Reduced cooperativeness and reward-dependence in depression with above-normal plasma vasopressin concentration.

The neuropeptide vasopressin is centrally involved in the regulation of social behaviour and response to stress. We previously found support for a subcategory of depression defined by above-normal plasma vasopressin (AVP) concentration. This subcategory is validated by a positive family history of depression and correlating plasma AVP and cortisol concentrations. The data support the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression. The aim of the present study was to test whether above-normal plasma AVP concentration in depression is related to personality characteristics reflecting a specific social behaviour style. The data of 78 patients from a previously investigated sample were reanalysed. Fifty-eight patients were available after 2 years, 15 of whom with initially above-normal plasma AVP. The dimensions of the Temperament and Character Inventory (TCI) were scored, with particular focus on the dimensions of Cooperativeness (CO) and Reward-dependence (RD). Normative subjects and other depressed subjects were used as controls. After full remission, patients with initially above-normal AVP had low CO compared with normal and patient controls. During depression, these patients had both low CO and low RD compared with normal controls and low RD compared with patient controls. Low CO is a presumably premorbid trait and reduced RD a state-dependent characteristic in depression with above-normal plasma AVP. The low CO further supports the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression.

Elevated plasma arginine vasopressin levels in veterans with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with altered hypothalamic-pituitary-adrenal (HPA) axis functioning. Arginine vasopressin (AVP), in conjunction with corticotrophin releasing hormone, has shown to be an important modulator of the HPA axis. In order to evaluate the effect of trauma and PTSD on central AVP secretion we assessed plasma AVP levels in equally trauma exposed veterans with and without PTSD and a non-traumatized healthy control group. METHODS: Assessment of plasma AVP in 29 male veterans with PTSD, 29 traumatized veterans without PTSD, matched for age, gender, year and region of deployment (trauma controls), and 26 age matched healthy controls. RESULTS: Plasma AVP levels were higher in PTSD patients compared to both healthy controls (p = 0.004) and trauma controls (p < 0.001). In PTSD patients without a comorbid MDD a significant correlation was observed between plasma AVP levels and symptoms of avoidance measured with the Clinician Administered PTSD Scale (CAPS). CONCLUSION: Elevated plasma AVP levels are specifically related to PTSD and not to exposure to traumatic stress during deployment. Our results indicate that AVP may play a role as an anxiogenic factor, but they do not support a role for AVP in the altered response to dexamethasone in PTSD.

Altered brain stem responsivity to duodenal pain after a single stressful experience.

A single session of foot shock stress produces stable and long lasting sensitization of behavioral, hormonal and intestinal motility responses to novel stressful stimuli in laboratory rats. This is reflected in increased expression of the activity marker protein Fos in brain areas involved, following an external stressor. We present data from awake, freely moving rats in which a silicone balloon was surgically implanted in the duodenum. Firstly, cardiovascular reflexes to distentions were studied using telemetry with surgically implanted transmitters, 2 weeks after a single, 15-min session of foot shocks. The distentions caused characteristic, bi-phasic responses in both mean arterial blood pressure and heart rate that were not different between preshocked and control animals. Secondly, the numbers of Fos immunopositive cells were quantified in selected brain areas, 1 h after repeated distention of the duodenum. We found an increase in distention-induced Fos in preshocked rats in the nucleus tractus solitarius and a weaker effect in the central nucleus of the amygdala. This could be a first indication that altered visceral afferent processing in previously stressed rats, found earlier for the colon, may be a general and not an organ-specific phenomenon.

The development of various somatic markers is retarded in an animal model for schizophrenia, namely apomorphine-susceptible rats.

