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Prolactin and corticosterone response to repeated footshock stress in male rats
Abstract
The prolactin (PRL) and corticosterone (CORT) responses to footshock stress were measured in rats after the first, fifth, and 57th exposure to the stress procedure. No reduction in the PRL or CORT responses was seen after repeated application of the footshock stress and the animals showed similar behavioral responses throughout. These results indicate that the hormonal and behavioral responses to footshock stress are not attenuated after an animal has been repeatedly exposed to the stress.
... Finally, we compared the overall degree of habituation across naïve (unstressed) animals and animals exposed to stress and found no significant difference across all three datasets (Figure 6(f ); ordinary one-way aNOVa: F(2,53) = 1.514, p = 0.23) indicating that stress does not significantly impact the overall degree of innate fear habituation. together, these data suggest that previous footshock stress, which likely results in a transient elevation of stress hormones (Bonini et al., 2016;Ratner et al., 1989), significantly delays the rate of innate fear habituation but has little effect on overall freezing levels or the total degree of habituation across trials. ...
To survive predation, animals must be able to detect and appropriately respond to predator threats in their environment. Such defensive behaviors are thought to utilize hard-wired neural circuits for threat detection, sensorimotor integration, and execution of ethologically-relevant behaviors. Despite being hard-wired, defensive behaviors (i.e. fear responses) are not fixed, but rather show remarkable flexibility, suggesting that extrinsic factors such as threat history, environmental contexts, and physiological state may alter innate defensive behavioral responses. The goal of the present study was to examine how extrinsic and intrinsic factors influence innate defensive behaviors in response to visual threats. In the absence of a protective shelter, our results indicate that mice showed robust freezing behavior following both looming (proximal) and sweeping (distal) threats, with increased behavioral vigor in response to looming stimuli, which represent a higher threat imminence. Repeated presentation of looming or sweeping stimuli at short inter-trial intervals resulted in robust habituation of freezing, which was accelerated at longer inter-trial intervals, regardless of contextual cues. Finally, prior stress history such as acute foot shock further disrupted innate freezing habituation, resulting in a delayed habituation phenotype, consistent with a heightened fear state. Together, our results indicate that extrinsic factors such as threat history, environmental familiarity, and stressors have robust and diverse effects on defensive behaviors, highlighting the behavioral flexibility in how mice respond to predator threats.
... However, other studies found that stress-linked cortisol changes did not affect prolactin levels [19,78,79] or have even reported a negative correlation between cortisol and prolactin levels [21,22,30,80,81]. Sobrinho et al. [22] suggested that this negative correlation might be due to the fact that prolactin release acts as an alternative form, rather than an extension of, the more common cortisol response, thus each hormone could be released in response to specific emotions [22].In fact, neural pathways responsible for cortisol and prolactin responses to stress are different in rodents [82], who often release prolactin in response to acute psychological stress [83]. Likewise, in sheltered dogs, whereas serum prolactin levels decreased in response to stress, no changes were observed in serum cortisol concentrations [58]. ...
Simple Summary
Although cortisol is usually considered the main reference for the assessment of stress, in some animal species it has been shown that prolactin can be used as a biomarker of both acute and chronic stress. Behavioural parameters can also be used to assess the state of welfare and stress. This study was aimed at evaluating the possible relationship between serum prolactin, serum cortisol and behavioural signs of stress in domestic dogs. To reduce the possible influence of some factors, the study was performed on a homogeneous sample formed by 40 castrated male Spanish Greyhound dogs housed in a dog shelter. The weak negative correlation found between serum cortisol and prolactin values agrees with results obtained in other studies, indicating that prolactin response might be an alternative to cortisol response.
Abstract
Prolactin has been recently regarded as a potential biomarker of both acute and chronic stress in several species. Since only few studies until now have focussed on domestic dogs, this study was aimed at evaluating whether prolactin, cortisol and stress behaviour correlated with each other in sheltered dogs. Both cortisol and prolactin analysis were performed in serum samples through a hormone-specific ELISA kit. For each dog, a stress score was calculated by summing the number of occurrences of stress-related behaviours. The presence/absence of fear during the time spent in the collection room was also scored for each individual. Results revealed a weak negative correlation between cortisol and prolactin levels. Neither of the hormones was correlated with the stress score, nor did their values seem to be influenced by showing fear in the collection room. The weak negative correlation found between cortisol and prolactin values agrees with results obtained in other studies, indicating that prolactin response might be an alternative to cortisol response. This, together with the high serum prolactin levels compared to those reported by other authors for healthy domestic dogs, may indicate that prolactin might be a good biomarker of chronic stress, and although further studies are needed to better understand the potential role of prolactin in the evaluation of canine welfare.
... Repeated exposure to the same stressor leads to gradual reduction of the stress response to that stressor (homotypic habituation; [10,[15][16][17][18][19]). Behavioral and endocrine habituation to a stressor is a key component of adaptation, and contributes to coping strategies, which in turn are associated with vulnerability to the effects of stress [20,21]. The degree of habituation depends on the severity of the stressor [10][11][12][22][23][24], with much less habituation to severe stressors [11,[25][26][27][28][29]. This reduced habituation parallels greater adverse effects of severe stress in rodent models of anxiety and depressive behavior. ...
