Heart rhythm characterisation during unexplained transient loss of consciousness in dogs.

The identification of the heart rhythm during an episode of transient loss of consciousness (TLOC) is considered the reference standard method to elucidate the underlying aetiology. This study aimed to characterise heart rhythm in dogs during TLOC using Holter and external loop recorder monitoring. We retrospectively reviewed 24-h Holter monitoring and external loop recorder tracings from 8084 dogs. Heart rhythms from dogs that experienced TLOC during the recording was analysed to identify rhythm disturbances that occurred during episodes of TLOC. Electrocardiograms (ECGs) were subsequently categorised into Type 1 (ventricular arrest), Type 2 (sinus bradycardia), Type 3 (no/slight rhythm variations), and Type 4 (tachycardia). Transient LOC was documented in 92 dogs over 230 episodes of TLOC. Percentage of cases with ECGs compatible with each classification were as follows: 72.1%, Type 1; 6.1%, Type 2; 20.9%, Type 3; and 0.9%, Type 4. Cardiac rhythm during the TLOC could have been a consequence of a neurocardiogenic mechanism in 46.7% cases, while intrinsic rhythm disturbances of the sinus node or of the atrioventricular node were diagnosed in 31.5% cases. In two cases, tachycardia was the possible cause of the TLOC. ECG patterns in dogs presenting with multiple TLOC episodes were completely reproducible during each episode. TLOC in dogs was primarily caused by ventricular arrest. Most dogs with TLOC had electrocardiographic finding suggestive of a reflex or neurally-mediated syncope, but one third had an ECG more suggestive of a conduction disorder. Distinguishing these two entities could help inform diagnostic, therapeutic, and prognostic plans.

Indications for permanent pacing in dogs and cats.

Pacemaker implantation is considered as a standard procedure for treatment of symptomatic bradycardia in both dogs and cats. Advanced second-degree and third-degree atrioventricular blocks, sick sinus syndrome, persistent atrial standstill, and vasovagal syncope are the most common rhythm disturbances that require pacing to either alleviate clinical signs or prolong survival. Most pacemakers are implanted transvenously, using endocardial leads, but rarely epicardial leads may be necessary. To decide whether a patient is a candidate for pacing, as well as which pacing modality should be used, the clinician must have a clear understanding of the etiology, the pathophysiology, and the natural history of the most common bradyarrhythmias, as well as what result can be achieved by pacing patients with different rhythm disturbances. The goal of this review was, therefore, to describe the indications for pacing by evaluating the available evidence in both human and veterinary medicine. We described the etiology of bradyarrhythmias, clinical signs and electrocardiographic abnormalities, and the choice of pacing modality, taking into account how different choices may have different physiological consequences to selected patients. It is expected that this review will assist veterinarians in recognizing arrhythmias that may require permanent pacing and the risk-benefit of each pacing modality and its impact on outcome.

Radiofrequency catheter ablation of accessory pathways in the dog: the Italian experience (2008-2016).

INTRODUCTION: Accessory pathways (APs) in dogs are mostly right-sided, display nondecremental conduction, and mediate atrioventricular reciprocating tachycardias (AVRTs). Radiofrequency catheter ablation (RFCA) is considered the first-line therapy in human patients to abolish electrical conduction along APs. ANIMALS: Seventy-six consecutive client-owned dogs. MATERIAL AND METHODS: Retrospective study to describe the precise anatomical distribution and the electrophysiologic characteristics of APs in a large population of dogs and to evaluate long-term success and complication rates of RFCA. RESULTS: Eighty-three APs were identified in 76 dogs (92.1% with single APs and 7.9% with multiple APs); 96.4% were right-sided, 3.6% left-sided. Conduction along the APs was unidirectional and retrograde in 68.7% of the cases and bidirectional in 31.3%. Accessory pathways presented retrograde decremental properties in 6.5% of the cases. They mediated orthodromic AVRT in 92.1% of the cases and permanent junctional reciprocating tachycardia in 6.5%. In one case, no AVRT could be induced. In 97.4% of dogs, RFCA was attempted with an acute success rate of 100%. In 7.7% of cases, recurrence of the tachycardia occurred within 18 months, followed by a second definitively successful ablation. A major complication requiring pacemaker implantation was identified in 2.6% of dogs. DISCUSSION: Accessory pathway distribution and electrophysiologic properties in these 76 dogs were similar to previous report. Long-term success and complication rates of RFCA in dogs appeared very similar to results of humans. CONCLUSION: Radiofrequency catheter ablation of APs can be performed with a high success rate and low incidence of complications.

