Chronic Swim Stress Research Articles

Piracetam potentiates neuronal and behavioral effects of ketamine

Introduction: Ketamine has a fast, but short-term antidepressant effect. To support the therapeutic effect, repeated administrations of the drug are needed, which causes cognitive disorders. The drugs with cerebroprotective action can potentially intensify the main and weaken the side effects of drugs. Materials and methods: The impact of ketamine (5 and 20 μM), piracetam (100 μM), and their combinations on the synaptic transmission was studied on hippocampal slices in the CA1 area of rat hippocampus by means of electrophysiological methods. In behavioral experiments were aimed at studying an impact of the used drugs on the predictors which mark depressant behavior of rats: the duration of immobilization in a forced swimming test and preference for the consumption of sucrose solution (comparably with water). The behavioral experiments were performed on intact rats and rats with behavioral depression induced by chronic swimming stress. Results and discussion: Ketamine (5 and 20 μM) potentiates synaptic transmission in the radial layer of the CA1 hippocampal area. At a smaller concentration, ketamine potentiates synaptic transmission only due to the postsynaptic action, and at a greater concentration – with help of post- and presynaptic action. Piracetam (100 µM), like ketamine at a concentration of 5 μM stimulated synaptic transmission, but to a lesser degree. Ketamine at a concentration 5 μM under combined effect with piracetam induced the same effect as that at a concentration of 20 μM without piracetam, only due to a postsynaptic action. Ketamine at doses of 5 and 20 mg/kg one hour after a single systemic administration resulted in the reduced immobilization duration, but not predictors of preference for consuming a sweet solution; piracetam at a dose of 100 mg/kg under these conditions had no impact on the parameters of the rats’ behavior. The studied behavior parameters in cases of behavioral depression also changed after a single administration of ketamine at the doses of 5 and 20 mg/kg. Piracetam significantly stimulated an antidepressant action of ketamine under these circumstances. Conclusion: Piracetam potentiates a ketamine-induced enhancement of the synaptic transmission at the radial layer of the CA1 hippocampal area when investigating at the brain slices. Piracetam stimulates an antidepressant action of a single dose of ketamine in cases of behavioral depression, though it has no antidepressant effect when administered at a single dose.

Characterization of the relaxin family peptide receptor 3 system in the mouse bed nucleus of the stria terminalis

The bed nucleus of the stria terminalis (BNST) is a critical node involved in stress and reward-related behaviors. Relaxin family peptide receptor 3 (RXFP3) signaling in the BNST has been implicated in stress-induced alcohol seeking behavior. However, the neurochemical phenotype and connectivity of BNST RXFP3-expressing (RXFP3+) cells have yet to be elucidated. We interrogated the molecular signature and electrophysiological properties of BNST RXFP3+ neurons using a RXFP3-Cre reporter mouse line. BNST RXFP3+ cells are circumscribed to the dorsal BNST (dBNST) and are neurochemically heterogeneous, comprising a mix of inhibitory and excitatory neurons. Immunohistochemistry revealed that ~48% of BNST RXFP3+ neurons are GABAergic, and a quarter of these co-express the calcium-binding protein, calbindin. A subset of BNST RXFP3+ cells (~41%) co-express CaMKIIα, suggesting this subpopulation of BNST RXFP3+ neurons are excitatory. Corroborating this, RNAscope® revealed that ~35% of BNST RXFP3+ cells express vVGluT2 mRNA, indicating a subpopulation of RXFP3+ neurons are glutamatergic. RXFP3+ neurons show direct hyperpolarization to bath application of a selective RXFP3 agonist, RXFP3-A2, while around 50% of cells were depolarised by exogenous corticotrophin releasing factor. In behaviorally naive mice the majority of RXFP3+ neurons were Type II cells exhibiting Ih and T type calcium mediated currents. However, chronic swim stress caused persistent plasticity, decreasing the proportion of neurons that express these channels. These studies are the first to characterize the BNST RXFP3 system in mouse and lay the foundation for future functional studies appraising the role of the murine BNST RXFP3 system in more complex behaviors.