Repeated stress can trigger a range of psychiatric disorders, including anxiety. The propensity to develop abnormal behaviors after repeated stress is related to the severity, frequency and number of stressors. However, the pattern of stress exposure may contribute to the impact of stress. In addition, the anxiogenic nature of repeated stress exposure can be moderated by the degree of coping that occurs, and can be reflected in homotypic habituation to the repeated stress. However, expectations are not clear when a pattern of stress presentation is utilized that diminishes habituation. The purpose of these experiments is to test whether interrupted stress exposure decreases homotypic habituation and leads to greater effects on anxiety-like behavior in adult male rats. We found that repeated interrupted restraint stress resulted in less overall homotypic habituation compared to repeated daily restraint stress. This was demonstrated by greater production of fecal boli and greater corticosterone response to restraint. Furthermore, interrupted restraint stress resulted in a lower body weight and greater adrenal gland weight than daily restraint stress, and greater anxiety-like behavior in the elevated plus maze. Control experiments demonstrated that these effects of the interrupted pattern could not be explained by differences in the total number of stress exposures, differences in the total number of days that the stress periods encompased, nor could it be explained as a result of only the stress exposures after an interruption from stress. These experiments demonstrate that the pattern of stress exposure is a significant determinant of the effects of repeated stress, and that interrupted stress exposure that decreases habituation can have larger effects than a greater number of daily stress exposures. Differences in the pattern of stress exposure are therefore an important factor to consider when predicting the severity of the effects of repeated stress on psychiatric disorders.
... Instead, prolactin surges are often considered as a part, if often absent in humans, of the overall stress response. Acute prolactin responses to "psychological" stress are commonplace in rodents (Ratner et al., 1989) but have been documented only sporadically in humans (Biondi and Picardi, 1999). An interesting observation was published by Reichlin (1988) who described a marked prolactin surge (from 40 ng/ml to 180 ng/ml) in a pregnant patient while arguing with the attending nurse during the course of a metabolic study. ...
... Thus, it has been repeatedly reported that a variety of anxiogenic stimuli, including novelty exposure, conditioned fear, acute or chronic restraint stress, nociceptive stimuli and exercise, all activate prolactin-releasing peptide neurons that regulate prolactin levels in several brain areas [38]. However, the implication of prolactin in anxiety and stress seems to vary with the particular type of stressful situation [50,65,66] and suggests that the amount of Table 3 Factor analyses for the N/NiH-HS rat sample (five-and two-factor solutions, for Experiment 1 Mean + SEM are shown. Groups: RHA-I (n = 10), RLA-I (n = 10) and HS (n = 20). ...
The purpose of the present study was to evaluate for the first time the stress-induced hypothalamus-pituitary-adrenal (HPA), adrenocorticotropic hormone (ACTH), corticosterone and prolactin responses of the National Institutes of Health genetically heterogeneous rat stock (N/Nih-HS rats) in comparison with responses of the relatively high and low stress-prone Roman Low- (RLA-I) and High-Avoidance (RHA-I) rat strains. The same rats were also compared (experiment 1) with respect to their levels of unconditioned anxiety (elevated zero-maze test), novelty-induced exploratory behavior, conditioned fear and two-way active avoidance acquisition. In experiment 2, naive rats from these three strains/stocks were evaluated for "depressive-like" behavior in the forced swimming test. N/Nih-HS and RLA-I rats showed significantly higher post-stress ACTH, corticosterone and prolactin levels than RHA-I rats. N/Nih-HS rats also presented the highest context-conditioned freezing responses, extremely poor two-way avoidance acquisition and very low novelty-induced exploratory behavior. Experiment 2 showed that, compared to RHA-I rats, N/Nih-HS and RLA-I rats displayed significantly less struggling (escape-directed) and increased immobility responses in the forced swimming test. Factor analysis of data from experiment 1 showed associations among behavioral and hormonal responses, with a first factor comprising high loadings of elevated zero-maze variables and lower loadings of conditioned fear, two-way avoidance acquisition and hormonal measures, while a second factor mainly grouped conditioned fear and two-way avoidance acquisition with novelty-induced exploration and post-stress prolactin. Thus, regarding their anxiety/fearfulness, passive coping style, "depressive-like" and stress-induced hormonal responses the N/Nih-HS rats resemble the phenotype profiles of the relatively high-anxious and stress-prone RLA-I rat strain.
... An important body of evidence indicates that anxiogenic/stressful stimuli activate prolactin-releasing peptide neurons that regulate prolactin levels in several brain areas (see [34], for review), and that prolactin involvement in anxiety and stress seems to vary with the particular type of stress [36,42,48], the amount of control an organism exerts over the stressor [42,44], and the animal's behavioral phenotype [27]. It is therefore all the more remarkable that the Roman rats exhibit large between-line/strain differences in stress-induced prolactin responses, which are particularly exacerbated in the RLA line/strain [41,42], as well as in other strains of rats selectively bred for high anxiety-related behavior [27]. ...
