S. Mechiel Korte

Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning.

In order to study mechanisms involved in the etiology of human affective disorders, there is an abundant use of various animal models. Next to genetic factors that predispose for psychopathologies, environmental stress is playing an important role in the etiology of these mental diseases. Since the majority of stress stimuli in humans that lead to psychopathology are of social nature, the study of consequences of social stress in experimental animal models is very valuable. The present review focuses on one of these models that uses the resident-intruder paradigm. In particular the long-lasting effects of social defeat in rats will be evaluated. Data from our laboratory on the consequences of social defeat on emotional behavior, stress responsivity and serotonergic functionality are presented. Furthermore, we will go into detail on hippocampal functioning in socially stressed rats. Very recent results show that there is a differential effect of a brief double social defeat and repetitive social defeat stress on dendritic remodeling in hippocampal CA3 neurons and that this has repercussions on hippocampal LTP and LTD. Both the structural and electrophysiological changes of principal neurons in the hippocampal formation after defeat are discussed as to their relationship with the maintenance in cognitive performance that was observed in socially stressed rats. The results are indicative of a large dynamic range in the adaptive plasticity of the brain, allowing the animals to adapt behaviorally to the previously occurred stressful situation with the progression of time.

Plasma catecholamine and corticosterone levels during manual restraint in chicks from a high and low feather pecking line of laying hens

Neurosympathetic and adrenal responsivity to manual restraint was studied in two White Leghorn chicken lines which differ in their tendency to feather peck. Blood samples were taken from freely moving cannulated birds during resting conditions and during manual restraint (placing the bird on its side for 8 min) to determine plasma noradrenaline. adrenaline and corticosterone. Plasma corticosterone levels in low feather peckers (LFP) were significantly higher during resting conditions and restraint as compared to the high feather peckers (HFP). In response to manual restraint the HFP hens showed a significantly larger plasma noradrenaline response than LFP hens. No difference in plasma adrenaline levels was observed under resting conditions or during manual restraint.

Adrenocortical reactivity and central serotonin and dopamine turnover in young chicks from a high and low feather-pecking line of laying hens.

Feather pecking in domestic fowl is a behavioral abnormality that consists of mild or injurious pecking at feathers of conspecifics. Previously, it was shown that chicks from a high feather-pecking (HFP) and low feather-pecking (LFP) line of laying hens already differ in their propensity to feather peck at 14 and 28 days of age. As a first step in investigating a possible relationship between the development of feather pecking and physiological and neurobiological characteristics of laying hens, two subsequent experiments were carried out. Firstly, we investigated the development of adrenocortical (re)activity in HFP and LFP chicks during the first 8 weeks of life. Secondly, we studied dopamine (DA) and serotonin (5-HT) turnover in the brain of 28-day-old HFP and LFP chicks. In both experiments, chicks were exposed to manual restraint (placing the chicks on its side for 5 min). Plasma corticosterone levels were lower (baseline on Days 3 and 56; restraint-induced on Days 3, 14 and 28) in HFP chicks. Both brain DA and 5-HT turnover were lower in the HFP chicks, as well. Possible consequences for the observed differences in (stress) physiology and neurobiology between the two lines in relation to the feather pecking are discussed.

Translational aspects of pharmacological research into anxiety disorders: The stress-induced hyperthermia (SIH) paradigm

In anxiety research, the search for models with sufficient clinical predictive validity to support the translation of animal studies on anxiolytic drugs to clinical research is often challenging. This review describes the stress-induced hyperthermia (SIH) paradigm, a model that studies the activation of the autonomic nervous system in response to stress by measuring body temperature. The reproducible and robust SIH response, combined with ease of testing, make the SIH paradigm very suitable for drug screening. We will review the current knowledge on the neurobiology of the SIH response, discuss the role of GABA(A) and serotonin (5-HT) pharmacology, as well as how the SIH response relates to infectious fever. Furthermore, we will present novel data on the SIH response variance across different mice and their sensitivity to anxiolytic drugs. The SIH response is an autonomic stress response that can be successfully studied at the level of its physiology, pharmacology, neurobiology and genetics and possesses excellent animal-to-human translational properties.

Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, characterized by impairments in social interaction and communication and the presence of limited, repetitive and stereotyped interests and behavior. Bowel symptoms are frequently reported in children with ASD and a potential role for gastrointestinal disturbances in ASD has been suggested. This review focuses on the importance of (allergic) gastrointestinal problems in ASD. We provide an overview of the possible gut-to-brain pathways and discuss opportunities for pharmaceutical and/or nutritional approaches for therapy.

Triple reuptake inhibitors for treating subtypes of major depressive disorder: the monoamine hypothesis revisited

Introduction: Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues. Areas covered: The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels. Expert opinion: In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: ‘the monoamine hypothesis revisited’ to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression.

Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

The behavioral effects of intracerebroventricular (i.c.v.) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 microliters)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 microliters)], or both antagonists (50 ng/2 microliters), were studied in two different animal models of fear and anxiety in rats. In the defensive burying paradigm simultaneous blockade of MR and GR increased immobility behavior, whereas a small decrease in defensive burying was seen. In the fear-potentiated startle test concurrent MR and GR blockade led to an increase in fear-potentiated startle at the highest loudness level (105 dB). In both tests the antagonists were not effective when given separately. The findings are discussed in terms of the involvement of GR and MR in neural mechanisms of fear and anxiety.

INVOLVEMENT OF HYPOTHALAMIC SEROTONIN IN ACTIVATION OF THE SYMPATHOADRENOMEDULLARY SYSTEM AND HYPOTHALAMO-PITUITARY-ADRENOCORTICAL AXIS IN MALE WISTAR RATS

Infusion of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (2.5-20 micrograms in 1 microliter during 15 min), into the paraventricular nucleus of the hypothalamus (PVN) in the rat dose dependently increased plasma adrenaline and corticosterone concentrations, without affecting plasma noradrenaline concentrations. The highest dose also increased plasma glucose levels significantly. The results suggest that both the sympathoadrenomedullary system and the hypothalamo-pituitary-adrenocortical axis are activated after stimulation of 5-HT1A receptors in the PVN.

Behavioral and neuroendocrine response to psychosocial stress in male rats: The effects of the 5-HT 1A agonist ipsapirone

The effect of the 5-HT 1A agonist ipsapirone on the behavior, plasma catecholamine, and corticosterone levels was studied in male Wistar rats during the psychosocial stress of confrontation with a confined dominant opponent 24 hr after defeat. The effect of the drug was also studied during a predefeat confrontation with the confined (would-be dominant) rat. Blood samples were withdrawn via a permanent heart catheter. The drug (5 mg/kg, ip) or vehicle was given 30 min before transportation to the experimental room. Ipsapirone had no major effects on the plasma hormone concentrations and had no influence upon the behavioral response to the confined rat. At the postdefeat test ipsapirone led to a significant increase of immobility, whereas both rearing and time spent sniffing the cage were diminished. Postdefeat psychosocial stress resulted in an increase of the hormone, particularly catecholamine levels. These responses were further elevated by the drug. The presence of high corticosterone levels in the home cage after postdefeat ipsapirone treatment leads to the hypothesis that postsynaptic 5-HT 1A receptor hypersensitivity develops after the social stress of defeat.

Stress―induced hyperthermia and infection―induced fever: Two of a kind?

Stress exposure activates the autonomic nervous system and leads to a body temperature increase (stress-induced hyperthermia, SIH). On the other hand, an activation of the immune system in response to an infection leads to fever. Both processes increase body temperature, and the relation between SIH and infection-induced fever has been subject to debate. It is not clear whether SIH is a form of fever, or whether both processes are more or less distinct. We therefore examined the relation between SIH and infection-induced fever by looking at the effects of a GABA(A) receptor agonist (diazepam) and a prostaglandin-synthesis blocking drug (acetylsalicylic acid, aspirin) on both the SIH response and fever in rats and mice. The present study shows that the benzodiazepine diazepam but not the prostaglandin-synthesis blocking drug aspirin dose-dependently attenuated the SIH response in both rats and mice. In contrast, aspirin reduced both LPS- and IL-1beta induced fever, whereas diazepam had little effect on these fever states. Altogether, our findings support the hypothesis that stress-induced hyperthermia and infection-induced fever are two distinct processes mediated largely by different neurobiological mechanisms.