical research. However, laboratory techniques used previously in rats and other larger animals to sample blood had to be adapted in mice due to their lower mouse plasma volume. Sampling is further confounded by the variability in plasma hormone and metabolite concentrations that can occur from the stress or the anesthesia that accompanies the collection. In this article, we describe in detail a protocol we developed for blood sampling in conscious, unrestrained mice. Our protocol implements the use of chronic indwelling catheters in the right external jugular vein, allowing the mice to recover fully in their home cages, untethered until the time of blood sampling. This protocol employs catheters that remain patent for days and does not require the purchase of expensive equipment. We validated this protocol by measuring the time course of plasma norepinephrine (NE) concentration during and after the relief of acute immobilization stress in wild type (WT) and pendrin knockout (KO) mice and compared these results with our previously published values. We found that following relief from immobilization stress, it takes longer for plasma NE concentration to return to basal levels in the pendrin KO than in the wild type mice. These results highlight the potential utility of this protocol and the potential role of pendrin in the neuroendocrine response to acute stress.


Subject(s)
Blood Specimen Collection/methods , Catheters, Indwelling , Animals , Blood Specimen Collection/instrumentation , Consciousness , Jugular Veins , Mice , Mice, Inbred C57BL , Movement , Norepinephrine/blood
3.
Psychoneuroendocrinology ; 77: 165-174, 2017 03.
Article in English | MEDLINE | ID: mdl-28064086

ABSTRACT

The oxytocin (OXT) system is functionally linked to the HPA axis in a reciprocal and complex manner. Certain stressors are known to cause the simultaneous release of OXT and adrenocorticotrophic hormone (ACTH) followed by corticosterone (CORT). Furthermore, brain OXT attenuates ACTH and CORT responses. Although there are some indications of CORT influencing OXT neurotransmission, specific effects of CORT on neurohypophyseal or intra-hypothalamic release of OXT have not been studied in detail. In the present set of experiments, adult male rats were adrenalectomized (ADX) or sham-operated and fitted with a jugular vein catheter and/or microdialysis probe targeting the hypothalamic paraventricular nucleus (PVN). Blood samples and dialysates were collected before and after forced swimming (FS) and analyzed for CORT, ACTH and AVP concentrations (in plasma) and OXT concentrations (in plasma and dialysates). Experimental treatments included acute infusion of CORT (70 or 175µg/kg i.v.) 5min prior to FS, or subcutaneous placement of 40% CORT pellets resulting in stable CORT levels in the normal basal range. Although ADX did not alter basal OXT concentrations either in plasma or in microdialysates from the PVN, it did cause an exaggerated peripheral secretion of OXT and a blunted intra-PVN release of OXT in response to FS. CORT pellets did not influence either of these ADX-induced effects, while acute infusion of 175µg/kg CORT rescued the stress-induced rise in OXT release within the PVN and modestly increased peripheral OXT secretion. In conclusion, these results indicate that CORT regulates both peripheral and intracerebral OXT release, but in an independent manner. Whereas the peripheral secretion of OXT occurs simultaneously to HPA axis activation in response to FS and is modestly influenced by CORT, HPA axis activation and circulating CORT strongly contribute to the stress-induced stimulation of OXT release within the PVN.


Subject(s)
Hypothalamo-Hypophyseal System/metabolism , Oxytocin/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Pituitary-Adrenal System/metabolism , Stress, Physiological/physiology , Adrenalectomy , Adrenocorticotropic Hormone/blood , Animals , Arginine Vasopressin/blood , Corticosterone/blood , Corticosterone/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Male , Paraventricular Hypothalamic Nucleus/drug effects , Pituitary-Adrenal System/drug effects , Rats , Rats, Wistar , Swimming
4.
Am J Physiol Endocrinol Metab ; 309(6): E534-45, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26173457

ABSTRACT

Pendrin (Slc26a4) is a Cl(-)/HCO3 (-) exchanger expressed in renal intercalated cells and mediates renal Cl(-) absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release.