Microarray technology was used to explore differences in brain gene expression under basal conditions in two strains of psychogenetically selected rats which differ in anxiety/stress responses, the inbred Roman High-(RHA-I) and Roman Low-(RLA-I) Avoidance rats. Microarray analysis detected 14 up-regulated and 24 down-regulated genes in RLA-I vs. RHA-I rats functionally related to neurobiological processes. The differentially expressed genes CAMKK2, CRHBP, EPHX2, HOMER3, NDN, PRL and RPL6 were selected for microarray validation using qRT-PCR. EPHX2, CAMKK2 (both up-regulated in RLA-I vs. RHA-I rats) and HOMER3 (down-regulated in RLA-I vs. RHA-I rats) showed a similar tendency and fold-change both in microarray and RT-PCR analyses; PRL (up-regulated in RLA-I vs. RHA-I rats), CRHBP and RPL6 (both down-regulated in RLA-I vs. RHA-I animals) showed a similar tendency but a different order of magnitude of change among experiments; finally, NDN was validated neither in tendency nor in magnitude of change.
... Instead, prolactin surges are often considered as a part, if often absent in humans, of the overall stress response. Acute prolactin responses to "psychological" stress are commonplace in rodents (Ratner et al., 1989) but have been documented only sporadically in humans (Biondi and Picardi, 1999). An interesting observation was published by Reichlin (1988) who described a marked prolactin surge (from 40 ng/ml to 180 ng/ml) in a pregnant patient while arguing with the attending nurse during the course of a metabolic study. ...
The present study describes the responses of cortisol, prolactin and growth hormone (GH) to emotions elicited during sessions in which an hypnoidal state was induced. The purpose of the study was to provide answers for the following questions: 1) Do sessions with an emotional content have more hormonal surges than baseline, relaxation-only, sessions? 2) Does the induction of a fantasy of pregnancy and nursing elicit a prolactin response? 3) Are there any associations between surges of different hormones? 4) Are hormonal responses related to the intensity, type, or mode of expression of the emotions? For this purpose, thirteen volunteers and twelve patients with minor emotional difficulties were studied during sessions under hypnosis. The period of observation lasted for about three hours. Heart rate (HR), skin conductance (SC) and vagal tone (VT) were monitored. Serum cortisol, prolactin and growth hormone were sampled every 15 minutes. The volunteers had three types of sessions- "blank", consisting of relaxation only (12 sessions), "breast feeding", in which a fantasy of pregnancy and breast feeding was induced (12 sessions) and "free associations" in which the subjects were encouraged to evoke experiences or feelings (17 sessions). The patients had only sessions of free associations (38 sessions). Sessions of free associations had more hormonal surges than "blank" and "breast feeding" sessions. This was true for cortisol (8/17 v.3/24; p < 0.03), prolactin (7/17 v. 3/24; p < 0.05) and GH (9/17 v. 4/24; p < 0.02). During the 55 sessions of free associations (volunteers plus patients) there were 32 surges of cortisol, 18 of prolactin and 28 of GH. Cortisol and prolactin surges were negatively correlated (p < 0.03). GH had no significant association with either cortisol or prolactin. Visible emotions were positively associated with GH surges (p < 0.05). but not with cortisol or prolactin. Cortisol surges were correlated positively with evocations of real events (p < 0.01) and negatively with evocations containing defensive elements (p < 0.01). Cortisol correlated positively with shock and intimidation (p < 0.02) and negatively with rage (p < 0.04). The AUC of the cortisol peaks during shock and intimidation was significantly higher than that of the pool of all other cortisol peaks (12.4 micromol x min x l(-1) v. 7.1 micromol x min x l(-1); p < 0.005). Rage had a marginally significant positive association with prolactin surges (p=0.07). The distribution of GH surges did not show any significant association with types of emotions. The present study provides evidence that cortisol, prolactin and GH respond to psychological stress in humans. However, they are regulated differently from one another. Cortisol and prolactin surges appear to be alternative forms of response to specific emotions. GH surges depend on the intensity of the emotion, probably as a consequence of the associated muscular activity. The current paradigm of stress, implying corticotrophin-releasing hormone (CRH) as the initial step of a cascade of events, is insufficient to account for the diversity of hormonal changes observed in psychological stress in humans.
Prolactin is practically ignored in the chapter of psychosomatic disorders of textbooks of psychiatry (1). There are two valid
reasons for this omission:
First, psychiatric difficulties associated with inappropriate lactation or hyperprolactinemia (except when induced by drugs)
are uncommon. Second, there is no conceptual framework to accommodate such uncommon observations that, when reported, appear
either as anecdoctal cases or as unexplained associations. For all practical and theoretical purposes the biology of “psychological
stress” has been described exclusively in terms of the hypothalamic-pituitary-adrenal axis and/or the sympathetic nervous
system.
Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors.
We have shown that tolerance to the behavioral effects of nicotine is partially dependent on conditioned environmental cues that predict drug delivery. The present research extends this finding to physiological effects of nicotine by assessing both the appetite-suppressing and adrenocortical-activating effects of nicotine, as measured by plasma corticosterone (CORT). In the first study, male rats on a 22-h food deprivation schedule were injected daily with 0.33 or 0.66 mg/kg (free base) of nicotine bitartrate or saline in a distinctive environment and tested for milk intake. Nicotine initially suppressed milk intake and tolerance developed over 10 days. Changing cues associated with drug administration partially reversed tolerance since injection of nicotine in a new environment reduced milk intake of tolerant animals. Similarly, animals who repeatedly received nicotine in one environment exhibited CORT levels lower than rats injected for the first time, and this tolerance also was partially reversed when administration occurred in the new environment. The second experiment indicated that the increased CORT of Experiment 1 was not a stress response associated with injecting animals in a different environment. These results indicate that tolerance to both behavioral and neuroendocrine effects of nicotine is influenced by conditioning.
