Unavoidable Stress Research Articles

Transcriptional profiles underlying vulnerability and resilience in rats exposed to an acute unavoidable stress

A complex interplay between gene and environment influences the vulnerability or the resilience to stressful events. In the acute escape deficit (AED) paradigm, rats exposed to an acute unavoidable stress (AUS) develop impaired reactivity to noxious stimuli. Here we assessed the behavioral and molecular changes in rats exposed to AUS. A genome-wide microarray experiment generated a comprehensive picture of changes in gene expression in the hippocampus and the frontal cortex of animals exposed or not to AUS. Exposure to AUS resulted in two distinct groups of rats with opposite behavioral profiles: one developing an AED, called "stress vulnerable," and one that did not develop an AED, called "stress resilient." Genome-wide profiling revealed a low percentage of overlapping mechanisms in the two areas, suggesting that, in the presence of stress, resilience or vulnerability to AUS is sustained by specific changes in gene expression that can either buffer or promote the behavioral and molecular adverse consequences of stress. Specifically, we observed in the frontal cortex a downregulation of the transcript coding for interferon-β and leukemia inhibitory factor in resilient rats and an upregulation of neuroendocrine related genes, growth hormone and prolactin, in vulnerable rats. In the hippocampus, the muscarinic M2 receptor was downregulated in vulnerable but upregulated in resilient rats. Our findings demonstrate that opposite behavioral responses did not correspond to opposite regulatory changes of the same genes, but resilience rather than vulnerability to stress was associated with specific changes, with little overlap, in the expression of patterns of genes.

Antidepressant Effect of Hypoxic Preconditioning Is Associated with Modification of Expression of Transcription Factor c-Fos in Rat Brain in Response to Unavoidable Stress

Development of post-stress depression in rats was accompanied by long-term moderate activation of the expression of transcription factor c-Fos in the neocortex, hippocampus, and paraventricular nucleus of the hypothalamus. Hypoxic preconditioning preventing depressive state in rats under conditions of unavoidable stress considerably enhanced c-Fos expression in the studied brain regions during the early stages of stress response (days 1-5) and promoted its normalization at later terms (10 days). Disturbances in the wavy dynamics of c-Fos expression can contribute to the pathogenic mechanisms of depression, in particular and induce hyperproduction of hypothalamic neurohormone corticoliberin, whereas potentiation of early expression of this factor in response to stress is obviously necessary for prevention of post-stress disorders.

Passive Response to Stress in Adolescent Female and Adult Male Mice after Intermittent Nicotine Exposure in Adolescence

Smoking is frequently co-morbid with depression. Although it is recognized that depression increases the risk for smoking, it is unclear if early smoking exposure may increase the risk for depression. To test this possibility we assessed the effects of adolescent nicotine exposure on the Forced Swim Test (FST), which is used as a measure of passive coping, and depressive-like behavior in rodents, and on the open field test (OFT), which is used as a measure of locomotion and exploratory behavior. Male and female mice received daily saline or nicotine (0.3 or 0.6 mg/kg) injections from postnatal day (PD) 30 to PD 44. FST and OFT were performed either 1 or 30 days after the last injection (PD 45 and PD 74, respectively). In females, treatment with 0.3 mg/kg nicotine lead to increased FST immobility (64%) and decreased OFT locomotor activity (12%) one day following the last nicotine injection (PD 45); while no effects were observed in adulthood (PD 74). In contrast, on PD45, nicotine treatment did not change the male FST immobility but lead to lower OFT locomotor activity (0.6 mg/kg, 10%). In adulthood (PD 74), both nicotine doses lead to higher FST immobility (87%) in males while 0.6 mg/kg nicotine to lower OFT locomotor activity (13%). The results (i) identify females as more vulnerable to the immediate withdrawal that follows nicotine discontinuation in adolescence and (ii) suggest that adolescent nicotine exposure may enhance the risk for passive response towards unavoidable stress in adult males.

Behavioral and autonomic responses to acute restraint stress are segregated within the lateral septal area of rats.