Subject(s)
Adrenal Medulla/metabolism , Anion Transport Proteins/genetics , Chloride-Bicarbonate Antiporters/genetics , Epinephrine/metabolism , Norepinephrine/metabolism , RNA, Messenger/metabolism , Stress, Psychological/metabolism , Adrenal Glands/metabolism , Animals , Anion Transport Proteins/metabolism , Blood Pressure , Chloride-Bicarbonate Antiporters/metabolism , Gene Expression Profiling , Immunoblotting , Immunohistochemistry , Kidney/metabolism , Mice , Mice, Knockout , Rats , Restraint, Physical , Reverse Transcriptase Polymerase Chain Reaction , Sulfate Transporters
5.
J Psychiatr Res ; 44(2): 106-11, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19573876

ABSTRACT

Individuals exposed to psychological stressors may experience a long-term resetting of behavioral and neuroendocrine aspects of their "stress response" so that they either hyper or hypo-respond to subsequent stressors. These effects of psychological or traumatic stressors may be mimicked in rats using the resident-intruder model of social defeat. The social defeat model has been characterized to model aspects of the physiology and behavior associated with anxiety and depression. The objective of this study was to determine if behaviors elicited following repeated social defeat can also reflect aspects of ethologically relevant stresses associated with existing post traumatic stress disorder (PTSD) models. Socially defeated rats displayed weight loss and an enhanced and prolonged response to acoustic startle which was displayed for up to 10days following repeated social defeat. These data indicate that the severe stress of social defeat can produce physiologic and behavioral outcomes which may reflect aspects of traumatic psychosocial stress.


Subject(s)
Dominance-Subordination , Reflex, Startle/physiology , Social Behavior , Stress, Psychological/physiopathology , Stress, Psychological/psychology , Weight Gain/physiology , Acoustic Stimulation/methods , Analysis of Variance , Animals , Behavior, Animal , Disease Models, Animal , Male , Psychoacoustics , Rats , Rats, Long-Evans , Reaction Time/physiology
6.
Brain Res ; 1305: 47-63, 2009 Dec 11.
Article in English | MEDLINE | ID: mdl-19781533

ABSTRACT

Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of serotonergic systems in the brain. To evaluate the effects of early life experience, adverse experiences during adulthood, and potential interactions between these factors on serotonin transporter (slc6a4) mRNA expression, we investigated in rats the effects of maternal separation (180 min/day from days 2 to 14 of life; MS180), neonatal handing (15 min/day from days 2 to 14 of life; MS15), or normal animal facility rearing (AFR) control conditions with or without subsequent exposure to adult social defeat on slc6a4 mRNA expression in the dorsal raphe nucleus (DR) and caudal linear nucleus. At the level of specific subdivisions of the DR, there were no differences in slc6a4 mRNA expression between MS15 and AFR rats. Among rats exposed to a novel cage control condition, increased slc6a4 mRNA expression was observed in the dorsal part of the DR in MS180 rats, relative to AFR control rats. In contrast, MS180 rats exposed to social defeat as adults had increased slc6a4 mRNA expression throughout the DR compared to both MS15 and AFR controls. Social defeat increased slc6a4 mRNA expression, but only in MS180 rats and only in the "lateral wings" of the DR. Overall these data demonstrate that early life experience and stressful experience during adulthood interact to determine slc6a4 mRNA expression. These data support the hypothesis that early life experience and major stressful life events contribute to dysregulation of serotonergic systems in stress-related neuropsychiatric disorders.


Subject(s)
Maternal Deprivation , RNA, Messenger/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Social Behavior , Stress, Psychological/genetics , Analysis of Variance , Animals , Animals, Newborn , Autoradiography , Behavior, Animal/physiology , Image Processing, Computer-Assisted , In Situ Hybridization , Male , Neurons/metabolism , RNA, Messenger/metabolism , Raphe Nuclei/metabolism , Rats , Rats, Long-Evans , Serotonin Plasma Membrane Transport Proteins/metabolism , Video Recording
7.
J Cereb Blood Flow Metab ; 29(10): 1673-82, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19553908