The reliability of serum glucose concentrations as an index of habituation to chronic stress was evaluated in adult male rats. The glucose response to immobilization was attenuated by six days of previous chronic exposure to the same stressor, the degree of reduction being related to the duration (15 min, 1 hr or 4 hr) of the daily exposure to immobilization. In another experiment, three groups of rats were exposed to one of three stressors (handling plus change of room, restraint in tubes, or immobilization by wood boards), 1 hr daily for 27 days. On day 28, when faced with the same acute stressor to which they were chronically exposed, the rats showed a consistent reduction in glucose response, regardless of the type of stressor used. In addition, in stress-naive rats serum glucose levels were related to the intensity of the stressor as assessed by three independent measures (food intake, body weight changes, and adrenal weight after chronic exposure to the stressor). These data indicate that, under appropriate conditions, glucose levels can be a good index of both the intensity of acute stress experienced by the rats and their habituation to repeated stress.
Plasma noradrenaline (NA), adrenaline (A), corticosterone (CS) and glucose concentrations were determined in blood frequently sampled via a cardiac catheter from freely behaving rats exposed to five successive trials of water-immersion stress (WIS) with an interval between successive trials (interstressor interval; ISI) of either 24 hr or 72 hr. The first, acute exposure to WIS was accompanied by increased levels of plasma NA, A, CS and glucose which were substantially higher than those associated with handling or placement into a new cage. The magnitudes of the WIS-induced plasma NA, A, CS and glucose responses gradually declined across trials. However, five WIS exposures at a 24-hr ISI resulted in a faster and greater decrement of the plasma A, CS and glucose responses than five exposures at a 72-hr ISI. The data indicate that frequency of stressor presentation (i.e., length of interstressor interval) affects the adaptation pattern of neuroendocrine and metabolic responses to chronic intermittent stress. This finding supports the hypothesis that neuroendocrine adaptation to stress is (at least partly) similar to the process of behavioral or neurophysiological habituation to a sensory stimulus.
This study examined the relationship between serum prolactin levels and behavior in infants and toddlers who experienced two potentially stressful experiences (developmental testing and venipuncture). Serum prolactin levels showed considerable consistency over a 3-month period (r = 0.64 between study entry and three months, p < 0.001, n = 50). There was also stability in having either a normal or a high value (> or = 25 ng/ml). Among children who had a normal value on initial testing, 97% also has a normal value after 3 months; 55% of those with initial high values continued to have high values (chi 2 = 19.26, p < 0.001). Children with high serum prolactin levels were more likely to be rated as unusually hesitant and unhappy during developmental testing. Overall, 53% of the children with serum prolactin levels > or = 25 ng/ml were considered abnormal in affect, compared to 20% of those with lower serum prolactin values (total n = 138, chi 2 = 13.56, p < 0.001). These results suggest that, even in early life, serum prolactin levels may reflect characteristic individual behavioral and neuroendocrine responses to stress.
Recently, we reported that rats exposed to a single and short session of inescapable footshocks showed alterations in behavioural response to environmental stimuli which developed progressively over a week and remained present for at least 28 days. The aim of the present study was to investigate whether these behavioural changes were accompanied by alterations in the brain-pituitary-adrenal axis. Male Wistar rats were subjected to 10 inescapable footshocks (S) of 6 s duration and 1 mA intensity during a period of 15 min. Control rats (C) were placed in the shock apparatus for 15 min without receiving shocks. The effects of these experimental procedures were studied 14 days later. Exposure to shocks did not affect basal plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). However, the novelty-induced ACTH response was increased in S rats as compared to C rats whereas the CORT response did not differ between C and S rats. The ACTH content of the anterior pituitary gland and adrenal weight were not affected by exposure to inescapable footshocks 14 days earlier. Quantitative immunocytochemistry of vasopressin (AVP) and corticotropin-releasing factor (CRF) in the external zone of the median eminence showed that prior footshock exposure increased the AVPi stores to 167% as compared to C rats, whereas CRFi content was not changed. In addition, S rats showed increased mineralocorticoid (MR) and glucocorticoid (GR) receptor binding capacity in the hippocampus as compared to C rats, whereas affinities were not affected. We conclude that a single and short session of inescapable footshocks has long-lasting effects on brain-pituitary-adrenal functioning concomitant with behavioural alterations.