Antistress potential of Convolvulus pluricaulis choisy in chronic cold swim-ming stress rat model

People are using this herb Convolvulus pluricaulis choisy for enhancing mind power- learning, memory and recall. Various toxicological evaluations of this herb have suggested that it is a relatively safe compound to treat many diseases. Anti-stress activity of aqueous extract of C. pluricaulis Choisy (Sankhapuspi) (AECP) was investigated against experimentally induced stress in rats using cold water forced swimming stress model in rats. Three doses 100 mg/kg body weight (bw), 150 mg/kg bw and 200 mg/kg bw of AECP was treated orally to the stress induced rats for the evaluation of anti-stress activity. The parameters like body weight measurement, lipid peroxidation and cortisol levels were estimated to determine the anti-stress activity. The stress induced animals post-treated with AECP-100, AECP - 150 and AECP-200 mg/kg bw significantly restored the altered body weight and serum cortisol and lipid peroxidation levels, when compared with stress control group. The results of this research showed that the AECP showed a significant dose-dependent anti-stress activity due to its neuroprotective and antioxidant activity.

Simultaneous impairment of passive avoidance learning and nociception in rats following chronic swim stress.

Background:Stress can alter response to nociception. Under certain circumstances stress enhances nociception, a phenomenon which is called stress-induced hyperalgesia (SIH). While nociception has been studied in this paradigm, possible alterations occurring in passive avoidance (PA) learning after exposing rats to this type of stress has not been studied before.Materials and Methods:In the current study, we evaluated the effect of chronic swim stress (FS) or sham swim (SS) on nociception in both spinal (tail-flick) and supraspinal (53.5°C hot-pate) levels. Furthermore, PA task was performed to see whether chronic swim stress changes PA learning or not. Mobility of rats and anxiety-like behavior were assessed using open-field test (OFT).Results:Supraspinal pain response was altered by swim stress (hot-plate test). PA learning was impaired by swim stress, rats in SS group did not show such impairments. Rats in the FS group showed increased mobility (rearing, velocity, total distant moved (TDM) and decreased anxiety-like behavior (time spent in center and grooming) compared to SS rats.Conclusions:This study demonstrated the simultaneous impairment of PA and nociception under chronic swim stress, whether this is simply a co-occurrence or not is of special interest. This finding may implicate a possible role for limbic structures, though this hypothesis should be studied by experimental lesions in different areas of rat brain to assess their possible role in the pathophysiology of SIH.

Altered Neurogranin Phosphorylation and Protein Levels Are Associated with Anxiety- and Depression-Like Behaviors in Rats Following Forced Swim Stress

Here we tested the hypothesis that stress-induced alterations in Neurogranin (Ng) synthesis and/ or utilization might underlie stress-related depression and anxiety. Rats were randomly divided into five conditions: chronic swim stress (CS), acute swim stress (AS), and three control groups. The CS group was exposed to daily swim stress (5 min/day) for 14 consecutive days, the AS group received a single swim stress, and control groups were maintained in a stress-free condition. Both before and after swim stress, rats were tested for body weight gain, open-field locomotor activity, and saccharine preference. Ng and phospho-Ng (P-Ng) levels in the hippocampus and prefrontal cortex were determined by Western blot analysis. Compared to controls, CS animals displayed significantly decreased body weight gain, ambulation, and saccharine intake, and increased grooming behavior. CS animals had decreased Ng levels in the hippocampus and prefrontal cortex. In CS animals, Ng levels were positively correlated with saccharine intake and ambulation, and inversely correlated with grooming behavior. Compared to controls, AS increased immobility behavior and P-Ng and Ng levels in the hippocampus and prefrontal cortex. In AS animals, immobility behavior was positively correlated with the P-Ng in the prefrontal cortex. Thus, CS and AS produced opposing effects on Ng and P-Ng levels in the hippocampus and prefrontal cortex. Low Ng levels in the hippocampus were associated with anhedonic behavior in CS animals, whereas high P-Ng levels in the prefrontal cortex were associated with anxiety-like behavior in AS animals. Thus, Ng dysfunction might contribute to the neural mechanisms underlying stress-induced depression and anxiety.

