Petra Netter

Psychosocial stress in tree shrews: Clomipramine counteracts behavioral and endocrine changes

Male tree shrews (Tupaia belangeri) provide an animal model to study the neurobehavioral consequences of chronic psychosocial stress. When living in visual and olfactory contact with a male conspecific by which it has been defeated, the subordinante tree shrew shows dramatic behavioral, physiological, and neuroendocrine changes. Because the over all pattern of these changes resemble a depression-like symptomatology, we investigated to what extent the behavioral and endocrine changes in subordinate animals can be reversed by treatment with the tricyclic antidepressant clomipramine. In the present study, animals were subjected to a 10-day period of psychosocial conflict to elicit stress-induced behavioral and endocrine alterations before the onset of drug treatment, and psychosocial stress continued throughout the treatment period of 30 days. Clomipramine was administered orally once daily at a dose of 50 mg/kg. The drug had a time-dependent restorative influence on marking and grooming behavior, locomotor activity, risk assessment, as well as on urinary cortisol and norepinephrine excretion. It, thus, appears that the clomipramine treatment counteracts the behavioral and endocrine effects of chronic psychosocial stress in tree shrews, and the time course of recovery corresponds closely to that observed when treating depressed patients in the clinic.

Serotonin and dopamine as mediators of sensation seeking behavior

The purpose of the present paper was to investigate the relationship of the serotonergic and dopaminergic systems to subscales of sensation seeking (SS). Two of the subscales, Disinhibition (DIS) and Experience Seeking (ES), were chosen for analysis based on their representation of the two major factors obtained in a factor analysis: DIS represents a factor of lack of impulse control and ES a factor of novelty seeking. In studies 1 and 2 responsivity to a serotonergic (5-HT) challenge by a 5-HT1a receptor agonist (ipsapirone) was investigated by drug-induced prolactin (PRL) and cortisol responses, as well as by emotional states and behavioral measures. The dopaminergic (DA) response to a DA agonist (lisuride) and antagonist (fluphenazine) was analyzed in a condition of smoking deprivation (study 3) using PRL responses, emotional states, and behavioral measures of nicotine craving as dependent variables. In the studies of the serotonergic system, high ES subjects showed a blunted cortisol response in both studies and high DIS subjects demonstrated a blunted PRL response in study 2. A frequently observed side effect of serotonergic agonists, increase in emotional arousal, was not observable with ipsapirone in high ES and high DIS subjects as compared to low scorers. Behavioral aggression, which had been experimentally induced in study 2, was increased in high ES as well as in high DIS by the 5-HT1a agonist which exerted antiaggressive effects in low scorers. These findings were found compatible with the idea of a generally low responsivity of the serotonergic system in high ES as well as in high DIS types of sensation seekers of 5-HT1a subsensitivity in high DIS and subsensitivity of other postsynaptic 5-HT receptors in high ES. There was no association between SS subscales and DA-induced decrease of PRL, but high ES subjects seemed to tolerate nicotine deprivation better than low ES subjects indicating that they were less susceptible to deprivation of nicotine-induced DA. But craving for nicotine was increased in high ES subjects by the DA agonist lisuride as opposed to the antagonist, which was taken as evidence that DA stimulation may induce approach behavior in high ES. Although only two subscales had been selected for the investigation, this approach suggests both common and different relationships between SS subscales and neurotransmitter systems.

Changes in cortisol secretion during shiftwork: implications for tolerance to shiftwork?

The present study was conducted to determine the size of changes and the time point of those changes in biological rhythms during night-shift and whether they are associated with tolerance to shiftwork. The adrenal hormone cortisol has frequently been investigated in the field of shiftwork since it follows a pronounced circadian variation and has been demonstrated to be affected by night-work. However, studies are restricted with respect to sample size, number of measurements or duration of sampling periods. Therefore, a sample of 24 night-shift workers was investigated in a cardiac emergency unit for seven nights. Saliva samples were collected frequently for determination of cortisol. A total of 28 cortisol measurements in each subject were made in order to decide whether the circadian rhythm changed, and if so at which time point. A clear reversal of circadian function could be observed for the total group (mean cortisol concentrations) after the fifth night. However, inspection of individual patterns revealed that six out of 24 subjects did not change in circadian function. These subjects exhibited lower durations of and less consistency in recovery sleep across the following days after night-work. With respect to personality dimensions a pattern associated with neuroticism can be observed in subjects without appropriate changes in cortisol rhythm. However, owing to the small sample size of non-adapters these results are preliminary and should be replicated with larger samples. The overall relationship between neuroticism and low adaptability has been discussed.