A wide array of physical and psychological stressors alter the secretion of anterior pituitary hormones. However, both the qualitative and the quantitative features of the stressors as well as its duration markedly influence the final endocrine response. In addition, among all anterior pituitary hormones, only ACTH and prolactin levels appear to reflect the intensity of the stress experienced by the animals. Although physical stressors show a somewhat specific neuroendocrine profile, the response of the pituitary-adrenal (PA) and sympathomedulloadrenal axes are common to almost all stressors. After an initial stimulatory effect of stress, an inhibition of all anterior pituitary hormones, except ACTH, can be found provided the stressor is intense enough. The mechanisms responsible for this biphasic response to stress are likely to be located at sites above the pituitary. When the animals are repeatedly exposed to the same stressor, some behavioural and physiological consequences of stress exposure are reduced, suggesting that the animals become adapted to the stimulus. This process has been also termed habituation. Among all the pituitary hormones, only ACTH and prolactin levels are reduced as a consequence of repeated exposure to the same (homotypic) stressor, although some negative results have been reported. However, it has been recently reported that subtle changes in the characteristics of the stressors or in their regularity can greatly influence adaptation, and these factors might explain failure to find adaptation of ACTH and prolactin in some works. Habituation of ACTH and prolactin, when observed, appears to be specific for the chronically applied stressor so that the potentiality of the PA axis and prolactin to respond to a novel (heterotypic) stressor can be preserved. In the case of the PA axis, an intact or potentiated response to a novel stressor is observed in spite of presumably negative feedback exerted by daily stress-induced glucocorticoid release and the high resting levels of glucocorticoids. This phenomenon has been termed as facilitation and can be unmasked alternating stress. Although with the exception of the PA axis, developmental aspects of anterior pituitary response to stress have been poorly studied, available data suggest that dramatic changes occur in some hormones during weaning, with some, but less profound, change thereafter. Responsiveness to stressors appears to mature with age, but developmental patterns differ among the various anterior pituitary hormones.
The effect of regularity of exposure to two different chronic stressors (noise or immobilization (IMO)) on the pattern of habituation of pituitary-adrenal (PA) hormones, prolactin and glucose was evaluated in adult male rats. Animals were chronically subjected to either regular or irregular time schedule of noise (30 min/day) or IMO (2 h/day) for two weeks. The day after the last stress session the rats were killed without stress or after having been subjected to 30 min of the homotypic stressor. Whereas regular noise did not affect food intake, body weight gain or adrenal weight, irregular noise decreased body weight gain and induced a moderate adrenal hypertrophy. In addition, previous daily exposure to regular but not to irregular noise reduced both prolactin and corticosterone responses to acute noise. In contrast, glucose response to acute noise was reduced after both regular and irregular exposure to chronic noise. Either regular or irregular exposure to chronic IMO decreased food intake and body weight and increased adrenal weight to the same extent. Likewise, no influence of regularity of exposure to chronic IMO on corticosterone and prolactin responses to acute IMO was observed. However, habituation of the ACTH response to acute IMO was observed in rats subjected to chronic regular IMO, but not in rats subjected to chronic irregular IMO. Finally, acute IMO-induced hyperglycemia diminished to the same extent after regular and irregular IMO. From these results we can conclude that: first, the process of habituation of the PA axis to chronic stress is greatly dependent upon factors such as regularity of exposure to the stressor and stressor intensity, and second, the influence of regularity on the pattern of habituation to a repeated stressor is dependent on the physiological variable we are dealing with.
Acute exposure to a novel environment, such as an open field, generally results in a prolactin surge, while several days of exposure to the open field is often characterized by a decline in prolactin. As exposure to the open field is a psychological stressor, altering the animal's interpretation of the event should alter prolactin levels. In the present study, juvenile male and female rats were habituated to the open field for 1 or 5 days prior to testing in the chamber alone or with a same-sex conspecific. Levels of prolactin were measured across all rats, and play (pins) was recorded for animals tested with a conspecific. Five days of habituation to the chamber resulted in lower levels of prolactin and more play than 1 day of habituation. Across both conditions of habituation, testing with a conspecific caused lower levels of prolactin than testing alone. In addition, play and prolactin were negatively correlated. The presence of a conspecific in a stressful situation may have reduced stress by altering the animal's negative interpretation of the open field. Further, as the intensity of the social interaction increased (more play), prolactin levels decreased.
Low-level exposure to volatile organic compounds may produce symptoms in humans reporting multiple chemical sensitivity (MCS) through altered hypothalamic-pituitary-adrenal (HPA) axis functioning. We determined whether repeated formaldehyde (Form) exposure would alter corticosterone (CORT) levels in a rat model of MCS. Male Sprague-Dawley rats were given acute chamber exposures to Air or Form (0.7 or 2.4 ppm), and trunk blood was collected 20 or 60 min later. All groups showed increased CORT levels above naïve basal levels at 20 min and a return to baseline by 60 min, with no differences between treatment groups. The second experiment examined the effect of repeated Form exposure (1 h/day x 5 days/week x 2 or 4 weeks) on basal CORT levels and after a final challenge. Basal CORT was increased above naïve values after 2 week exposure to Air or 0.7 ppm Form. By 4 week, CORT levels in the Air group returned to naïve values, but remained elevated in the 0.7 ppm Form group. There were no differences in basal CORT levels among either 2.4 ppm exposed groups. After a final Air or Form challenge, the 2 and 4 week Air and 0.7 ppm Form groups had elevated CORT levels similar to their acute response, while the 2 and 4 week 2.4 ppm Form groups had elevated CORT levels compared to their acute response, indicating enhanced reactivity of the HPA axis to subsequent Form. These findings suggest that altered HPA axis functioning occurs after repeated low-level Form exposure, and may have implications for mechanisms mediating MCS in humans.