Effects of chronic swim stress on endocrine and cardiac function in angiotensin AT1a receptor knockout mice

Stress increases circulating angiotensin II (AngII) which contributes to stimulation of adrenal Ang type 1 receptors (AT1R), mediating stress‐induced hormone release. The goal was to assess the influence of chronic swim stress on adrenal and cardiac function in AT1aR knockout mice. Adult male AT1R knockout (KO) and wild type (WT) mice (n=6) were used; groups were exercise (KO and WT) and sedentary (KO and WT). Exercise paradigm was swimming, 1 hour 3d/wk for 7 weeks. Urine and plasma corticosterone (CORT) were measured by RIA. Cardiac function was assessed by echocardiography (Echo). Results showed that plasma CORT was lower in chronic exercise as compared to sedentary groups (3 fold decrease). Urinary CORT was used to show the dynamic response to exercise stress. The stimulatory change was 10 fold higher in WTEX as compared to 5 fold in KOEX. Echo showed a higher ejection fraction (EF%) in KOEX (75%) vs. WTEX (55%). Assessment of mitral valve function showed a higher A‐wave velocity in KOEX as compared to WTEX. Ang AT1aR deficient mice showed improved cardiac response and reduced adrenal stress response to chronic exercise.

The effect of citalopram on chronic stress-induced depressive-like behavior in rats through GSK3β/β-catenin activation in the medial prefrontal cortex

Antidepressant treatments enhance synaptic connectivity in stress-sensitive brain regions such as the medial prefrontal cortex (mPFC). The mPFC plays a key role in controlling cognition and emotion. While several signaling pathways are involved in this enhancement process, the exact mechanisms are not fully established. In the present study, we evaluated the role of the glycogen synthase kinase 3β (GSK3β)/β-catenin signaling pathway in the antidepressant effect of citalopram in rats exposed to forced swim stress. The acute stress group received the classic, two-day variant of the forced swimming test (FST), whereas the chronic stress group received swim stress for 14 consecutive days. We found that rats exposed to acute swim stress showed depressive-like behaviors and expressed normal GSK3β and β-catenin levels in the mPFC. Chronic swim stress, also induced a significant behavior changes but was associated with decreased levels of phosphorylated GSK3β and β-catenin in the rat's mPFC. Chronic citalopram treatment alleviated these behavioral changes in chronically stressed rats and normalized the downregulation of GSK3β/β-catenin signaling. Our results suggest that GSK3β/β-catenin signaling plays an important role in chronic but not acute stress-related depression and contributes, at least in part, to the antidepressant effects of citalopram in distinct brain regions associated with mood regulation.

Forced swimming stress does not affect monoamine levels and neurodegeneration in rats

The current study was aimed to investigate the correlations between immobility time in the forced swimming test (FST, a behavioral indicator of stress level) and hippocampal monoamine levels (markers of depression), plasma adrenalin level (a peripheral marker of stress) as well as fluoro-jade C staining (a marker of neurodegeneration). Male Sprague-Dawley rats were subjected to acute, sub-chronic (7 d) or chronic (14 d) FSTs and immobility time was recorded. Levels of noradrenalin, serotonin and dopamine in the hippocampus, and adrenalin level in the plasma were quantified by high-performance liquid chromatography with electrochemical detection. Brain sections from rats after chronic forced swimming or rotenone treatment (3 mg/kg subcutaneously for 4 d) were stained with fluoro-jade C. The rats subjected to swimming stress (acute, sub-chronic and chronic) showed long immobility times [(214 +/- 5), (220 +/- 4) and (231 +/- 7) s, respectively], indicating that the animals were under stress. However, the rats did not exhibit significant declines in hippocampal monoamine levels, and the plasma adrenalin level was not significantly increased compared to that in unstressed rats. The rats that underwent chronic swimming stress did not manifest fluoro-jade C staining in brain sections, while degenerating neurons were evident after rotenone treatment. The immobility time in the FST does not correlate with markers of depression (monoamine levels) and internal stress (adrenalin levels and neurodegeneration), hence this parameter may not be a true indicator of stress level.

