Dirk S. Fokkema

Neuroendocrine states and behavioral and physiological stress responses.

Publisher Summary This chapter presents a novel, behavioral physiological stress concept that originates from the classical view that stress is a response. This new concept is extended to environment, behavior, and physiology, and it incorporates the novel neuroendocrine views including the neuropeptide concept. Stress is viewed as a general biological and usually functional response to environmental and bodily demands. A stress depends on interactions among environment, individual characteristics and the properties of stressors, stress, and the physiological systems, and also among the nervous system, peripheral organ systems, and the neuroendocrine system. To adapt to the altering social and physical environmental demands, man and other animals require a chain of behavioral, neuroendocrine, and autonomic physiological and metabolic responses to maintain bodily and mental homeostasis. The neuroendocrine state of the brain is given a central position in determining the state of health or disease of mind and body.

Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity

The present dose-response study sought to determine the effects of subanesthetic dosages (4-16 mg/kg) of ketamine on locomotion, sensorimotor gating (PPI), working memory, as well as c-fos expression in various limbic regions implicated in the pathogenesis of schizophrenia. In addition, we examined whether ketamine-induced locomotion was influenced by the dark/light cycle. We found that ketamine increased locomotor activity in a dose dependent manner, but found no influence of the dark-light cycle. Additionally, ketamine dose-dependently interrupted PPI, resulting in prepulse facilitation at doses of 8 and 12 mg/kg. The dose of 12 mg/kg also induced impairments in working memory assessed by the discrete-trial delayed-alternation task. C-fos expression indicated that the dose-dependent behavioral effects of ketamine might be related to changes in the activity of limbic regions, notably hippocampus and amygdala.

Individual characteristics of behavior, blood pressure, and adrenal hormones in colony rats

Previous experiments suggested that rats with an active behavioral strategy and high endocrine and blood pressure responses to social interactions would be at risk to get a high blood pressure. To test this hypothesis, a long-term study of social behavior was performed in laboratory colonies of rats. The more aggressive rats, as indicated by individual precolony resident-intruder tests, are more aggressive in the colony also. After colony aggregation, the aggressive rats appeared to have higher resting blood pressures. The dominant rat (although aggressive, too) and the nonaggressive rats have lower blood pressures. Plasma levels of catecholamines and corticosterone after colony experience do not show a relation with blood pressure but reflect the rats original precolony aggressive characteristic. We conclude that the individual characteristic of an active social strategy is a risk factor that indeed predicts the development of high blood pressure, possibly by way of the associated higher physiological reactivity we found earlier. Chronic environmental factors that are hard to control for the animal, like involvement in social processes or possibly other continuous challenges, may stimulate the prone physiology to develop an elevation of blood pressure.

Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat

One of the functions of group II metabotropic glutamate receptors (mGluR2/3) is to modulate glutamate release. Thus, targeting mGluR2/3s might be a novel treatment for several psychiatric disorders associated with inappropriate glutamatergic neurotransmission, such as schizophrenia. In an effort to evaluate the antipsychotic properties of LY379268, a potent and selective mGluR2/3 agonist, we examined its effect on ketamine-evoked hyperlocomotion and sensorimotor gating deficit (PPI) in rats, an animal model of schizophrenia. We also measured the ex vivo tissue level of glutamate (Glu), dopamine (DA) and serotonin (5-HT) as well as the DA metabolites DOPAC and the major 5-HT metabolite HIAA to determine the neurochemical effects of ketamine (12 mg/kg) and LY379268 (1 mg/kg) in the dentate gyrus (DG). While LY379268 (1-3 mg/kg) reduced ketamine-evoked hyperlocomotion (12 mg/kg), it could not restore ketamine-evoked PPI deficits (4-12 mg/kg). In the DG we found that ketamine decreased Glu and DA levels, as well as HIAA/5-HT turnover, and that LY379268 could prevent ketamine effects on Glu level but not on monoamine transmission. These results may indicate that the inability of LY379268 to reverse PPI deficits is attributable to its lack of effect on ketamine-induced changes in monoamine transmission, but that LY379268 can prevent ketamine-evoked changes in glutamate, which is sufficient to block hyperlocomotion. In addition to the partial effectiveness of LY379268 in the ketamine model of schizophrenia, we observed a dual effect of LY379268 on anxious states, whereby a low dose of this compound (1 mg/kg) produced anxiolytic effects, while a higher dose (3 mg/kg) appeared to be anxiogenic. Additional work is needed to address a possible role of LY379268 in schizophrenia and anxiety treatment.

Acute and Conditioned Blood Pressure Changes in Relation to Social and Psychosocial Stimuli in Rats

The naturally occurring tendency to compete with other rats for territorial space has been used to study individual behavior characteristics and blood pressure reactivity to social stimuli in adult male TMD-S3 rats. The competitive characteristics of the individual rats are consistent in two different social situations (victory and defeat). Blood pressure responses during the victory of home territory rats over intruders was more pronounced in the more competitive animals. In addition to defeat by a trained fighter rat, the experimentals were also psychosocially stimulated by the fighter while it was confined in a small wire mesh cage. The blood pressure response to this event was enhanced by the prior defeat of the test animal by the one now confined to the small cage. This response was more pronounced in competitive rats. This approach has potential as an animal model of etiological processes in socially induced hypertension.