Two types of aggression are differentially related to serotonergic activity and the A779C TPH polymorphism

The authors investigated whether different types of aggression relate to the A779C tryptophan hydroxylase (TPH) polymorphism and to serotonergic activity in volunteers. A factor analysis of the Buss-Durkee Hostility Inventory yielded 2 factors representing Neurotic Hostility (NH) and Aggressive Hostility (AH). The authors used a neuroendocrine challenge with Citalopram in 48 volunteers and increased cortisol concentrations only in those with high levels of AH. Finally, an association study with 58 volunteers revealed that the A779C TPH polymorphism significantly relates to AH, with the highest aggression levels for the genotype AA and the lowest aggression levels for the genotype CC, but not to NH. Results are discussed with respect to inconsistent findings in the literature, which may be explained by this distinction of types of aggression.

Cortisol reaction in success and failure condition in endogenous depressed patients and controls.

The authors studied differences in cortisol response to controllable and uncontrollable stress and its relationship to Seligmans theory of learned helplessness in hospitalized unipolar depressed patients (11 nontreated, acutely depressed; 11 treated patients) and 11 age and sex matched controls hospitalized for traumatic surgery. Control and lack of control were achieved by induction of success and failure in a simple number addition test and applied in balanced order on 2 consecutive days. Saliva cortisol samples were collected before and after the test. No group differences in baseline cortisol levels were observed. Cortisol increased after uncontrollable and decreased after controllable stress in control patients, whereas cortisol decreased after both conditions in the acutely depressed group and less so in the treated group, although they were as emotionally upset after failure as controls. Thus, the normally observed ability of the neuroendocrine system to discriminate between controllable and uncontrollable stress deteriorates with increasing severity of depression.

Blunted ACTH and Cortisol Responses to Systemic Injection of Corticotropin-Releasing Hormone (CRH) in Fibromyalgia

Abstract: Thirteen female patients suffering from fibromyalgia (FM) and thirteen female age‐matched controls were intravenously injected with a bolus dose of 100 μg corticotropin‐releasing hormone (CRH), and the evoked secretion pattern of ACTH, cortisol, somatostatin, and growth hormone (GH) was followed up for two hours, together with the plasma levels of CRH. The increases of ACTH and cortisol following CRH were not significantly different between controls and FM patients. The increase of plasma CRH following its injection was significantly higher in FM patients and lasted about 45 min, paralleled by an increase of somatostatin with a similar time course. Basal GH levels were significantly lower in FM patients. GH increased in FM patients 90 min after injection of CRH, coincident with decreasing CRH and somatostatin levels, while GH levels in controls rather decreased with the lowest values occurring 90 min after CRH. The results support the concept that the hormonal secretion pattern frequently observed in FM patients is primarily caused by CRH, possibly as a response to chronic pain and stress. The elevated levels of CRH in the circulation of FM patients suggest elevated levels of CRH‐binding protein, which could explain why the levels of ACTH and cortisol between controls and FM following CRH do not differ.

A neurochemical model underlying differences in reaction times between introverts and extraverts

Abstract Based on a model for action of the mesostriatal dopamine (DA) system the assumption is made that DA activity modulates the threshold for behavioral responses to sensory input. This modulating function of DA activity on the transmission of sensory input into motor output is most likely reflected in reaction time tasks. This study attempted to relate a model of DA activition of differences in reaction times between introverts and extraverts. Experiment 1 addressed the question of whether haloperidol-induced deviations from the psysiological level of DA activity would differentially affect reaction times of extraverts and introverts. The DA receptor blocker haloperidol caused a marked impairment in reaction time performance in both, extraverts and introverts, but no relationship between Extraversion and reaction time performance was found. In Experiment 2, biosynthesis of DA, as measured by biochemical analysis of urine samples, was significantly reduced by alpha- p -tyrosine (AMPT). Although there were no differences in DA activity between extraverts and introverts after treatment with AMPT, reaction time performance was markedly decreased in introverts, but not in extraverts, as compared to the respective placebo groups. The outcome of the two experiments suggests individual differences between extraverts and introverts in responsivity to experimentally induced changes in DA activity. Introverts appear to be more sensitive to changes in DA activity than activity than extraverts whereas the latter can be characterized by more effective neuronal compensatory mechanisms for maintaining homeostasis in neurotransmission. Furthermore, responsivity to changes in DA activity seems to be mediated by up-regulation of postsynaptic receptors.