ABSTRACT

Cardiac arrest and cardiopulmonary resuscitation (CA/CPR) increase the risk for affective disorders in human survivors. Postischemic anxiety- and depressive-like behaviors have been documented in animal models of CA/CPR; however, the stability of post-CA/CPR anxiety-like behavior over time and the underlying physiologic mechanisms remain unknown. The hypothalamic-pituitary-adrenal (HPA) axis and the corticotropin releasing factor (CRF) system may mediate the pathophysiology of anxiety and depression; therefore, this study measured CA/CPR-induced changes in CRF receptor binding and HPA axis negative feedback. Mice were exposed to CA/CPR or SHAM surgery and assessed 7 or 21 days later. Consistent with earlier demonstrations of anxiety-like behavior 7 days after CA/CPR, increased anxiety-like behavior in the open field was also present 21 days after CA/CPR. On postoperative day 7, CA/CPR was associated with an increase in basal serum corticosterone concentration relative to SHAM, but this difference resolved by postoperative day 21. The Dexamethasone Suppression Test showed that the CA/CPR group had enhanced negative feedback compared with SHAM controls at postoperative day 21. Furthermore, there was a gradual increase in CRF(1) receptor binding in the paraventricular nucleus of the hypothalamus and bed nucleus of the stria terminalis, as well as a transient decrease of both CRF(1) and CRF(2A) receptors in the dorsal hippocampus. Therefore, sustained changes in activity of the HPA axis and the CRF system after CA/CPR may contribute to the postischemic increase in affective disorders.


Subject(s)
Cardiopulmonary Resuscitation/adverse effects , Heart Arrest/complications , Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/physiopathology , Animals , Anxiety , Corticosterone/blood , Corticotropin-Releasing Hormone , Heart Arrest/therapy , Hypothalamus , Mice , Receptors, Corticotropin-Releasing Hormone/analysis , Receptors, Corticotropin-Releasing Hormone/metabolism , Time Factors
8.
Eur J Neurosci ; 25(10): 3091-8, 2007 May.
Article in English | MEDLINE | ID: mdl-17561822

ABSTRACT

In this study we addressed whether certain behavioural measures, endocrine levels and specific stress-related proteins exhibit long-term alterations in adult rats following repeated postnatal maternal separation. Rats were subjected to daily maternal separation for 15 min (HMS15) or 180 min (HMS180) from postnatal day 2-14. Adult HMS180 animals were hypoactive and had increased levels of stereotypy compared to HMS15 and normal animal facility-reared (AFR) animals. HMS180 animals also had augmented plasma adrenocorticotropin (ACTH) and corticosterone (CORT) concentrations following an acute stressor, compared to the other two groups. We assessed persistent changes in proteins regulated by stress in hippocampus, cortex, ventral tegmental area, nucleus accumbens, striatum and amygdala. Western blotting analysis revealed a decrease in the levels of mature brain-derived neurotrophic factor (BDNF) in hippocampus and striatum, but an increase in the ventral tegmental area in the HMS180 rats. Levels of pro-BDNF were significantly increased in the ventral tegmental area of HMS180 animals but were unchanged in other brain regions compared to the other two groups. Levels of the transcription factors cAMP response element binding protein (CREB) and DeltaFosB were unchanged in all of the brain regions studied in the maternally separated rats. These data show that maternal separation induces long-term changes in BDNF expression, and more specifically the processing of BDNF, in the hippocampus, striatum and ventral tegmental area. Recognition of these adaptations begins to define the brain regions, and neural circuitry, associated with persistent alterations induced by early life stressors and the development of mood disorders.