BackgroundThe Lateral Septal Area (LSA) is involved with autonomic and behavior responses associated to stress. In rats, acute restraint (RS) is an unavoidable stress situation that causes autonomic (body temperature, mean arterial pressure (MAP) and heart rate (HR) increases) and behavioral (increased anxiety-like behavior) changes in rats. The LSA is one of several brain regions that have been involved in stress responses. The aim of the present study was to investigate if the neurotransmission blockade in the LSA would interfere in the autonomic and behavioral changes induced by RS.Methodology/Principal FindingsMale Wistar rats with bilateral cannulae aimed at the LSA, an intra-abdominal datalogger (for recording internal body temperature), and an implanted catheter into the femoral artery (for recording and cardiovascular parameters) were used. They received bilateral microinjections of the non-selective synapse blocker cobalt chloride (CoCl2, 1 mM/ 100 nL) or vehicle 10 min before RS session. The tail temperature was measured by an infrared thermal imager during the session. Twenty-four h after the RS session the rats were tested in the elevated plus maze (EPM).Conclusions/SignificanceInhibition of LSA neurotransmission reduced the MAP and HR increases observed during RS. However, no changes were observed in the decrease in skin temperature and increase in internal body temperature observed during this period. Also, LSA inhibition did not change the anxiogenic effect induced by RS observed 24 h later in the EPM. The present results suggest that LSA neurotransmission is involved in the cardiovascular but not the temperature and behavioral changes induced by restraint stress.

Morphine sensitization as a model of mania: Comparative study of the effects of repeated lithium or carbamazepine administration

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats. The first aim of the study was to examine the effects of carbamazepine, a standard antimanic treatment, on the stress resilience of sensitized rats, to further characterize morphine sensitization as a model of manic symptom. Carbamazepine administration abolished stress resilience but did not interfere with the expression of sensitization. The second aim of the study was to assess whether repeated carbamazepine treatment affected the dopaminergic and behavioral responses to a natural reward, a palatable food (vanilla sugar, VS), in non food-deprived sensitized and control rats and compare these possible effects with those of repeated lithium administration. Control and sensitized rats showed increased extraneuronal dopamine levels in the nucleus accumbens shell after VS consumption and competence to acquire an instrumental VS-sustained appetitive behavior (VAB). Repeated carbamazepine treatment abolished the dopaminergic response to VS consumption and disrupted the competence to acquire VAB in control rats. Lithium-treated rats showed a dopaminergic response to VS and easily acquired the appetitive behavior. In sensitized rats, neither carbamazepine nor lithium administration interfered with the dopaminergic response to VS and the acquisition of VAB. In summary, the effect of carbamazepine on the stress resilience of sensitized rats further supported the hypothesis that morphine sensitization might model some symptoms of mania. Moreover, in control rats carbamazepine treatment elicited an anhedonia-like condition that clearly distinguished the effects of this drug from those of lithium.

Paraventricular nucleus modulates autonomic and neuroendocrine responses to acute restraint stress in rats

The paraventricular nucleus of the hypothalamus (PVN) has been implicated in several aspects of neuroendocrine and cardiovascular control. The PVN contains parvocellular neurons that release the corticotrophin release hormone (CRH) under stress situations. In addition, this brain area is connected to several limbic structures implicated in defensive behavioral control, as well to forebrain and brainstem structures involved in cardiovascular control. Acute restraint is an unavoidable stress situation that evokes corticosterone release as well as marked autonomic changes, the latter characterized by elevated mean arterial pressure (MAP), intense heart rate (HR) increases and decrease in the tail temperature. We report the effect of PVN inhibition on MAP and HR responses, corticosterone plasma levels and tail temperature response during acute restraint in rats. Bilateral microinjection of the nonspecific synaptic blocker CoCl 2 (1 mM/100 nL) into the PVN reduced the pressor response; it inhibited the increase in plasma corticosterone concentration as well as the fall in tail temperature associated with acute restraint stress. Moreover, bilateral microinjection of CoCl 2 into areas surrounding the PVN did not affect the blood pressure, hormonal and tail vasoconstriction responses to restraint stress. The present results show that a local PVN neurotransmission is involved in the neural pathway that controls autonomic and neuroendocrine responses, which are associated with the exposure to acute restraint stress.