Changing psychobiological stress reactions by manipulating cognitive processes

This study aimed at manipulating psychobiological reactions to public speaking stress by means of verbal comments during the anticipation period. Sixty male students were instructed to give a public talk in 10 min. Twenty subjects each were randomly assigned to one of three experimental conditions: During anticipation of the speech the experimenter remained silent in the control condition, gave feedback that the subject was physiologically aroused and nervous in the second (arousing manipulation), or that he was physiologically calm and relaxed in the third condition (reassuring manipulation). Within the three stress conditions heart rate, systolic blood pressure, cortisol, and electrodermal responses were highest in the condition with reassuring manipulation and lowest in the condition without manipulation. Emotional stress reactions were highest in the condition with arousing manipulation and lowest in the condition with reassuring manipulation. Compared to the group without manipulation clear intraindividual discrepancies between emotional and somatic stress reactions could be observed in the group with reassuring manipulation (emotional < somatic arousal) and the group with arousing manipulation (emotional > somatic arousal). The two groups were significantly different in their discrepancy scores. It was concluded that the arousing manipulation seemed to have induced a sensitive, the reassuring manipulation a defensive coping style.

Oral application of citalopram (20 mg) and its usefulness for neuroendocrine challenge tests

The present study was conducted to investigate whether a single oral dosage of 20 mg of the selective serotonin reuptake inhibitor citalopram could be used as a tool to stimulate hormone secretion in neuroendocrine challenge paradigms. A total number of 48 healthy male subjects received either 20 mg citalopram or placebo in a randomized, double-blind cross-over design at an interval of 1 wk between both sessions. Citalopram was well tolerated without side-effects. Growth hormone (GH), prolactin (Prl) and cortisol (Cort) were determined in blood samples obtained at different time-points across the experiment according to drug kinetics. While GH and Prl were not changed after citalopram Cort levels increased as compared to the placebo condition, significantly about 2 h after drug intake. Results will be discussed in respect of the question of whether or not Prl and GH responses after treatment with i.v. applications of SSRIs reflect sertonergic involvement.

Endocrine responses after d-fenfluramine and ipsapirone challenge : Further support for cloninger's tridimensional model of personality

The tridemensional model of personality introduced by Cloninger relates aspects of novelty seeking to the dopaminergic, harm avoidance (HA) to the serotonergic, and reward dependence to the noradrenergic neurotransmitter system. Using a neuroendocrine challenge paradigm, this study investigates whether subjects characterized by blunted cortisol (CORT) responses after ipsapirone (IPS) relate to different subfactors of HA from those characterized by blunted prolactin (PRL) responses after treatment with d-fenfluramine (D-FEN). Moreover, subjects blunted in both responses should differ in scale values of subfactors of HA from those with only one or no blunted reactions. In the first part of the experiment, 16 healthy male volunteers were treated with 15 mg D-FEN. The second part of the study (about 1 year later) consists of a challenge with the partial 5-hydroxytryptamine-1a (5-HT1a) agonist IPS (10 mg) in the same subjects. The results indicate that blunted PRL responses are accompanied by high values in HA, while the main effect of IPS responsivity did not relate significantly to this dimension. With respect to the subscales of HA, subjects blunted in both responses (PRL–/C–) exhibit significantly higher levels in fatigability and asthenia when compared to all other groups (PRL–/C+, PRL+/C–,PRL+/C+). The data demonstrate that combined challenge tests may shed more light on the biological basis of personality and that HA and most clearly fatigability and asthenia relate to the 5-HT system.