Subject(s)
Behavior, Animal/physiology , Brain-Derived Neurotrophic Factor/metabolism , Brain/metabolism , Maternal Deprivation , Mood Disorders/metabolism , Stress, Psychological/metabolism , Adrenocorticotropic Hormone/metabolism , Animals , Animals, Newborn , Brain/anatomy & histology , Brain/physiopathology , Corpus Striatum/anatomy & histology , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Corticosterone/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Female , Limbic System/anatomy & histology , Limbic System/metabolism , Limbic System/physiopathology , Male , Mood Disorders/etiology , Mood Disorders/physiopathology , Motor Activity/physiology , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Long-Evans , Stereotyped Behavior/physiology , Stress, Psychological/physiopathology , Time , Time Factors
9.
J Am Assoc Lab Anim Sci ; 45(2): 13-20, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16542037

ABSTRACT

We evaluated the effect of ketamine-xylazine-acepromazine anesthesia (31.25, 6.25, and 1.25 mg/kg subcutaneously, respectively) on postsurgical recovery in male Sprague-Dawley (Crl:SD) rats undergoing laparotomy with and without the postoperative analgesic ketorolac. Recovery was determined by changes in body weight (BW) and water intake. The time of ketorolac administration (5 mg/kg intramuscularly), 60 min after anesthetic injection, was based on return of the pedal withdrawal reflex in Long-Evans (HsdBlu:LE) rats undergoing stereotaxic surgery in a separate experiment. Results were compared with those of housing and anesthesia controls as well as of laparotomized rats receiving a single sugared treat for nonpharmacologic management of postoperative pain. Surgery took place on day 0; the first 24 h postsurgery was considered the "acute phase," and days 1 through 4 comprised the "recovery phase." Results suggest that 1) the anesthetic mixture is fast- and long-acting and provides sufficient immobility, loss of consciousness, and analgesia; 2) during the acute phase, rats subjected to laparotomy did not lose more BW than rats exposed to anesthesia alone; 3) water intake during both phases did not significantly differ between treatment groups; 4) postsurgical ketorolac administration did not minimize BW loss during the acute phase nor cause any adverse effects under this anesthetic regimen; and 5) provision of single sugared treats had salutary effects on BW recovery. This finding suggests that postsurgical BW loss after use of this anesthetic mixture is due to distress unrelated to pain; this nonpain distress may have masked potential beneficial effects of ketorolac.


Subject(s)
Acepromazine , Anesthesia , Animals, Laboratory/surgery , Ketamine , Pain, Postoperative/veterinary , Rats/surgery , Xylazine , Acepromazine/administration & dosage , Anesthetics, Combined/administration & dosage , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Drinking , Ketamine/administration & dosage , Ketorolac/administration & dosage , Laparotomy , Male , Pain, Postoperative/drug therapy , Pain, Postoperative/prevention & control , Postoperative Period , Rats, Long-Evans/surgery , Rats, Sprague-Dawley/surgery , Recovery of Function , Time Factors , Weight Loss , Xylazine/administration & dosage
10.
J Endocrinol ; 186(3): R7-R12, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16135661

ABSTRACT

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%. Thus, immediate up-regulation of 11beta-HSD2, the feto-placental barrier to maternal corticosteroids, may protect the fetus against stress-induced high levels of maternal corticosteroids, but exposure to chronic stress greatly diminishes this protection.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Placenta/enzymology , Stress, Psychological/enzymology , Animals , Chronic Disease , Enzyme Activation , Female , Pregnancy , Rats , Rats, Inbred Lew , Up-Regulation
11.
Am J Physiol Gastrointest Liver Physiol ; 289(4): G704-12, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15994424

ABSTRACT

In rodents, maternal pup interactions play an important role in programming the stress responsiveness of the adult organism. The aims of this study were 1) to determine the effect of different neonatal rearing conditions on acute and delayed stress-induced visceral sensitivity as well as on other measures of stress sensitivity of the adult animal; and 2) to determine the role of corticotropin-releasing factor receptor (CRF-R) subtype 1 (CRF(1)R) in mediating visceral hypersensitivity. Three groups of male Long-Evans rat pups were used: separation from their dam for 180 min daily from postnatal days 2-14 (MS180), daily separation (handling) for 15 min (H), or no handling. The visceromotor responses (VMR) to colorectal distension, stress-induced colonic motility, and anxiety-like behavior were assessed in the adult rats. The VMR was assessed at baseline, immediately after a 1-h water avoidance (WA) stress, and 24 h poststress. Astressin B, a nonselective CRF-R antagonist, or CP-154,526, a selective CRF(1)R antagonist, was administered before the stressor and/or before the 24-h measurement. MS rats developed acute and delayed stress-induced visceral hyperalgesia. In contrast, H rats showed hypoalgesia immediately after WA and no change in VMR on day 2. MS rats with visceral hyperalgesia also exhibited enhanced stress-induced colonic motility and increased anxiety-like behavior. In MS rats, both CRF-R antagonists abolished acute and delayed increases in VMR. Rearing conditions have a significant effect on adult stress responsiveness including immediate and delayed visceral pain responses to an acute stressor. Both acute and delayed stress-induced visceral hypersensitivity in MS rats are mediated by the CRF/CRF(1)R system.