The hypothalamic-pituitary-adrenal (HPA) axis is an extremely sensitive physiological system whose activation, with the consequent release of ACTH and glucocorticoids, is triggered by a wide range of psychological experiences and physiological perturbations (stressors). The HPA axis is also activated by a high number of pharmacological agents that markedly differ in structure and function, although the precise mechanisms remain in most cases unknown. Activation of the HPA axis is the consequence of the convergence of stimulatory inputs from different brain regions into the paraventricular nucleus of the hypothalamus (PVN), where the most important ACTH secretagogues (corticotrophin releasing factor, CRF, and arginin-vasopressin, AVP) are formed. Plasma levels of ACTH and corticosterone (the latter under more restricted conditions), are considered as good markers of stress for three main reasons: (a) their plasma levels are proportional to the intensity of emotional and systemic stressors, (b) daily repeated exposure to a stressor usually resulted in reduced ACTH response to the same stressor, that is termed adaptation or habituation; and (c) chronic exposure to stressful situations results in tonic changes in the HPA axis that can be used as indices of the accumulative impact of these situations. These changes can be evaluated under resting conditions (i.e. adrenal weight, CRF and AVP gene expression in the PVN) or after some challenges (administration of CRF, ACTH or dexamethasone) that are classical endocrinological tests. There is also evidence that the activation of the HPA axis may also reflect subtle changes in the characteristics of the stressful situations (unpredictability, lack of control, omission of expected rewards, presence of conspecifics), although this is a topic that requires further studies.
Plasma corticosterone elevations have been shown to occur in response to exposure to a novel environment and to the delivery of painful stimulation, such as footshock. The present experiment investigated the effects of experience with these types of stimuli upon the responsivity of the pituitary-adrenal system. When mice were subjected to repeated footshock, the adrenocortical response was increased. When animals were repeatedly shocked in a specific environment, the adrenocortical-stimulating properties of the situational stimuli were also elevated. On the other hand, plasma corticosterone elevations in response to merely being placed in an experimental chamber were not affected by 10 exposures to the situation. Previous data showed that animals that had been shocked in one environment were generally more responsive to many types of stimulus changes. Such a pattern of results suggests that the pituitary-adrenal system is subject to sensitization processes and that the central nervous system substrate which controls its function is one that is normally involved with the production of states of arousal. This configuration of results was quite pronounced in the female mouse regardless of hormonal state, and it was absent in the intact male. The results of studies with gonadectomized males suggested that testosterone inhibits sensitization.
The effect of restraint on plasma prolactin and corticosterone concentrations was investigated in chronically catheterized, ovariectomized (OVX) or ovariectomized, oestrogen-treated (OVX-PEP) rats. Restraint was induced by tying the hind legs together. In OVX rats, prolactin levels were unchanged following restraint, either during the morning (10.00 h) or afternoon (14.00 h). Prolactin levels increased in OVX-PEP animals when restraint was initiated in the morning; when restraint was initiated in the afternoon the prolactin response depended upon the level of prolactin before restraint. If levels were low (pre-surge) the response to restraint was similar to that observed in the morning; if prolactin levels were high (surge) the response to restraint was reversed and the prolactin level declined. The morning prolactin response to restraint was significantly inhibited and the afternoon surge was retarded in adrenalectomized OVX-PEP (OVX-PEP-ADX) rats; however, in OVX-PEP animals maintained on 0-9% NaCl drinking solution, the morning prolactin response to restraint was also blunted, although the afternoon surge was normal. In OVX-PEP-ADX animals injected with either vehicle alone, or 2 or 4 mg corticosterone for 4 days, and sampled on the morning of day 5, the prolactin response to restraint was absent. Furthermore, when OVX-PEP animals were injected daily with either vehicle or 4 mg corticosterone/day, they showed no increase in prolactin in response to restraint when values were compared with those of uninjected animals. Corticosterone levels after restraint were higher than initial values in all of the above experimental conditions.
Corticosterone, prolactin, and growth hormone responses to 5 s of handling or 3 min of novel environment were compared in rats at crest and trough of the diurnal adrenal rhythm 0, 5, 15, 30, and 60 min after stimulation. All hormones responded to stimulation, corticosterone and prolactin with a dramatic rise, and growth hormone with a precipitous fall. Resting corticosterone levels evidenced the expected diurnal variation, and prolactin but not growth hormone also showed a baseline diurnal variation of small magnitude at the times studied. Growth hormone response characteristics were unaffected by time of day or type of stimulation. Both corticosterone and prolactin response profiles differed at both times of day and following both types of stimulation. Corticosterone and prolactin levels were highly correlated and each was negatively correlated with growth hormone levels. This study confirms that hormone responses to stress are complex and depend not only on the stimulus but the context of stimulation.
Rats were exposed to 15 min of restraint or footshock or forced running in an activity wheel once a day for 10 days. Control groups were handled only. On the 11th day, rats from each stressor group and controls were exposed to 15 min of one stressor in a crossed design such that all combinations of one chronic stressor and one acute stressor were performed. Rats were sacrificed immediately following removal from their home cage or after 15 min stressor exposure on the 11th day and plasma corticosterone and prolactin and pituitary cyclic AMP levels were determined. There were no measured differences in these stress indices among groups of rats sacrificed immediately upon removal from their home cage on day 11 regardless of previous history on days 1 through 10. Plasma corticosterone and plasma prolactin and pituitary cyclic AMP levels were elevated in all rats exposed to any of the three stressors immediately prior to sacrifice as compared to all rats not exposed to stress immediately before sacrifice. However, plasma prolactin and pituitary cyclic AMP responses to each of the 3 stressors were attenuated in rats which had previous exposure to that specific stressor as compared to rats which had previous experience with a different or no stressor. We conclude that habituation results from behavioral experience with a particular stressor rather than biochemical adaptation resulting from repeated challenge to hormonal and neurochemical systems responsive to stress.