Different effects of chronic forced swim and restraint stress upon the rat spatial learning and memory

Objective To observe the effect of chronic forced swim or restraint stress on the rat's spatial learning and memory performance.Methods Twenty-four adult male Sprague-Dawley rats were randomly divided into three groups:control group(rats receiving neither stress);chronic forced swim stress (FST) group(rats were forced to swim daily for 20 minutes during 14 days);and chronic restraint stress (CRS) group(rats were loosely restrained daily in a transparent plastic cylinder which made the rats could not move freely for 6 hours during 14 days).1,2 or 3 weeks after the final secession of either stress,the navigation test and probe test of Morris water maze were employed to evaluate the rat's spatial learning and memory ability,respectively.Results (1) 1 and 2 weeks after the final stress secession,the averaged escape latency of FST group in the navigation test was significantly shortened [1week:FST (14.56±2.17)s,(17.93±2.08)s,CONTROL(26.12±5.04)s,(25.22±2.80)s,t=11.21 and 7.25,P＜0.05];meanwhile,the averaged ratio of time spent in the target quadrant for the FST group in the probe test was significantly higher than that of the control group(P＜0.05).3 weeks after the final stress secession,there was no significant difference in the escape latencies and the ratio of time spent in the target quadrant between control and FST group.(2) 1 week after the final stress secession,both the averaged escape latency in the navigation test and the averaged ratio of time spent in the target quadrant for the probe test of CRS group were significantly changed when compared with that of the control group (P＜0.05).While 2 or 3 weeks after the final stress secession,these differences disappeared.Conclusion Chronic forced swim enhanced while the chronic low intensity restrain impaired rat's spatial learning and memory.These effects could not last long since the difference disappeared as the rats withdrew from the stress for a relatively long period.Different patterns of chronic stress gave rise to different reversible influences upon the rat's spatial learning and memory. Key words: Stress ; Forced swim ; Chronic restraint ; Navigation test ; Probe test ;

Effects of chronic swim stress on EtOH-related behaviors in C57BL/6J, DBA/2J and BALB/cByJ mice

There is a strong clinical relationship between stress and stress-related disorders and the incidence of alcohol abuse and alcoholism, and this relationship appears to be partly genetic in origin. There are marked strain differences in ethanol (EtOH)-related behaviors and reactivity to stress, but little investigation of the interaction between the two. The present study assessed the effects of chronic exposure to swim stress on EtOH-related behavior in three common inbred strains of mice, C57BL/6J, DBA/2J and BALB/cByJ. After establishing baseline (10%) EtOH self-administration in a two-bottle free choice test, mice were exposed to daily swim stress for 14 consecutive days and EtOH consumption was measured as a percent of baseline both during stress and for 10 days afterwards. A separate experiment examined the effects of 14 days of swim stress on sensitivity to the sedative/hypnotic effects of an acute injection of 4g/kg EtOH. Results showed that stress produced a significant decrease in EtOH consumption, relative to pre-stress baseline, in DBA/2J and BALB/cByJ, but not C57BL/6J mice. By contrast, stress increased sensitivity to the sedative/hypnotic effects of EtOH in all three strains. These findings demonstrate that chronic swim stress produces reductions in EtOH self-administration in a strain-dependent manner, and that these effects may be restricted to strains with a pre-existing aversion to EtOH. Present data also demonstrates a dissociation between effects of this stressor on EtOH self-administration and sensitivity to EtOH's sedative/hypnotic effects. In conclusion, strain differences, that are likely in large part genetic in nature, modify the effects of this stressor on EtOH's effects in a behavior-specific manner.

Chronic swim stress alters sensitivity to acute behavioral effects of ethanol in mice

Epidemiological data support a strong link between stress, stress-related disorders and risk for alcoholism. However, precisely how stress might impact sensitivity to the intoxicating effects of ethanol or the willingness to voluntary consume ethanol remains unclear. The present study assessed the effects of daily exposure to forced swim stress on subsequent sensitivity to the sedative/hypnotic, hypothermic, ataxic (measured using accelerating rotarod), and anxiolytic-like (measured using elevated plus-maze) effects of ethanol, and ethanol consumption and preference in a two-bottle choice paradigm, in male C57BL/6J mice. Stress effects on the sedative/hypnotic effects of the barbiturate pentobarbital were also tested. Results showed that chronic (fourteen days) but not acute (one or three days) swim stress significantly potentiated the sedative/hypnotic and hypothermic effects of 4 g/kg, but not 3 g/kg, ethanol. The sedative/hypnotic effects of pentobarbital were attenuated by chronic swim stress. Irrespective of chronicity, swim stress did not alter the ataxic or anxiolytic-like effects of ethanol, or alter ethanol self-administration either during or after stress. These data provide further evidence that stress alters the intoxicating effects of high doses of ethanol in a behaviorally selective manner.