Subject(s)
Hyperalgesia/physiopathology , Maternal Deprivation , Receptors, Corticotropin-Releasing Hormone/physiology , Stress, Psychological/physiopathology , Animals , Anxiety/psychology , Behavior, Animal/physiology , Corticotropin-Releasing Hormone/physiology , Defecation/physiology , Gastrointestinal Motility/physiology , Handling, Psychological , Hyperalgesia/psychology , Individuality , Rats , Rats, Long-Evans , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Stress, Psychological/psychology
12.
Neuropsychopharmacology ; 30(12): 2192-204, 2005 Dec.
Article in English | MEDLINE | ID: mdl-15920504

ABSTRACT

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. Neonatal maternal separation was associated with regionally specific alterations in CRF receptor type 1 (CRF1) mRNA density in HMS180 rats. No rearing-associated differences in CRF2alpha binding were apparent in either the lateral septum or the ventromedial hypothalamus. These findings indicate that early rearing conditions can permanently alter the developmental set-point of central CRF systems, and potentially influence the expression of behavioral and endocrine responses to stress throughout life, thereby providing a possible neurobiological substrate for the relationship between early life events and increased vulnerability for hypothalamic-pituitary-adrenal axis and coping skill alterations and the frequency of mood disorders in patients with a history of such experiences.


Subject(s)
Animals, Newborn/physiology , Corticotropin-Releasing Hormone/physiology , Adrenocorticotropic Hormone/cerebrospinal fluid , Adrenocorticotropic Hormone/metabolism , Animals , Behavior, Animal/physiology , Corticosterone/cerebrospinal fluid , Corticosterone/metabolism , Corticotropin-Releasing Hormone/metabolism , Female , Hypothalamus/physiology , Image Processing, Computer-Assisted , In Situ Hybridization , Male , Physical Stimulation , Pregnancy , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Radioimmunoassay , Rats , Rats, Long-Evans , Receptors, Corticotropin-Releasing Hormone/biosynthesis , Receptors, Corticotropin-Releasing Hormone/genetics , Reflex, Startle , Stress, Psychological/physiopathology
13.
Psychoneuroendocrinology ; 30(6): 520-33, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15808921

ABSTRACT

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. This study assessed whether or not prolonged HMS (180 min/day, HMS180) on post-natal days 2-14 sensitizes the adult limbic hypothalamo-pituitary-adrenal (LHPA) axis to chronic variable stress (CS) compared to brief HMS (15 min/day, HMS15). We examined regional mRNA densities of corticotropin-releasing factor (CRF), its receptor CRF1, glucocorticoid receptor (GR), and mineralocorticoid receptor (MR); regional CRF1 and CRF2alpha binding, and pituitary-adrenal responses to an acute air-puff startle (APS) stressor in four groups: HMS15, nonstressed; HMS15, stressed; HMS180, nonstressed; HMS180, stressed. As expected we observed exaggerated pituitary-adrenal responses to APS, increased regional CRF mRNA density, decreased regional CRF1 binding, and decreased cortical GR mRNA density in nonstressed HMS180 vs. HMS15 animals. However, in contrast to our hypothesis, CS decreased pituitary-adrenal reactivity and central amygdala CRF mRNA density in HMS180 rats, while increasing cortical GR mRNA density and CRF1 binding. CS had no effect on the pituitary-adrenal response to APS in HMS15 rats, despite tripling hypothalamic paraventricular CRF mRNA density. The data suggest that many effects of prolonged HMS are reversible in adulthood by CS, while the neuroendocrine adaptations imbued by brief HMS are sufficiently stable to restrain pituitary-adrenal stress responses even following CS.