Effects of Hypoxic Preconditioning on Expression of Transcription Factor NGFI-A in the Rat Brain after Unavoidable Stress in the “Learned Helplessness” Model

We report here our immunocytochemical studies establishing that the development of a depression-like state in rats following unavoidable stress in a "learned helplessness" model is accompanied by stable activation of the expression of transcription factor NGFI-A in the dorsal hippocampus (field CA1) and the magnocellular paraventricular nucleus of the hypothalamus, along with an early wave of post-stress expression, which died down rapidly, in the ventral hippocampus (the dentate gyrus) and a long period of up to five days of high-level expression in the neocortex. In rats subjected to three sessions of preconditioning consisting of moderate hypobaric hypoxia (360 mmHg, 2 h, with intervals of 24 h), which did not form depression in these circumstances, there were significant changes in the dynamics of immunoreactive protein content in the hippocampus, with a stable increase in expression in the ventral hippocampus and only transient and delayed (by five days) expression in field CA1. In the neocortex (layer II), preconditioning eliminated the effects of stress, preventing prolongation of the first wave of NGFI-A expression to five days, while in the magnocellular hypothalamus, conversely, preconditioning stimulated a second (delayed) wave of the expression of this transcription factor. The pattern of NGFI-A expression in the hippocampus, neocortex, and hypothalamus seen in non-preconditioned rats appears to reflect the pathological reaction to aversive stress, which, rather than adaptation, produced depressive disorders. Post-stress modification of the expression of the product of the early gene NGFI-A in the brain induced by hypoxic preconditioning probably plays an important role in increased tolerance to severe psychoemotional stresses and is an important component of antidepressant mechanisms.

Immobility and Hyperthermia in the Tail Suspension Test: Association with the Porsolt Test and the Reflex Startle Reaction in 11 Inbred Mouse Strains and the Effects of Genetic Knockout of MAO A

Immobility and hyperthermia induced by unavoidable stress imposed by the tail suspension test (TST) and the acoustic startle reaction were assessed in mice of 11 inbred strains and in Tg8 mice, which have genetic knockout of MAO A. Sharp genotypic differences in immobility were seen, while there was no correlation with the hyperthermic response to the TST. A correlation was found between the extent of immobility in the TST and the startle reaction. Studies of 11 strains of mice revealed a positive correlation between the duration of immobility in the TST and the Porsolt "despair test." Genetic knockout of MAO A, one of the key enzymes in catecholamine and serotonin metabolism in the brain, weakened the startle reaction and TST-induced hyperthermia but had no significant effect on the immobility of Tg8 mice, which provides evidence of differences in the neurochemical regulation of these reactions. These data provide grounds for using the TST as a "dry" Porsolt test and identify TST-induced hyperthermia as a model for reactions to unavoidable stress.

The insular cortex modulates cardiovascular responses to acute restraint stress in rats

Acute restraint is an unavoidable stress situation that evokes marked and sustained cardiovascular changes, which are characterized by blood pressure and heart rate increases. In the present study, we tested the hypothesis that insular cortex mediates cardiovascular responses to acute restraint stress in rats. To that purpose, the insular cortex synaptic transmission was inhibited by bilateral microinjection of the nonselective synaptic blocker cobalt chloride (CoCl 2, 1 mM/100 nL). Insular cortex pretreatment with CoCl 2 decreased restraint-evoked pressor and tachycardiac responses, thus indicating an involvement of synapses within the insular cortex on the modulation of cardiovascular responses to restraint stress. The present results indicate that insular cortex synapses exert a facilitatory influence on blood pressure and HR increase evoked by acute restraint stress in rats.