Avoiding being dragged away: finding egg cases of Schroederichthys bivius (Chondrichthyes: Scyliorhinidae) associated with benthic invertebrates.

Egg cases of the narrowmouthed catshark Schroederichthys bivius were recorded entangled with sponges, corals and tubeworms at different sites in the south-west Atlantic Ocean. This work sheds light on the importance of benthic invertebrates in the life cycle of oviparous chondrichthyan species.

Egg cases of the graytail skate Bathyraja griseocauda and the cuphead skate Bathyraja scaphiops from the south-west Atlantic Ocean.

Egg cases of Bathyraja griseocauda were larger (140-142 mm in length) than those of Bathyraja scaphiops (88-90 mm in length) and their surface was relatively smooth, without denticles, prickles or any ornamentation. Egg cases of B. scaphiops had a relative coarse surface, covered with prickles of similar size. An identification key for the all described egg cases from Bathyraja occurring in the south-west Atlantic Ocean is provided.

Paroxysmal atrial fibrillation in seven dogs with presumed neurally-mediated syncope.

OBJECTIVES: To document the electrocardiographic findings of vagally-induced paroxysmal atrial fibrillation following a presumed reflex syncopal episode in the dog. ANIMALS: Seven dogs with a syncopal episode followed by a paroxysm of atrial fibrillation recorded on a 24-hour Holter. METHODS: Twenty-four hour Holter monitors were retrospectively reviewed, analysing the cardiac rhythm associated with syncopal events. Each recording was analysed from 10 min before the syncopal episode to until 10 min after a normal sinus rhythm had returned. RESULTS: Nine episodes were recorded in seven dogs, with one patient experiencing three events during one Holter recording. Five of the seven dogs presented with underlying structural heart disease. In two the syncopal episodes occurred following exercise, two associated with coughing and three were during a period of rest. All dogs had documented on the Holter recording a rhythm abnormality during syncope. The most common finding leading up to the syncopal event was development of a progressive sinus bradycardia, followed by sinus arrest interrupted by a ventricular escape rhythm and then ventricular arrest. This was then followed by an atrial fibrillation. The atrial fibrillation was paroxysmal in seven recordings and persistent in two. In two dogs, the atrial fibrillation reorganised into self-limiting runs of atypical atrial flutter. CONCLUSIONS: This combination of electrocardiographic arrhythmias are probably caused by an inappropriate parasympathetic stimulation initiating a reflex or neurally-mediated syncope, with abnormal automaticity of the sinus node and of the subsidiary pacemaker cells and changes in the electrophysiological properties of the atrial muscle, which promoted the paroxysmal atrial fibrillation.

Long-term Intrinsic Rhythm Evaluation in Dogs with Atrioventricular Block.

BACKGROUND: Atrioventricular block (AVB) is a conduction abnormality along the atrioventricular node that, depending on etiology, may lead to different outcomes. OBJECTIVES: To evaluate variations of intrinsic rhythm (IR) in dogs that underwent pacemaker implantation (PMI). ANIMALS: Medical records of 92 dogs affected by 3rd degree atrioventricular block (3AVB), advanced 2nd degree AVB (2AVB), paroxysmal 3AVB, 2:1 2AVB, or 3AVB with atrial fibrillation (AF) were retrospectively reviewed. METHOD: The patient IR was documented with telemetry on the day of 1--(95% CI, 1-2), 33--(95% CI, 28-35), 105--(95%CI, 98-156), and 275 days (95%CI, 221-380) after PMI. According to AVB grade at different examinations, AVB was defined as progressed, regressed, or unchanged. RESULTS: In 48 dogs, 3AVB remained unchanged, whereas in 7 it regressed. Eight cases of 2AVB progressed, 3 regressed and 2 remained unchanged. Eight cases of paroxysmal 3AVB progressed and 3 remained unchanged. Four dogs affected by 2:1 2AVB progressed, 2 regressed, and 1 remained unchanged. All cases with 3AVB with AF remained unchanged. Regression occurred within 30 days after PMI, whereas progression was documented at any time. Variations in IR were associated with type of AVB (P < .03) and time of follow-up (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: The degree of AVB assessed at the time of PMI should not be considered definitive because more than one-third of the cases in this study either progressed or regressed. Additional studies would be necessary to elucidate possible causes for transient AVB in dogs.

Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns.

OBJECTIVE: The purpose of this observation was to evaluate the safety and efficacy of hydrocortisone (HC) for the treatment of refractory hypotension in term and preterm infants. A secondary purpose was to determine the utility of serum cortisol concentrations in predicting the response to treatment. STUDY DESIGN: This is a retrospective observational study of 117 infants treated with a standardized HC protocol for refractory hypotension. Refractory hypotension was defined as a mean arterial pressure (MAP) less than the gestational age (GA) despite a total inotrope dose of 20 microg per kg per min. Baseline serum cortisol concentrations were determined prior to treatment with stress dose HC. RESULT: Treatment with HC increased the MAP at 2, 6, 12 and 24 h after initiation, decreased the total inotrope dose at 6, 12 and 24 h, and was associated with resolution of oliguria. There was no correlation between the pretreatment baseline cortisol concentration and GA, birth weight or the response to treatment. The incidence of grades III to IV intraventricular hemorrhage, periventricular leukomalacia, bacterial or fungal sepsis and spontaneous intestinal perforation (SIP) after HC treatment was similar to institutional historic controls prior to institution of this standardized HC protocol. CONCLUSION: HC treatment was associated with a rapid resolution of cardiovascular compromise. The incidence of significant side effects was similar to that in previously published reports, including a comparable incidence of SIP. On the basis of our results, measuring baseline serum cortisol concentration to guide the management of refractory hypotension is unwarranted.

Behavioral/environmental intervention improves learning after cerebral hypoxia-ischemia in rats.

BACKGROUND AND PURPOSE: In premature infants, many of whom experience ischemic brain insults, the environment of rearing influences cognitive outcome. We developed a model to evaluate the effect of rearing conditions on learning after unilateral cerebral hypoxia-ischemia (HI) in 7-day-old (P7) rats. We hypothesized that neonatal handling would benefit rats recovering from an episode of HI. METHODS: Seventeen litters of P7 Long-Evans rats underwent either HI (right carotid ligation followed by 1.5 hours in 8% O(2)) or control procedures. From P8 to P14, randomized litters were either handled (15 minutes of separation from dam per day) or nonhandled. After P55, learning was tested in the Morris water maze. To evaluate injury severity, hippocampal, cortical, and striatal volumes were measured. RESULTS: In water-maze performance, ANCOVA revealed an interaction between handling and severity of hippocampal damage. Among HI rats, handled rats learned faster when hippocampal damage was moderate (P<0.01, repeated-measures ANOVA), with no benefit when damage was mild or severe. CONCLUSIONS: These observations suggest the beneficial cognitive effect of neonatal handling was limited to animals with moderate damage. Neonatal handling in post-HI rats may be a useful model in which to study mechanisms underlying the benefits of post-HI developmental intervention.

Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human development.

Since the work of Hans Selye, stress has been associated with increased activity of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis. Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under conditions of trauma and prolonged stress presently challenges basic concepts in stress research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking. We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis. We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol under adverse early life conditions in humans adds to the importance of understanding the implications of hypocortisolism for health and development.

Effects of prenatal dexamethasone on spatial learning and response to stress is influenced by maternal factors.

The present study investigated the effect of prenatal dexamethasone (Dex) exposure on early perinatal events, hippocampal function, and response to stress. Pregnant rats received Dex in the evening water (2.5 microg/ml) or tap water (Veh) from gestational day 15 until delivery. On the day of parturition, pups were randomized, cross-fostered, and reduced to eight or nine per dam. Four groups resulted: Veh-Veh (offspring exposed to Veh in utero, rearing mother treated with Veh during gestation), Veh-Dex, Dex-Veh, and Dex-Dex. Spatial visual memory was evaluated with the Morris water maze. The corticosterone response to restraint stress was examined, and the expression of hippocampal glucocorticoid and mineralocorticoid receptors mRNA was determined by in situ hybridization. Exposure to Dex caused restlessness in mothers, low birth weights, and poor weight gain in the offspring. The Dex-Dex males had impaired spatial learning, inability to rapidly terminate the adrenocortical response to stress, and decreased hippocampal glucocorticoid receptor (GR) mRNA expression. In contrast, Dex-exposed animals reared by Veh-treated mothers had adequate spatial learning, enhanced glucocorticoid feedback, and increased hippocampal GR mRNA. We conclude that the environment provided by a healthy mother during the postnatal period can prevent the detrimental effects of prenatal Dex administration on cognition, GR mRNA expression of the hippocampus, and the quality of the stress response.