Subject(s)
Corticotropin-Releasing Hormone/metabolism , Hypothalamo-Hypophyseal System/metabolism , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Glucocorticoid/metabolism , Stress, Psychological/metabolism , Adaptation, Physiological , Adrenocorticotropic Hormone/blood , Analysis of Variance , Animals , Animals, Newborn/psychology , Chronic Disease , Corticosterone/blood , Corticotropin-Releasing Hormone/genetics , Disease Models, Animal , Female , Handling, Psychological , Hypothalamo-Hypophyseal System/physiopathology , Male , Maternal Deprivation , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology , RNA, Messenger/analysis , Random Allocation , Rats , Rats, Long-Evans , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Glucocorticoid/genetics , Receptors, Mineralocorticoid/genetics , Receptors, Mineralocorticoid/metabolism , Reflex, Startle/physiology , Stress, Psychological/physiopathology , Tissue Distribution
14.
Biol Psychiatry ; 57(4): 373-81, 2005 Feb 15.
Article in English | MEDLINE | ID: mdl-15705353

ABSTRACT

BACKGROUND: Early adverse experiences represent risk factors for the development of anxiety and mood disorders. Studies in nonhuman primates have largely focused on the impact of protracted maternal and social deprivation, but such intense manipulations also result in severe social and emotional deficits very difficult to remediate. This study attempts to model more subtle developmental perturbations that may increase the vulnerability for anxiety/mood disorders but lack the severe deficits associated with motherless rearing. METHODS: We investigated the consequences of repeated maternal separations between 3 to 6 months of age on rhesus monkeys' hypothalamic-pituitary-adrenal (HPA) axis function and acoustic startle reactivity. RESULTS: Repetitive maternal separation led to increased cortisol reactivity to the separation protocol in female infants and alterations in mother-infant interaction. It also resulted in a flattened diurnal rhythm of cortisol secretion and increased acoustic startle reactivity at later ages. CONCLUSIONS: Macaques with adverse rearing exhibited short-term and long-term alterations in HPA axis function and increased acoustic startle response comparable with changes associated with mood/anxiety disorders. The magnitude of HPA axis reactivity to the separations and the alterations in mother-infant relationship detected during the separation protocol predicted some of the alterations in HPA axis and emotionality exhibited later in life.


Subject(s)
Circadian Rhythm/physiology , Hydrocortisone/blood , Maternal Deprivation , Reflex, Acoustic/physiology , Acoustic Stimulation/methods , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Behavior, Animal , Dose-Response Relationship, Radiation , Female , Hypothalamo-Hypophyseal System/physiology , Macaca mulatta , Male , Pituitary-Adrenal System/physiology , Sex Factors , Video Recording/methods
15.
Psychopharmacology (Berl) ; 176(3-4): 248-55, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15173929

ABSTRACT

RATIONALE: Certain adverse events in childhood, such as loss of a parent or sexual abuse, are associated with an increased vulnerability to develop depression later in life. Prolonged, daily maternal separation of rat pups induces several behavioral, endocrine and neurochemical changes similar to those observed in human depression. OBJECTIVES: Because dysfunction of brain serotonergic systems has been implicated in the pathophysiology of depression, the effects of neonatal maternal separation on these systems was studied in adult rats. METHODS: Male rat pups were subjected to daily maternal separation for 180 min (HMS180) from postnatal day 2 to day 14. Neonatal handled rats, i.e., pups undergoing daily 15-min separations during the same time period (HMS15), were chosen as a control group, since the 180-min separations involved handling of the pups, i.e., the pups were removed from the home cage during the separations. As adults, the effect of citalopram (0.05-0.80 mg/kg, intravenous) on the firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN) was studied. RESULTS: The inhibitory effect of citalopram on serotonergic cell firing was significantly enhanced at doses of 0.1 mg/kg and 0.4 mg/kg in the HMS180 compared with that in the HMS15 rats. However, the number of binding sites and mRNA expression of the 5-HT transporter and 5-HT(1A) receptors in the DRN did not differ between the two rearing groups. CONCLUSION: These findings suggest that early life stress gives rise to persistent changes in the function, but not the density or mRNA expression of central 5-HT(1A) receptors and/or 5-HT transporters.