Location Matters? A Comparison of Placement Conditions for Hurricane Evacuees in Houston and Louisiana

In the late summer of 2005, hurricanes Katrina and Rita inflicted overwhelming destruction causing residents in affected areas to evacuate and relocate to Houston and various parts of Louisiana. The purpose of this study is to examine how the residential environment and FEMA intervention have affected stress levels experienced by evacuees. Our research questions are: Are there socioeconomic and demographic differences between evacuees sent to Houston and those housed in FEMA trailer parks? How have hurricane evacuees experienced stress differently in Houston and Louisiana? And what factors affect levels of stress? The analysis uses survey data collected from 682 evacuees residing in Houston and various FEMA parks in Louisiana. Our findings highlight the importance of proper planning for evacuations after natural disasters such as hurricanes, including a better understanding of the environment at the place of destination for the evacuees. While evacuation from one's home causes unavoidable stress, the manner by which evacuations are executed have much to do with the magnitude of stress.

P.1.c.0511 Heterodimerization of mu opioid receptor and nociceptin/orphanin FQ peptide receptor alters g protein coupling

Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have structural homology with classic opioids, but constitute a distinct neurotransmitter system because they lack affinity for the opioid peptides and receptors. This neurotransmission is implicated in several physiologic processes, but the role played by NOP receptors during stress situations remains unclear. The acute restraint stress (RS) is a model of unavoidable stress, characterized by sustained increases in mean arterial pressure (MAP), heart rate (HR) and a drop in tail temperature. On another side, the prelimbic (PL) and infralimbic (IL) cortices, subdivisions of the medial prefrontal cortex (MPFC), are implicated in the modulation of functional responses caused by RS. Considering that, the objective of the present study was to investigate the involvement of PL and IL NOP receptors in the control of autonomic responses induced by RS. Bilateral microinjection of nociceptin (NOP agonist) into the PL reduced the cardiovascular responses evoked by RS. Bilateral microinjection of UPF-101 (NOP antagonist) into the PL potentiated the pressor and tachycardiac responses evoked by RS, in a dose-dependent manner. Local pretreatment with UPF-101 blocked the RS-evoked changes following nociceptin administration into the PL. None of these treatments affected the drop in tail temperature induced by RS. Otherwise, the administration of nociceptin or UPF-101 into the IL had no effect on RS-evoked autonomic changes. To investigate the peripheral mechanism involved in the increase in the RS-evoked cardiovascular responses induced by the blockade of PL NOP receptors, rats were intravenous pretreated with either homatropine or atenolol. The intravenous treatment with homatropine blunted the increase in the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101, while the intravenous treatment with atenolol did not affect the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101. In conclusion, our study shows an influence of the PL N/OFQ neurotransmission, but not the IL NOP receptors, in the control of cardiovascular responses observed during acute stress, by increasing cardiac parasympathetic activity.

Dopamine D 1 receptor-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of M r 32 kDa phosphorylation pattern in striatal areas of morphine-sensitized rats

Morphine sensitization is a model of latent, functionally inducible increase in dopamine D 1 receptor–mediated transmission, which may be unmasked by an external stimulus. Morphine-sensitized rats present dopamine D 1 receptor–dependent stereotypies upon morphine challenge and resilience to unavoidable stress-induced behavioral deficits. This tonic increase in dopamine D 1 dopaminergic transmission is counter-adaptive to an enhanced μ-opioid receptor-dependent signaling in striatal areas. Control and sensitized rats show a similar dopamine and cAMP-regulated phosphoprotein of M r 32 kDa (DARPP-32) phosphorylation pattern in striatal areas. Acute morphine administration induced an early increase and delayed decrease in phospho-threonine (Thr)34 DARPP-32 levels accompanied by a delayed increase in phospho-Thr75 DARPP-32 levels in the nucleus accumbens and caudate-putamen of sensitized rats, while it had no effects in control animals. The administration of a selective dopamine D 1 receptor antagonist (SCH 23390) before morphine challenge prevented the behavioral and neurochemical modifications in sensitized rats. 6-Methyl-2-(phenylethynyl)-pyridine, a selective metabotropic glutamate receptor 5 (mGluR 5) antagonist, administered 1 h after morphine challenge, prevented the delayed phosphorylation changes, but it had no effect when administered before challenge. Moreover, the DARPP-32 phosphorylation pattern in the caudate-putamen of sensitized rats after unavoidable stress exposure was studied. The stress-induced neurochemical modifications and their sensitivity to receptor antagonists were similar to those observed after acute morphine administration. In conclusion, these results suggest that in the experimental conditions used an increase in dopamine output in striatal areas is followed by a complex neurochemical pattern, in which the initial stimulation of dopamine D 1 receptors triggers a sequence of signaling events that lead to an mGluR 5-mediated increase in phospho-Thr75 DARPP-32 levels. Since DARPP-32 phosphorylated in Thr75 inhibits cAMP-dependent protein kinase (PKA) activity, the final result is a decrease in the dopamine D 1 receptor–dependent phosphorylation events.