Although it is known that the number of presentations of a stressor can influence the adrenocortical stress response, relatively little information exists on how stressor intensity affects this process. To evaluate this, we repeatedly presented rats with stressors of 3 different intensities and sampled blood for corticosterone. The first major finding was that the rat's initial adrenocortical responsiveness regardless of the stressor employed was a critical variable. Rats that showed a small corticosterone response showed no evidence of habituation or of differences due to stressor intensity. Rats that showed an initial robust response all showed partial habituation of their corticosterone response over time but the patterns varied with stressor intensity. Handled and prone restrained rats showed the same pattern but rats subjected to the more intense stressor of supine restraint showed delay in habituation and tonically elevated responses. These data indicate that individual differences in reactivity to stressors as well as stressor intensity can influence the pattern of the stress response over the course of repeated administration of the stressor.
Exposure to acute inescapable shock resulted in a decline of hypothalamic norepinephrine (NE), and an increase of plasma corticosterone concentrations. With repeated application of the stressor over 15 successive days the reduction of NE was eliminated and concentrations of the amine actually exceeded those of control animals. In contrast to the NE variations, plasma corticosterone concentrations were elevated irrespective of whether mice received a single or repeated sessions of inescapable footshock. Moreover, unlike NE concentrations, handling mice on successive days in the absence of the shock treatment was sufficient to provoke a modest, but reliable increase of corticosterone concentrations. It is suggested that the hypothalamic NE and plasma corticosterone changes may be reflective of different attributes of the stressor or are subserved by different mechanisms. It is suggested that variations in both these systems represent adaptive changes to meet environmental demands.
It is well known that stress is a stimulant for prolactin release. However, relatively few studies have investigated the role of psychological factors in prolactin secretion, and investigators have typically used one-time exposure and a single collection period in their studies. In our studies, attempts were made to carefully characterize the prolactin response to different psychological stressors by serially sampling blood from an indwelling cannula and to determine if repeated exposure to the stressor leads to habituation of the prolactin response. Exposure of the male rats to different novel situations such as being placed in a new cage, being placed on a platform in water, or being handled resulted in increased prolactin levels. As the rats habituated behaviorally to repeated exposure to similar situations, the prolactin response also attenuated. These findings show that psychological factors do play a role in influencing prolactin secretion and are consistent with the idea that as the psychological stress imposed by a stimulus becomes habituated, the prolactin response to that stimulus also becomes habituated.
Plasma prolactin and TSH concentrations were measured by radioimmunoassay in lactating rats after exposure to ether fumes, suckling, treatment with nicotine or injection of synthetic TRH. Both 100 ng and 100 μg of TRH caused a significant elevation in plasma prolactin within 2 min after injection. Prolactin remained elevated for 30 min after administration of 100 μg. The response seen after injection of 100 ng of TRH was similar to the rise in plasma prolactin seen after treatment with nicotine of exposure to ether. However, neither nicotine nor ether fumes caused an increase in plasma TSH. Suckling caused a marked increase in circulating levels of both prolactin and TSH but the rise in plasma prolactin preceded the rise in plasma TSH by more than 5 min. In contrast, TRH caused a rapid (within 2 min) increase in circulating prolactin and TSH. Neither nicotine nor ether altered TSH release in response to TRH and nicotine did not block the rise in plasma prolactin after TRH. In cycling rats, plasma prolactin but not TSH rose on the afternoon of proestrus. Nicotine treatment delayed the rise in prolactin and again was without effect on plasma TSH concentration. Exogenous TRH increased plasma prolactin and TSH concentration early on the afternoon of proestrus similar to the results seen in lactating rats. The data indicate that TRH can increase radioimmunoassayable plasma prolactin in addition to TSH in lactating and cycling rats but TRH alone is not the factor responsible for the rise in plasma prolactin seen after exposure to ether, suckling or treatment with nicotine nor for the prolactin surge seen on the afternoon of proestrus.
Normal male rats were subjected to a variety of stress stimuliincluding simple handling, transfer from room to room, ether anesthesia alone or combined with bleeding, the injection of saline or epinephrine, and restraint. The ensuing secretory responses of prolactin, LH, GH and FSH were then determined. Although the secretion of all 4 hormones is affected by stress and their secretory responses have a nonspecific character, they differ both in susceptibility and reactivity to stress stimulation. The secretions of prolactin and GH are the most susceptible, and whereas the secretion of prolactin is enhanced, the secretion of GH is inhibited. The secretion of LH is less susceptible and the secretory responses are more complex: an initial stimulatory phase is often followed by an inhibitory phase. The secretion of FSH is the least susceptible, but when a secretory response is elicited, it is paralleled by the secretory change in LH.Copyright © 1974 S. Karger AG, Basel
Exposure of male C.S.F. rats to novel apparatus raised plasma corticosterone levels, but the effect habituated. Two aspects of shock predictability were studied: temporal regularity vs irregularity of shock and presence or absence of a warning signal. Irregular shock produced a greater corticosterone response than regular shock but only if both were signalled. The addition of an escape contingency to a signalled, irregular shock resulted in lowered escape latency but no corresponding change in corticosterone levels occurred. In most experimental treatments in which shock was used the corticosterone levels did not habituate even after 4 days of treatment. The results were discussed in terms of: (i) role of psychological component in psychosomatic stress, (ii) the conflict of data between behavioural and physiological measures of aversiveness, and (iii) possible neuroendocrine pathways in psychological stress.