Maternal deprivation regulates serotonin 1A and 2A receptors in the infant rat.

UNLABELLED: Several studies have demonstrated that 5-HT1A and 5-HT2A receptors are altered in rat brain following chronic stress. While this is true in the adult animal, this may be different in the developing animal, which has a limited corticosterone response to acute challenges between days 3 and 14 of life. METHODS: We investigated the effect of maternal deprivation on 5-HT2A and 5-HT1A receptor mRNA levels in the developing brain. In situ hybridization was used to quantify gene expression in rat pups at three ages: 6, 9, and 12 days old. In each age group, half were maternally deprived for 24 h and half were kept with their mothers. Maternally deprived animals showed elevated ACTH and corticosterone plasma levels when compared to NDEP animals, significantly elevated 5-HT1A mRNA levels in the CA1 hippocampal region and, significantly elevated 5-HT2A mRNA levels in the parietal cortex. No changes were observed in 5-HT1A or 5-HT-transporter mRNA levels in the dorsal raphe. Our results indicate that post-synaptic 5-HT receptors in the developing hippocampus and cortex are sensitive to maternal deprivation. Because hippocampal 5-HT1A gene expressions are known to decrease in the adult animal after chronic glucocorticoid elevation, this data also suggests that other mechanisms, perhaps central, predominate during development.

Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress.

BACKGROUND: When rats are subjected to chronic stress for 2 weeks, a significant decrease in hippocampal serotonin (5-HT)1A messenger RNA (mRNA) is observed. We wanted to investigate whether stress, administered for shorter periods of time, would result in decreases in 5-HT1A gene expression in hippocampus. METHODS: In one experiment, rats were either stressed daily for 1 week or implanted with two corticosterone pellets to produce elevated corticosterone levels. In another experiment, rats were subjected to a severe acute stressor and sacrificed 1 day or 1 week after the stressor. RESULTS: We found that 24 hours after the acute stress, rats showed a significant decrease in 5-HT1A mRNA levels in CA1 and the dentate gyrus compared to controls. No significant changes in 5-HT1A mRNA levels were detected in any of the other groups. CONCLUSIONS: Although 1 week of chronic stress is not sufficient to cause significant decreases in hippocampal 5-HT1A mRNA levels, a severe and prolonged acute stress is capable of down-regulating, at least transiently, 5-HT1A mRNA gene expression in hippocampus.

Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder.

Hippocampal glucocorticoid receptors (GR and MR) play an important role in glucocorticoid negative feedback. Abnormalities in negative feedback are found in depression and in post-traumatic stress disorder (PTSD), suggesting that GR and MR might be involved in the pathophysiology of these disorders. Enhanced negative feedback, the PTSD-specific neuroendocrine abnormality, can be induced in animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session, 'no stress' interval and a testing session one week later). In the current study, we examined hippocampal GR and MR mRNA distribution in the same animals that exhibited altered negative feedback following the SPS. Seven groups of adult Sprague-Dawley male rats (seven animals each) were used in two studies, comparing unstressed controls to acutely stressed animals (SPS: 24 h group), SPS animals (seven and 14 days), and SPS + chronic stress animals. GR and MR mRNA distribution across hippocampal subfields was studied using in-situ hybridization with 35S-labelled cRNA probes. Acute stress produced down-regulation of GR and MR mRNA across all hippocampal subfields. Seven days later (SPS-7 group), there was a differential recovery, with GR mRNA reaching higher than the prestress levels, and MR mRNA remaining down-regulated. The same differential regulation was present in the 14-day group. Chronically stressed animals that exhibited normal fast feedback also had normalization in their GR and MR mRNA levels. The MR/GR ratio was decreased only in animals that had enhanced fast feedback. These findings suggest that the increase in GR, in hippocampus is involved in the fast feedback hypersensitivity observed in the SPS animals, and might also underlie enhanced dexamethasone sensitivity found in PTSD. Since differential activation of GR and MR can modulate memory, behavioural responsivity, anxiety and fear, change in MR/GR ratio might also explain other PTSD-related phenomena.

Stress and the developing limbic-hypothalamic-pituitary-adrenal axis.