Opposite role of infralimbic and prelimbic cortex in the tachycardiac response evoked by acute restraint stress in rats

The ventral medial prefrontal cortex (vMPFC) comprises the prelimbic cortex (PL) and the infralimbic cortex (IL). Conflicting results have been reported from studies aiming to investigate the role played by the vMPFC in behavioral and autonomic responses evoked in rodents exposed to experimental protocols that promote defense responses. Acute restraint is an unavoidable stress situation that evokes marked and sustained cardiovascular changes, which are characterized by elevated blood pressure (BP) and intense heart rate (HR) increases. We report here a comparison between the effects of pharmacological inhibition of IL and PL neurotransmission on BP and HR responses evoked by acute restraint in rats. Bilateral microinjection of 200 nl of the unspecific synaptic blocker CoCl(2) (1 mM) into the PL increased HR response associated with restraint, without affecting the restraint-induced BP response. However, when local synapses in the IL were inhibited by bilateral injection of CoCl(2) into that area, the restraint-induced HR increases were significantly reduced, without a significant effect on the concomitant BP response. No responses were observed when CoCl(2) was microinjected into structures surrounding the vMPFC, such as the cingulate cortex area 1, the corpus callosum, or the tenia tecta. The present results confirm the involvement of the vMPFC in modulation of the tachycardiac response evoked by acute restraint but not of the restraint-evoked blood pressure response. They also indicate that the IL and PL areas have opposite roles in the cardiac response, facilitating and reducing, respectively, restraint-evoked tachycardiac responses.

Effects of Exogenous Application of Corticotropin-Releasing Hormone to Slices of the Olfactory Cortex from Rats with an Active Strategy of Adaptive Behavior on the Water-Immersion Model of Depression

Experiments were performed on male Wistar rats. The specimens with an active strategy of behavior were exposed to unavoidable water-immersion stress. Surviving slices of the olfactory cortex were obtained 10 days after stress. The neurohormone had a strong inhibitory effect in 40% slices from active rats. The activity of glutamate receptors decreased, while the function of GABA receptors increased in 60% slices. Our results indicate that the depressive state of behaviorally active animals due to exposure to unavoidable stress is not necessarily mediated by the corticoliberinergic mechanisms in cortical structures.

Electrophysiological characteristics of depressive states in rats with passive strategies of adaptive behavior

The behavior of rats in a T-maze was used to select individuals with a passive strategy of adaptive behavior from a population of Wistar rats. These animals were subjected to water immersion and olfactory cortex slices were prepared from the brain 10 days later and used for recording of evoked focal potentials and the effects of tetanic stimulation. Postsynaptic potentials, of both the AMPA and NMDA types, were initially of decreased amplitude in passive rats. After unavoidable stress, the suppression of excitatory potentials increased and there was a simultaneous increase in the amplitude of inhibitory GABAB-ergic mechanisms. Addition of corticoliberin (10(-10) M) to the incubation medium led to reversible blockade of synaptic transmission. Tetanic stimulation of slices from stressed rats led to the development of posttetanic depression in 84% of cases and to post-tetanic potentiation in 12%; this is evidence for profound changes in synaptic transmission. Thus, activation of corticoliberinergic mechanisms in cortical structures does not promote recovery from depressive states in rats with the passive behavioral strategy induced by unavoidable stress.