Repeated swim stress leads to down-regulation of vesicular monoamine transporter 2 in rat brain nucleus accumbens and striatum

We assessed the impact of chronic swim stress in rats (daily for 3 weeks) on vesicular monoamine transporter 2 (VMAT2) in the nucleus accumbens and striatum. Exposure to repeated swim stress resulted in significant reduction in VMAT2 density in nucleus accumbens (20%, p<0.01) and striatum subregions (21–38%, p<0.001). The down-regulation of VMAT2 in this dopaminergic regions may serve as an adaptatory mechanism in the response to prolonged stress, and may be relevant to chronic stress-induced depression.

Postnatal repeated maternal deprivation produces age-dependent changes of brain-derived neurotrophic factor expression in selected rat brain regions

Background Adverse life events occurring early in development may alter the correct program of brain maturation and render the organism more vulnerable to psychiatric disorders. Identification of persistent changes associated with these events is crucial for the development of novel therapeutic strategies. Methods We used postnatal repeated maternal deprivation (MD) from postnatal day (PND) 2–14 to investigate changes in brain-derived neurotrophic factor (BDNF) levels. RNase protection assay and enzyme linked immunosorbent assay were employed to determine the anatomic profile of neurotrophin expression at different ages following MD. Results We found that MD produces a short-term up-regulation of neurotrophin expression in hippocampus and prefrontal cortex, as measured on PND 17, whereas at adulthood, a selective reduction of BDNF expression was observed in prefrontal cortex. When adult animals were challenged with a chronic swim stress paradigm, both a reduced expression of BDNF in prefrontal cortex and a significant reduction in striatal protein levels were found only in control subjects, whereas levels in the MD group were not further decreased. Conclusions Our data suggest that MD produces a significant reduction of BDNF expression within prefrontal cortex and striatum, which may render these structures less plastic and more vulnerable under challenging conditions.

κ Opioid Receptor Antagonism and Prodynorphin Gene Disruption Block Stress-Induced Behavioral Responses

Previous studies have demonstrated that stress may increase prodynorphin gene expression, and kappa opioid agonists suppress drug reward. Therefore, we tested the hypothesis that stress-induced release of endogenous dynorphin may mediate behavioral responses to stress and oppose the rewarding effects of cocaine. C57Bl/6 mice subjected to repeated forced swim testing (FST) using a modified Porsolt procedure at 30 degrees C showed a characteristic stress-induced immobility response and a stress-induced analgesia observed with a tail withdrawal latency assay. Pretreatment with the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI; 10 mg/kg, i.p.) blocked the stress-induced analgesia and significantly reduced the stress-induced immobility. The nor-BNI sensitivity of the behavioral responses suggests an activation of the kappa opioid receptor by a stress-induced release of dynorphin peptides. Supporting this hypothesis, transgenic mice possessing a disrupted prodynorphin gene showed no increase in immobility or stress-induced analgesia after exposure to repeated FST. Because both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of forced swim stress on cocaine-conditioned place preference (CPP). FST-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place preference for the drug-paired chamber over the responses of unstressed mice. Surprisingly, nor-BNI pretreatment blocked stress-induced potentiation of cocaine CPP. Consistent with this result, mice lacking the prodynorphin gene did not show a stress-induced potentiation of cocaine CPP, whereas wild-type littermates did. The findings suggest that chronic swim stress may activate the kappa opioid system to produce analgesia, immobility, and potentiation of the acute rewarding properties of cocaine in C57Bl/6 mice.