Subject(s)
Citalopram/pharmacology , Maternal Deprivation , Neurons/physiology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/physiology , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Animals , Autoradiography , Binding Sites , Dose-Response Relationship, Drug , Electrophysiology , Female , In Situ Hybridization , Male , Membrane Glycoproteins/biosynthesis , Membrane Transport Proteins/biosynthesis , Nerve Tissue Proteins/biosynthesis , Neurons/drug effects , Pregnancy , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Radioligand Assay , Raphe Nuclei/cytology , Raphe Nuclei/drug effects , Rats , Receptor, Serotonin, 5-HT1A/biosynthesis , Receptor, Serotonin, 5-HT1A/drug effects , Serotonin Plasma Membrane Transport Proteins , Serotonin Receptor Agonists/pharmacology
16.
Neuropsychopharmacology ; 29(4): 641-8, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15034558

ABSTRACT

Almost four decades of intensive research have sought to elucidate the neurobiological bases of depression. Epidemiological studies have revealed that both genetic and environmental factors contribute to the risk for depression. Adverse early-life experiences influence neurobiological systems within genetic limits, leading to the neurobiological and behavioral manifestations of depression. We summarize the burgeoning evidence concerning a pre-eminent role of early adverse experience in the pathogenesis of depression. The available data suggest that (1) early adverse experience contributes to the pathophysiology of depression, (2) there are neurobiologically different subtypes of depression depending on the presence or absence of early adverse experience, likely having confounded previous research on the neurobiology of depression, and (3) early adverse experience likely influences treatment response in depression. Classification of depression based on developmental and neurobiological features will likely considerably improve future research in the field of depression, and might lead to optimized treatment strategies that directly target different neurobiological pathways to depression.


Subject(s)
Depression/etiology , Life Change Events , Neurobiology , Stress, Physiological/complications , Animals , Depression/classification , Depression/genetics , Depression/therapy , Environment , Humans , Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/physiopathology , Stress, Physiological/metabolism
17.
Biol Psychiatry ; 55(4): 367-75, 2004 Feb 15.
Article in English | MEDLINE | ID: mdl-14960289

ABSTRACT

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. We also examined regional mineralocorticoid receptor and glucocorticoid receptor messenger RNA density in these two groups. RESULTS: HMS180 rats appeared to escape dexamethasone suppression of plasma adrenocorticotropic hormone and corticosterone faster than their HMS15 counterparts (p <.01). In situ hybridization analysis revealed increased hippocampal mineralocorticoid receptor messenger RNA density (p <.05) with decreased cortical (p <.05) and hippocampal (p <.05) glucocorticoid receptor messenger RNA density in HMS180 versus HMS15 animals. CONCLUSIONS: These results are consistent with the hypothesis that in rats exposed to moderate neonatal handling-maternal separation, enhanced proactive feedback maintains the hypothalamic-pituitary-adrenal axis during the diurnal trough, while decreased reactive feedback contributes to prolonged responsiveness of the hypothalamic-pituitary-adrenal axis following an acute stressor.