The postnatal limbic-hypothalamic-pituitary-adrenal (LHPA) axis in the rodent is remarkably different from the adult, both in structure and function. The first 2 weeks postnatally are characterized by a 'silent period' during which the developing animal is hyporesponsive to stress (stress hyporesponsive period-SHRP), followed by a new and unique phase of stress responsiveness when the animal fails to swiftly terminate glucocorticoid secretion. In this review, we summarize our work which focuses on the regulatory biology of the components of the LHPA system and the consequences of its disruption on the adaptive responses of the developing organism. We find that the animal during the first 2 weeks of life responds to an intermittent chronic challenge increasing anterior pituitary POMC post-translational events, while the adult increases genomic events. The result for both the mature and the developing animal is the same, an increase in corticosterone (CS) levels. In addition, we have found evidence of impaired rate sensitive feedback in the weanling animal, as well as changes in ACTH clearance. Similar to the young animal emerging from SHRP, maternally deprived pups during the first week of life exhibit a substantial and sustained ACTH and CS response to stress. In the deprived animal these changes are accompanied by decreases in mineralocorticoid receptor gene expression in the hippocampus, suggesting that changes in mineralocorticoid to glucocorticoid receptor ratios may be important in this phenomena. What has become evident from our studies is that mechanisms underlying normal LHPA development are dynamic, age dependent and distinct to the strategies used by the mature organism to cope with stress.

Alpha, beta, and gamma mineralocorticoid receptor messenger ribonucleic acid splice variants: differential expression and rapid regulation in the developing hippocampus.

Two different types of corticoid receptor molecules bind circulating corticosterone in brain: mineralocorticoid receptors (MR) and glucocorticoid receptors. MR exhibit the highest affinity for the endogenous glucocorticoid in the rat, corticosterone. During development, low corticosterone levels influence neurogenesis, and these effects are probably MR mediated. Three MR complementary DNA clones, alpha, beta, and gamma, have been identified in the rodent. All of these MR complementary DNA clones have identical coding regions, but differ significantly at the 5'-untranslated end. Although the functional significance of these three messenger RNA (mRNA) species remains unknown, one hypothesis is that they reflect the ability of the brain to regulate the expression of MR, allowing multiple factors to differentially control transcription in a tissue- and time-specific manner. To investigate this possibility, we examined the presence of these distinct mRNA forms in the developing rat hippocampus (HC). In situ hybridization with specific alpha, beta, and gamma complementary RNA probes was performed in the HC of 3-, 5-, 7-, 12-, 14-, 28-, 35-, and 65-day-old animals. We found that there is differential expression of these forms in each of the HC subfields from infancy to adulthood. y expression appears to be associated with periods of cell birth and increased axonal sprouting. beta expression, on the other hand, may be best linked to periods of synaptogenesis, growth of commissural and associative terminal fields, and possibly active pruning. To explore the possibility that the differential gene expression may be related to corticosterone environment, adrenalectomy was performed. A rapid modulation of the MR mRNA variants (14 h) in an age- and site-specific fashion was seen. These findings suggest that the variation in expression and regulation during development of the multiple MR transcripts could reflect a complex pattern of developmental regulation that may involve a multitude of factors unique to each postnatal age and to the different neuronal populations within the hippocampal formation.

Lymphocytic hypophysitis presenting with diabetes insipidus in a 14-year-old girl: case report and review of the literature.

UNLABELLED: Lymphocytic hypophysitis is a rare disorder predominantly affecting females during the antepartum or postpartum period. It is characterized by destruction and lymphocytic infiltration of the pituitary gland, probably by an autoimmune process, leading to a pituitary mass lesion and/or various degrees of hypopituitarism. The lesion is usually confined to the adenohypophysis. Posterior pituitary gland or stalk involvement is rare, although patients presenting with diabetes insipidus have been reported. We describe a girl aged 13 years 9 months with lymphocytic hypophysitis who presented with diabetes insipidus and secondary amenorrhea. MRI of the brain revealed a 1 cm enhancing mass in the pituitary stalk. A biopsy of the mass by right pterional craniotomy showed lymphocytic infiltration without neoplastic cells or granuloma formation. To our knowledge, this is the youngest reported patient with a diagnosis of lymphocytic hypophysitis. In this case report, her clinical presentation is discussed along with a review of the literature. CONCLUSION: We present the first childhood case of lymphocytic hypophysitis which is an autoimmune inflammatory disorder of the pituitary gland. Although this is a rare condition in adults, it also needs to be considered in the pediatric population. Conservative management is preferred unless there are signs of increased intracranial pressure. Most importantly, close monitoring for multiple hormone deficiencies is indicated in this condition.