Effect of diazepam on the immune response of rats exposed to acute and chronic swim stress

To examine the effect of the anti-stress agent diazepam on the immune response, rats were exposed either to acute swim stress, i.e., swimming once only for 30 minutes (non-trained swimmers), or to chronic stress with gradual progressive training for 6 weeks (trained swimmers). Both groups of animals were divided into subgroups treated before swimming with and without diazepam, 1 mg/kg, administered i.m. The phagocytic capacity and superoxide anion generation of the peritoneal macrophages was examined. In addition, the proliferative response of the splenic cells (splenocytes) to concanavalin A (Con A) and phytohemagglutinin (PHA), as well as the serum corticosterone levels were investigated. Diazepam abolished increased superoxide anion production in both non-trained and trained swimmers. In non-trained swimmers, the number of latex particles internalized by each cell was decreased and further reduced by the drug. In trained rats treated with diazepam, the percentage of phagocytosing cells remained reduced compared to controls, whereas the drug prevented a decrease in the engulfing capacity of individual cells. Diazepam lowered the suppressed proliferative response of the splenocytes to PHA found in non-trained swimmers. It is concluded that diazepam modifies the immune response of rats exposed to acute and chronic swim stress.

Effect of different chronic intermittent stressors and acetyl-l-carnitine on hypothalamic beta-endorphin and GnRH and on plasma testosterone levels in male rats.

Chronic stress affects the reproductive function by modifying the neuroendocrine homeostasis. The aim of the present study was to clarify the neuroendocrine and the gonadal changes following chronic intermittent stress in male rats and the action of a neuroactive drug, acetyl-l-carnitine (ALC). The effect of two different stressors, cold water swimming or ether, on central beta-endorphin (beta-EP) and GnRH contents, and on plasma testosterone levels was investigated. In addition, the response to an acute stress in chronically stressed rats, treated or untreated with ALC (10 mg/day/rat p.o.), was evaluated. The stressors were applied twice a day for 10 days, and rats were killed before, during and after the last stress session. Mediobasal hypothalamus (MBH) beta-EP and GnRH contents, and plasma testosterone levels were evaluated by radioimmunoassay. The following results were obtained: (1) both chronic swimming and ether stress caused a decrease in hypothalamic beta-EP contents; (2) MBH GnRH contents increased after chronic swimming stress but not after ether stress; (3) chronic swimming stress induced a twofold decrease in plasma testosterone levels, while no changes were observed after ether stress; (4) the treatment with ALC prevented the decrease in plasma testosterone levels after chronic swimming stress, and (5) acute stress in chronically stressed animals caused an increase in MBH-beta-EP. The present data showed that chronic swimming stress reduces the reproductive capacity and impairs the capacity to respond to the acute stress and that ALC modulates the hormonal changes to physical stress and prevents the antireproductive effect of chronic cold swimming.

Chronic swim stress enhances the motoric inhibiting effects of a muscarinic agonist

The authors previously demonstrated that chronic inescapable swim stress and footshock increase the capacity of a fixed dose of a muscarinic agonist to produce hypothermia in the rat. This project was designed to determine whether chronic inescapable swim stress in cold water would render a low dose of a muscarinic agonist, devoid of an effect on motor behavior in the naive rat (i.e., prior to subjection to the course of swim stress), an inhibitor of mobility. The study involved two groups of rats, an experimental group which received arecoline and a control group which received saline five minutes prior to being placed in an open field. Number of crossings, the dependent variable, was measured in both groups before and after a 14-day course of twice daily inescapable swim stress of 10 minutes duration at 12°C. The arecoline-treated group, as hypothesized, exhibited a significantly greater reduction in number of crossings than the saline-treated groups following the course of swim stress.

Induction of the Intermediate Lobe Pro-Opiomelanocortin System with Chronic Swim Stress and β-Adrenergic Modulation of this Induction