The neuroendocrine and neurochemical responses of rats to 5 min of cold exposure versus 5 min of forced immobilization were determined and compared. We found that plasma hormones and brain neurochemical systems responded differently to the two different stressors. Plasma prolactin levels were elevated over 10-fold in the immolilized group, while rising only 2-fold in the cold stress group. Levels of corticosterone were significantly increased and growth hormone levels were decreased in both stressed groups as compared to controls. Levels of cyclic GMP were markedly elevated in 11 brain regions following cold exposure. Surprisingly, no elevation of cyclic GMP was found after forced immobilization. Cyclic AMP, norepinephrine, and dopamine levels throughout the 17 regions of brain examined showed no significant response to 5 min of either stressor. Lesions of the ventral medial tegmental area did not affect the cyclic GMP or neuroendocrine responses to cold stress. Lesion of the nucleus locus ceruleus did not affect the cyclic GMP response but significantly reduced growth hormone levels in the cold-stressed rats.
The effects of five putative stressors (saline injection, cold exposure, forced running, immobilization, and footshock) on levels of pituitary cyclic AMP, plasma prolactin, corticosterone and growth hormone were examined. In naive rats exposed to 15 min of these stressors for the first time, running, immobilization and footshock increased levels of pituitary cyclic AMP, plasma corticosterone and prolactin and decreased growth hormone, typical of stress response in the rat. Cold exposure only increased corticosterone and saline injection did not affect any measured parameter. In rats chronically exposed to the same stressor (once a day for 15 min) for 10 days immediately prior to the experiment, an attenuated pituitary cyclic AMP and plasma prolactin response was seen upon application of 15 min of that stressor on the day of the experiment, compared to the responses observed in the naive rats.
The changes of plasma corticosterone and prolactin levels have been studied in rats after single, repeated or cross exposition to the moderate stressors: handling and transfer. The diminution of corticosterone and prolactin response has been found after repeated handling, but not after repeated transfer. The corticosterone level was significantly elevated in both cross-transfer and cross-handling groups and plasma prolactin level was significantly higher in the cross-handling animals. Both hormones manifested a parallel reaction to stress, prolactin being more difficult to obtain diminution of the reaction, corticosterone being more adaptable to repeated stress. It is concluded that the cross-adaptation between used stressful stimuli apparently could not be demonstrated, but, in contrast, the organism adapted to one stimulus possesses a greater corticosterone and prolactin reaction when being exposed to the new stimuli.
Male rats exposed to a novel environment exhibited a marked rise of plasma corticosterone in response to the initial exposure. These animals showed a significant but not complete habituation of their adrenal response after 18 exposures. Following their first exposure to a novel environment, animals with bilateral lesions in the dentate gyrus of the hippocampus had plasma corticosterone concentrations which were significantly lower than those observed for the control animals. Whereas the control groups demonstrated a significant decrease in their adrenal response following 18 exposures (habituation), there was no decrease of the adrenocortical response to novelty stress within the dentate-lesioned group between trials 1 and 18. The effect of the dentate lesions appeared to be specific to the behavioral stress: dentate lesions failed to alter resting levels, or the animal's adrenal responses to laparotomy stress and ether inhalation.
Observations in the rhesus monkey are described suggesting a close relationship between emotional responses to environmental factors and pituitary-adrenal cortical activity, as judged by plasma and urinary 17-OH-CS levels. Substantial elevations of plasma 17-OH-CS levels occurred in a group of normal monkeys following their first experience with a handling and venipuncture procedure. This effect did not occur in subsequent experiments of the same type. Animals placed in a chair restraining apparatus for the first time showed a moderate rise in urinary and plasma 17-OH-CS levels during the first few days but thereafter stabilized at low levels for at least 3 weeks. It is concluded that the chair technique is, therefore, suitable for studies of ACTH regulation and perhaps many types of biological studies. Urinary 17-OH-CS levels were approximately 30% lower on weekends than weekdays in monkeys kept in a laboratory room, presumably reflecting the influence of the animal's interaction with the everyday environment on the pituitary-adrenal cortical system.
Handbook of RIA Parameters of novelty shock, predictability and response contingency in corticosterone release in rats
- References Abraham Ge Bassett Jr
- Caimcross D King
- Mg
REFERENCES Abraham GE (1977) Handbook of RIA. Clin Biochern 5: 591-656. Bassett JR, Caimcross D, King MG (1973) Parameters of novelty shock, predictability and response contingency in corticosterone release in rats. Physiol Behav 10: 901-907.