Increased stress vulnerability after a prefrontal cortex lesion in female rats

Neuroimaging studies in patients suffering from affective disorders have shown decreased volume and reduced regional cerebral blood flow in multiple areas of the prefrontal cortex, including the medial prefrontal cortex and the orbitofrontal cortex. This aberrant brain activity is among other things attributed to chronic stress. Affective disorders occur more often in women than in men. In the current experiment, female mPFC-lesioned and non-lesioned rats were subjected to 3 weeks of chronic unpredictable stress in order to determine the role of the mPFC in dealing with chronic stress, and the consequences of mPFC damage for coping with consecutive stressful events. mPFC damage in female rats intensified the stress-induced activation of the dorsomedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus as measured with Fos expression changes and markedly increased plasma catecholamine levels after 3 weeks of unpredictable stress. Additionally, an mPFC lesion significantly reduced the time of appearance of stress-induced behavioral changes in the open field. Altogether, mPFC dysfunction affects the way female rats react to chronic stress, it not only increased the activation of brain regions involved in neuroendocrine and autonomic responses to stress but it also significantly reduced the time of onset of behavioral changes.

The psychobiology of strained breathing and its cardiovascular implications: A functional system review

Strained breathing is a natural respiratory pattern, with cardiovascular implications. It is associated with social factors, attention, expectation, and anxiety and with defense behavior in animals. An inhibition of active behavior is characteristic. Strained breathing is based on the functional heterogeneity of the medullary postinspiratory neurons. In stressful circumstances, muscle tension and laryngeal reflexes induce a strong reduction of airflow in the glottis, resulting in a prolonged Stage I of expiration and an elevated intrathoracic pressure. The resulting elevations of blood pressure and CO2 level further stimulate the strained breathing pattern. The straining factor intrathoracic pressure is an important psychophysiological parameter. Functional aspects of strained breathing may be an elevated brain perfusion and the prevention of hyperventilation. It induces blood pressure oscillations and respiratory sinus arrhythmia. Frequent strained breathing may contribute to cardiovascular pathology and sleep apnea, creating a link between functional behavior and disease.

Ketamine administration disturbs behavioural and distributed neural correlates of fear conditioning in the rat

The neurotransmitter glutamate and its associated receptors perform an important role in the brain circuitry underlying normal fear processing. The glutamate NMDA receptor, in particular, is necessary for the acquisition and recollection of conditioned-fear responses. Here the authors examine how acute blockage of the NMDA receptor with sub-anaesthetic doses of ketamine affects behavioural assays of fear-conditioned stress (e.g. freezing) and cFos expression in a network of brain areas that have previously been implicated in fear processing. Fear-conditioned rats displayed significantly more freezing behaviour than non-conditioned controls. In fear-conditioned rats that also received ketamine, this conditioning effect was largely neutralised. Fear conditioning also led to increased cFos expression in various areas central to fear processing, including the basolateral nucleus of the amygdala, the paraventricular nucleus of the hypothalamus and the anterior cingulate. Ketamine abolished such increases in cFos expression in most brain areas investigated. The present study therefore demonstrates that systemic ketamine administration in rats interferes with fear conditioning on a behavioural level and in a network of brain regions associated with fear and anxiety. The combination of ketamine and fear conditioning may therefore provide a useful model of abnormal fear processing, as observed in certain psychiatric conditions.

Individual Differences in Blood Pressure Reactivity and Behavior of Male Rats

One of the major concerns in research on the aetiology of coronary heart disease (CHD) and hypertension has been the question why some individuals suffer from these diseases while others are healthy, although exposed to seemingly identical external conditions. Since the early studies by Friedman and Roseman (1959), it has become increasingly clear that apart from environmental circumstances, personality factors are also important. In order to study the complex interplay between environmental variables and personality factors in the pathophysiology of the cardiovascular system, animal research is indispensable.

Abrupt rather than gradual hormonal changes induce postpartum blues-like behavior in rats

AIMS Postpartum blues is thought to be related to hormonal events accompanying delivery. We investigated whether blues-like symptoms depend on the rate of the decline of hormones, by comparing the behavioral consequences of an abrupt versus a gradual decline of gonadal hormones in an animal model. METHODS Female rats were treated with estrogen and progesterone for 23 days, administered either by injections or by subcutaneously implanted tubes filled with hormones. A gradual hormone decline was achieved by discontinuation of the injections; and rapid decline by removal of the tubes. Control groups received either a continued treatment or no hormones. In the period following the decline the stress-reactivity was tested with an acoustic startle test on 3 consecutive days, and anxiety behavior with an open-field test on the 2nd day. The Hypothalamus-, Pituitary-, Adrenal-axis (HPA-axis) response to stress was measured by assessing the corticosterone levels and hypothalamic c-fos expression stress-response at the 4th day. KEY FINDINGS The rapid decline of hormones induced an increased startle response lasting for two days, and increased anxiety-like behavior in the open field. This was not found in the gradual-decline and control groups. The HPA-axis response to stress was decreased in all hormone-treated animals. SIGNIFICANCE This animal study suggests that: 1) abrupt rather than gradual hormonal changes induce increased stress-reactivity and anxiety-like behavior; 2) postpartum blues may result from differences in the capacity to adapt to the changes of gonadal hormones; 3) Recovery of pregnancy-induced diminished HPA-axis response is independent of the postpartum hormone kinetics.