Kinetics of radiolabeled adrenocorticotropin hormone in infant and weanling rats.

Unlike the adult animal, the developing rat has a diminished ability to activate and inhibit the hypothalamic pituitary adrenal axis. In general, a gradual ACTH and corticosterone response to stressors appear after postnatal day 10 and is well established to adult level by weaning age. Although at this age the peak ACTH level is comparable to that of the adult, ACTH levels remain elevated for a longer period of time. The purpose of this study was to investigate the possibility that ACTH metabolism can, in part, explain this prolonged ACTH elevation after a challenge. The plasma half life of disappearance (t1/2, the apparent volume of distribution and metabolic clearance rate (MCR) were determined after injection of a tracer dose of 3-I125-Iodotyrosyl23 ACTH1-39 in rats at 14 and 25 days of age. An adult animal group (65 days old) was used for comparison. The t1/2 for ACTH decreases with age (14 day old = 7.47 +/- 0.9 min; 25 day old = 6.48 +/- 0.4 min; adult = 4.46 +/- 0.2 min) while the volume of distribution remains constant. The MCR is also decreased in the young animals (14 day old = 1.5 +/- 0.19 min; 25 day old = 1.6 +/- 0.18 min; adult = 3.0 +/- 0.56 min). For the first time, it is established that the young animals require longer to clear ACTH from an equivalent volume of blood when compared to the adult. Thus, the kinetic properties of ACTH are different in the developing animal and this partly explains the prolonged ACTH elevation observed after stress challenges.

Regulation of 5-HT receptors and the hypothalamic-pituitary-adrenal axis. Implications for the neurobiology of suicide.

Disturbances in the serotonin (5-HT) system is the neurobiological abnormality most consistently associated with suicide. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is also described in suicide victims. The HPA axis is the classical neuroendocrine system that responds to stress and whose final product, corticosteroids, targets components of the limbic system, particularly the hippocampus. We will review results from animal studies that point to the possibility that many of the 5-HT receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims. The results of these studies can be summarized as follows: (1) chronic unpredictable stress produces high corticosteroid levels in rats; (2) chronic stress also results in changes in specific 5-HT receptors (increases in cortical 5-HT2A and decreases in hipocampal 5-HT1A and 5-HT1B); (3) chronic antidepressant administration prevents many of the 5-HT receptor changes observed after stress; and (4) chronic antidepressant administration reverses the overactivity of the HPA axis. If indeed 5-HT receptors have a partial role in controlling affective states, then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.

Regulation of glucocorticoid and mineralocorticoid receptor mRNAs in the hippocampus of the maternally deprived infant rat.

The hypothalamic-pituitary-adrenal (HPA) axis in the developing rat has a limited response to acute challenges between days 3 and 14 of life. Several hypotheses have been proposed to explain this quiescent state. Immaturity of brain, pituitary and adrenal elements or excessive feedback inhibition are common explanations. Recently, a series of studies by Levine and co-workers has shown that prolonged maternal deprivation (24 h) results in increased basal and stress induced corticosterone (CS) levels. An increased adrenal response to ACTH along with an enhanced and sustained ACTH response have been implicated in this phenomenon. A brain structure that appears to be important for normal HPA function is the hippocampus, a structure rich in corticosteroid receptors, which has been hypothesized to play a role in the basal tone of the HPA and in the magnitude and duration of stress responses. Thus, to study further the possible mechanisms leading to an enhanced and sustained ACTH response that is seen in maternally deprived pups, we used in situ hybridization to investigate hippocampal mineralocorticoid (MR) and glucocorticoid receptor (GR) gene expression in 12 groups of animals: six groups involved 24 h maternally deprived (DEP) and non-deprived (NDEP) rat pups at three ages (6-, 9-, and 12-days-old); the other six groups included pups similarly treated, but challenged with an exposure to a mild stressor (saline injection) and sacrificed 1 h thereafter. We found: (1) an age effect for almost every hippocampal subfield for both MR and GR mRNAs: MR increases with age, while GR decreases: (2) down-regulation of MR mRNA in CA1 region in the DEP animals; and (3) down-regulation of GR mRNA, also in CA1, in the saline-injected DEP and NDEP animals. Our results indicate that corticoid receptors in the developing CA1 hippocampal region appear to be sensitive to circulating CS. They also suggest that the relative ratio of GR and MR in the CA1 region may contribute to the enhanced and sustained CS response seen after a mild stressor in deprived animals.