Swimming at 25-30 degrees C for 30 min stimulates release of beta-endorphin from both the anterior and intermediate lobe of the pituitary in rats. Measurement of N-acetyl beta-endorphin-immunoreactivity (IR), which is specific for intermediate lobe secretion, indicates a 2- to 3-fold increase in N-acetyl beta-endorphin IR in plasma following this challenge. When swim is repeated on a daily basis, there is an increase in the amount of N-acetyl beta-endorphin IR released with repeated swim over time. As well as increased response to the swim challenge, these animals demonstrate an increase in the resting plasma levels of N-acetyl beta-endorphin IR and an increase in the intermediate lobe content of N-acetyl beta-endorphin IR. Molecular sieving of plasma from rats which were swum repeatedly demonstrates that this N-acetyl beta-endorphin IR consists of both larger molecular weight N-acetyl beta-endorphin IR, e.g. N-acetyl beta-endorphin1-31 and C-terminally shortened forms, e.g. N-acetyl beta-endorphin1-27. Administration of propranolol (3 mg/kg), a beta-adrenergic antagonist, 30 min before the onset of swim is able to block the intermediate lobe release of N-acetyl beta-endorphin IR with acute swim challenge. However, repeated administration of propranolol in conjunction with repeated swim is not able to block the swim stress-induced increase in plasma N-acetyl beta-endorphin IR or the increase in N-acetyl beta-endorphin IR content of the intermediate lobe. This is not due to decreased sensitivity to propranolol with repeated administration since in rats given chronic propranolol treatment an acute dose of propranolol is still able to block swim stress-induced release of N-acetyl beta-endorphin IR. Similarly, it is not due to a decreased efficacy of this dose of propranolol in rats which were swum chronically.

Chronic stress supersensitizes rats to the inhibition of locomotion produced by arecoline

Chronic inescapable footshock and swim stress supersensitize a hypothalamic muscarinic mechanism which regulates core body temperature. We studied the inhibitory effects of arecoline, a muscarinic agonist, on locomotion in rats before and after chronic swim stress in order to examine the effects of stress on an extra-hypothalamic muscarinic mechanism. We counted crossings in an open field during the days before and after six days of twice-daily swim stress (8 minutes/session at 12C). We first examined the effects of eight doses of ip arecoline (0.01 to 2.0 mg/kg) and normal saline (N = 6 to 8 rats/group) on crossings before and after chronic stress. Doses greater than 0.25 mg/kg inhibited pre-stress crossings relative to saline and did not potentiate the inhibition of locomotion post-stress. The 0.125 mg/kg dose reduced crossings post-stress relative to saline. We reexamined the effects of the 0.125 mg/kg dose saline (N = 20 rats/group) on crossings before and after six days of swim stress. Chronic stress potentiated arecoline-induced inhibition of locomotion. Our results suggest that chronic uncontrollable stressors may supersensitize an extra-hypothalamic muscarinic mechanism involved in the stress response and the pathophysiology of stress-related disease such as major depression.

Secretion of Melanocyte-Stimulating Hormone and Adrenocorticotropin from Transplanted Pituitary Pars intermedia in Stressed and Nonstressed Rats

Rats bearing kidney grafts of the pituitary pars intermedia were divided into three groups: unstressed, acutely stressed, and chronically stressed. Corresponding sham-operated rats were used for comparisons. Twenty days after grafting, the rats were sacrificed and alpha-melanocyte-stimulating hormone (alpha-MSH), adrenocorticotropin (ACTH), and corticosterone were estimated in plasma. The adrenal/body weight ratio and DNA content of the glands were also investigated. The following results were obtained: MSH was found not to be increased in unstressed rats, but it was in grafted animals subjected to acute and chronic swimming stress. ACTH and corticosterone rose in all three groups. Adrenal/body weight ratio and DNA content increased only in grafted chronically stressed rats. Moreover, plasma corticosterone was found higher in grafted hypophysectomized rats than in non-grafted hypophysectomized animals. Administration of ergocryptine to nonstressed grafted rats induced a decrease in the blood content of ACTH and MSH, indicating that the grafts were the source of a part of the circulating ACTH. On the other hand, the fall in MSH levels could show the effect of the drug upon the pars intermedia. Comparison of the ratios of both hormones released in incubations showed that grafts secreted more ACTH than MSH; on the other hand, when intact neurointermediate lobes were incubated, MSH predominated over ACTH. For the first time it is demonstrated that the pars intermedia can secrete ACTH in vivo. Nevertheless, the ability to secrete this hormone is not a property of normal intact pars intermedia, but it manifests in the transplantations probably due to the overactivity of light cells induced by chronic stoppage of dopaminergic inhibition.