Subject(s)
Adaptation, Physiological/genetics , Hypothalamo-Hypophyseal System/metabolism , Maternal Deprivation , Pituitary-Adrenal System/metabolism , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/metabolism , Adaptation, Physiological/physiology , Adrenocorticotropic Hormone/blood , Animals , Animals, Newborn , Corticosterone/blood , Densitometry/methods , Dexamethasone/pharmacology , Feedback, Physiological , Female , Glucocorticoids/pharmacology , Hippocampus/metabolism , Hypothalamo-Hypophyseal System/drug effects , In Situ Hybridization/methods , Male , Pituitary-Adrenal System/drug effects , Pregnancy , RNA, Messenger/metabolism , Radioimmunoassay/methods , Rats , Rats, Long-Evans , Receptors, Glucocorticoid/chemistry , Receptors, Glucocorticoid/genetics , Receptors, Mineralocorticoid/chemistry , Receptors, Mineralocorticoid/genetics , Time Factors
18.
Neuropsychopharmacology ; 29(1): 1-14, 2004 Jan.
Article in English | MEDLINE | ID: mdl-12942143

ABSTRACT

To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)- or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH(2))(5) Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/depression.


Subject(s)
Anxiety/metabolism , Central Nervous System/metabolism , Neuropeptides/metabolism , Receptors, Neuropeptide/metabolism , Vasopressins/metabolism , Analysis of Variance , Animals , Antidiuretic Hormone Receptor Antagonists , Anxiety/genetics , Autoradiography/methods , Behavior, Animal , Binding Sites , Breeding , Central Nervous System/anatomy & histology , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Disease Models, Animal , Exploratory Behavior , Gene Expression , Genetics, Behavioral , In Situ Hybridization , Male , Maze Learning , Microdialysis/methods , Neuropeptides/genetics , Oxytocin/genetics , Oxytocin/metabolism , Protein Binding , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains/genetics , Rats, Wistar , Reaction Time , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Neuropeptide/genetics , Stress, Physiological/metabolism , Swimming , Time Factors , Vasopressins/genetics , Vasopressins/physiology
19.
Pharmacol Rev ; 55(1): 21-6, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12615952

ABSTRACT

Receptors for corticotropin-releasing factor (CRF) are members of a family of G protein-coupled receptors ("Family B") that respond to a variety of structurally dissimilar releasing factors, neuropeptides, and hormones (including secretin, growth hormone-releasing factor, calcitonin, parathyroid hormone, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal polypeptide) and signal through the cyclic AMP and/or calcium pathways. To date, three genes encoding additional CRF-like peptides (urocortins) have been identified in mammals. The urocortins and CRF bind with differential ligand selectivity at the two mammalian CRF receptors. This report was prepared by the International Union of Pharmacology Subcommittee on CRF Receptors, to summarize the current state of CRF receptor biology and to propose changes in the classification and nomenclature of CRF ligands and receptors.


Subject(s)
Receptors, Corticotropin-Releasing Hormone/classification , Terminology as Topic , Amino Acid Sequence , Animals , Humans , International Agencies , Ligands , Molecular Sequence Data , Receptors, Corticotropin-Releasing Hormone/chemistry , Sequence Alignment
20.
Brain Res Brain Res Protoc ; 10(2): 84-94, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12431707

ABSTRACT

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. Rats tolerate this simple and efficient vascular access technique as evidenced by the absence of overt morbidity or abnormal behaviors. Blood is easily sampled while the rats reside in their home cages. Because the sample volume is replaced, repeated sampling is possible without compromising blood volume. Successful adoption of this procedure by other investigators will be aided by the photographic illustrations accompanying this detailed description of the procedure. Application of this technique to monitor temporal changes in plasma stress hormones during stressor paradigms as well as after behavioral and pharmacological challenges is discussed.


Subject(s)
Blood Specimen Collection/methods , Catheters, Indwelling/standards , Jugular Veins/surgery , Microsurgery/methods , Vascular Surgical Procedures/methods , Animals , Blood Specimen Collection/instrumentation , Female , Heart Atria/metabolism , Heart Atria/surgery , Hormones/analysis , Hormones/blood , Jugular Veins/anatomy & histology , Male , Microsurgery/instrumentation , Pain/drug therapy , Pain/prevention & control , Postoperative Complications/drug therapy , Postoperative Complications/prevention & control , Rats , Rats, Long-Evans , Restraint, Physical , Stress, Physiological/blood , Stress, Physiological/physiopathology , Stress, Psychological/prevention & control , Vascular Surgical Procedures/instrumentation , Wakefulness/physiology
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