The possible use of hypoxic preconditioning for the prophylaxis of post-stress depressive episodes

The protective effects of hypoxic preconditioning on the development of depressive states in rat models were studied. Three episodes of intermittent preconditioning using hypobaric hypoxia (360 mmHg, 2 h) prevented the onset of depressive behavioral reactions, hyperfunction of the hypophyseal-adrenal system, and impairments in its suppression in the dexamethasone test in rats following unavoidable aversive stress in a model of endogenous depression. The anxiolytic and antidepressant actions of hypoxic preconditioning in experiments on rats were no less marked than those of the tetracyclic antidepressant ludiomil. The results obtained here provide evidence that preconditioning with intermittent hypobaric hypoxia increases resistance to psychoemotional stresses, has marked anxiolytic and antidepressant effects, and can be used for the prophylaxis of depressive episodes.

Hypothalamus–pituitary–adrenal modifications consequent to chronic stress exposure in an experimental model of depression in rats

The modifications in the hypothalamus–pituitary–adrenal (HPA) axis function induced by repeated unavoidable stress exposure, according to a standardized procedure used for inducing an experimental model of depression, were studied. Rats exposed to this procedure show hyporeactivity to both pleasurable and aversive stimuli and this condition is antagonized by the repeated administration of classical antidepressant drugs. We also studied whether imipramine administration during stress exposure would interfere with the possible modifications in the HPA axis. Rats were exposed to a 4-week stress procedure with and without imipramine treatment and then tested for escape, as compared with non-stressed control animals. Twenty-four hours later all rats were bled through a tail nick for plasma corticosterone measurement before and after dexamethasone (10 μg/kg) or corticotropin-releasing hormone (CRH, 1 μg/kg) administration. Rats were then killed, adrenals and thymus weighed, brain areas dissected out and frozen for glucocorticoid receptors (GRs) and corticotropin-releasing hormone receptor 1 (CRHR1) immunoblotting and for the assessment of hypothalamic corticotropin-releasing hormone levels. Results: Rats exposed to a 4-week unavoidable stress showed escape deficit and their basal plasma corticosterone levels were higher than those of control animals. Moreover, they had decreased response to dexamethasone administration, adrenal hypertrophy, and decreased GR expression in the hippocampus, hypothalamus, medial prefrontal cortex and pituitary. No significant modifications in CRHR1 expression were observed in the pituitary nor in different discrete brain areas. CRH levels in the hypothalamus and the plasma corticosterone response to CRH administration were found to be higher in stressed rats than in controls. Imipramine treatment offset all the behavioral and neurochemical stress-induced modifications. In conclusion, the present results strengthen the assumption that the escape/avoidance behavioral deficit induced by inescapable stress exposure is accompanied by steadily increased HPA activity, and that imipramine effect is strongly related to a normalization of HPA axis activity.

Role of the medial prefrontal cortex in cardiovascular responses to acute restraint in rats

The medial prefrontal cortex (mPFC) modulates neurovegetative and behavioral responses, being involved in memory, attention, motivational and executive processes. There is evidence indicating that mPFC modulates cardiovascular correlates of behavioral responses to stressful stimuli. Acute restraint is an unavoidable stress situation that evokes marked and sustained cardiovascular changes, characterized by elevated blood pressure (BP) and intense heart rate (HR) increase. We presently report effects of mPFC pharmacological manipulations on BP and HR responses evoked by acute restraint in rats. Bilateral microinjection of 200 nl of the unspecific synaptic blocker CoCl 2 (1 mM) in the mPFC prelimbic area (PL) increased HR response to acute restraint, without significant effect on the BP response. This result indicates that PL synaptic mechanisms have an inhibitory influence on restraint-evoked HR changes. Injections of the non-selective glutamatergic receptor antagonist kynurenic acid (0.02M) or the selective N-methyl- d-aspartic acid (NMDA) receptor glutamatergic antagonist (LY235959) (0.02 M) caused effects similar to cobalt, suggesting that local glutamatergic neurotransmission and NMDA receptors mediate the PL inhibitory influence on restraint-related HR responses. Pretreatment with the non-non- N-methyl- d-aspartic acid glutamatergic antagonist glutamatergic antagonist glutamatergic receptor antagonist NBQX (0.02 M) did not affect restraint-related cardiovascular responses, reinforcing the idea that NMDA receptors mediate PL-related inhibitory influence. Pretreatment with the glutamatergic-receptor antagonists did not affect baseline BP or HR values. I.v. pretreatment with the quaternary ammonium anticholinergic drug homatropine methyl bromide (0.2 mg/kg) also increased the restraint-related HR response to values similar to those observed after treatment with kynurenic acid or LY235959, thus, suggesting that PL inhibitory influence on restraint-evoked heart rate increase could be related to increased parasympathetic activity. This dose of homatropine had no significant effects on baseline BP or HR values. Results suggest a PL inhibitory influence on restraint-evoked HR increase. They also indicate that local NMDA receptors involved in parasympathetic activation mediate PL inhibitory influence on restraint-evoked HR increase.

Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression

Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Moreover, antidepressants show an anti-inflammatory action possibly related to their clinical efficacy. An improvement in psychiatric symptoms has been recently reported in patients treated with anti-inflammatory drugs for other indications. These data imply that inflammation may be involved in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy. The aim of the present study was to evaluate the behavioural effect of the co-administration of acetylsalicylic acid (ASA, 45 mg/kg or 22.5 mg/kg) and fluoxetine (FLX, 5 mg/kg) in the chronic escape deficit model of depression. The chronic escape deficit model is based on the modified reactivity of rats to external stimuli induced by exposure to unavoidable stress and allows evaluation of the capacity of a treatment to revert the condition of escape deficit. In this model, FLX alone needs to be administered for at least 3 weeks to revert this condition. Our results show that combined treatment of fluoxetine and ASA completely reverted the condition of escape deficit by as early as 7 days, the effect being already partially present after 4 days. The effect was maintained after 14 and 21 days of treatment. ASA alone was ineffective at any time tested and the effect of fluoxetine was significant only at 21 days. These results, together with clinical data from preliminary results, suggest that ASA might accelerate the onset of action of selective serotonin reuptake inhibitor antidepressants.

Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats

Nitric oxide (NO) plays an important role in initiation and maintenance of pain, and NO precursor nitroglycerin is able to activate spinal and brain structures involved in nociception. It is also known that acute and chronic stress induce biochemical changes affecting both pain threshold and behaviour, and that the biological pattern of depression can be mimicked in the laboratory using chronic unavoidable stress paradigms (learned helplessness). We, therefore, evaluated the effects of acute and chronic immobilization stress on pain response to nitroglycerin administration in the rat. Pain perception was expressed as the latency of response to a tail-flick test (hot stimulus). Measures were made 1, 2 and 4 h following nitroglycerin (10 mg/kg i.p.) or vehicle. Nitroglycerin caused hyperalgesia after 2 and 4 h ( p < 0.05 versus baseline). Acute stress (90 min) induced a clear analgesic state ( p < 0.01 versus non-stressed control animals), and nitroglycerin injection was unable to reverse stress-induced analgesia in this setting. By contrast, exposition to chronic immobilization stress (7 days) caused a significant increase in pain response ( p < 0.05); in this case, hyperalgesia was shown to be further enhanced by nitroglycerin administration ( p < 0.05 versus vehicle). These findings support the view that a condition of chronic stress used in the laboratory to reproduce the biological features of depression can enhance hyperalgesia induced by nitroglycerin administration. These observations may be relevant to pain disorders, and particularly to migraine, since nitroglycerin is able to induce spontaneous-like pain attacks in humans, and an unfavourable migraine outcome (transformation into a chronic daily headache) is associated with chronic stress and comorbid depression.