UNLABELLED: Although schizophrenia usually sets on after puberty, deviations of normal development exist in pre-schizophrenic children. To investigate the presence of early developmental abnormalities in a valid animal model for schizophrenia, we delineated line-specific developmental differences between apomorphine-susceptible rats (APO-SUS), which share many features with schizophrenic patients, and their counterpart, apomorphine-unsusceptible rats (APO-UNSUS). A battery of somatic developmental markers was assessed in naive animals on postnatal day (PND) 4 and in animals from PND 0 to PND 60. Three comparisons were made: naive APO-SUS and naive APO-UNSUS rats on PND 4; naive and handled APO-SUS and APO-UNSUS rats on PND 4; handled APO-SUS rats and handled APO-UNSUS rats across the initial 60 PND's. Naive APO-SUS rats developed much slower than naive APO-UNSUS rats as far as it concerns digit-separation, anogenital-distance, rooting-reflex, and body-displacement on PND 4, thereby underlining the validity of the APO-SUS rats as model for aspects of schizophrenia. Handling on PND 0-3 retarded the development of both types of rat, implying that early life events have long-lasting effects on pure-somatic markers. Finally, handling from PND 0 to PND 60 had a more pronounced retardation effect in APO-UNSUS rats than in APO-SUS rats. It is suggested that the APO-SUS rats are not affected as much as the APO-UNSUS rats, because they are already overwhelmed by other subliminal stimuli that have no effect on APO-UNSUS rats. IN CONCLUSION: (1) the APO-SUS rat, which is a valid model for schizophrenia, has a retarded development just as pre-schizophrenic children have; (2) early postnatal manipulations have immediate and long-lasting effects on the rodents' morphology; and (3) subchronic, early postnatal handling has a greater effect in APO-UNSUS rats than in APO-SUS rats. The impact of these data for APO-SUS rats as a model for schizophrenia is discussed.

Backtest type and housing condition of pigs influence energy metabolism.

The behavioral response of piglets in a backtest early in life seems indicative of their coping strategy at a later age. Coping characteristics may depend on the interaction between backtest classification and housing conditions. We studied whether growth rate and partitioning of energy in adult gilts were related to response in the backtest early in life, and to housing in groups or individual stalls. During the suckling period, female piglets were subjected to the backtest. Each piglet was restrained on its back for 1 min, and the number of escape attempts was scored. Thirty-six high-resisting gilts and 36 low-resisting gilts were selected. After weaning, pigs were housed in 12 groups of six (three high-resisting and three low-resisting). From 7 mo of age onward, 36 gilts out of six groups were housed in individual stalls, whereas the other gilts remained group housed. At 13 mo of age, gilts were housed in clusters of three (three high-resisting or three low-resisting) for an experimental period of 7 d in climatic respiration chambers. Group-housed gilts were loose housed, and stall-housed gilts were housed in stalls within the chamber. Despite the fact that high-resisting and low-resisting gilts did not differ (P = 0.269) in initial BW, low-resisting gilts showed a higher (P = 0.039) ADG during the experimental period in association with a higher (P = 0.043) energy metabolizability. This suggests that, in line with the theory on coping strategies, high-resisting gilts may have more difficulties in adapting to a change in environment, (i.e., the change from home pen to climatic chamber). Group- and stall-housed gilts differed (P = 0.001) in initial BW, with group-housed gilts being heavier. During the experimental period, stall-housed gilts showed lower energy metabolizability (P = 0.001), lower energy retention (P = 0.001), and a higher energy requirement for maintenance (P = 0.001) due to a higher activity-related heat production (P = 0.001). This finding suggests that stall housing might have a negative influence on performance and partitioning of energy when animals are adapting to a change in their environment.

Effect of response to backtest and housing condition on cell-mediated and humoral immunity in adult pigs.

Several recent studies in juvenile pigs demonstrated a relationship between the degree of resistance displayed early in life in a so-called "backtest" and parameters of cell-mediated and humoral immunity. Some of the immune characteristics were reported to depend on the interaction between backtest classification and housing system. In the present study, the effects of backtest classification and housing condition on immune reactivity in adult gilts were examined. At 10 and 17 days of age, female piglets were subjected to the backtest. In this test, each piglet is restrained on its back for 1 min and the number of escape attempts is scored. Pigs classified as high resisting (HR) or low resisting (LR) were selected and housed in groups of six gilts. At 7 months of age, half of the gilts were housed in individual stalls. At 12 months of age, gilts were challenged by immunization with DNP-KLH. Control gilts were treated similarly with a placebo. Blood samples were drawn prior to immunization (Day 0) and weekly thereafter until Day 28. No significant effects of backtest type on cellular and humoral responses against KLH were found. Furthermore, being housed in stalls as compared to groups had no consequences for the immune response and did not induce differences between HR and LR gilts. Differences in behavior and physiology found previously between HR and LR gilts, particularly in gilts in stall housing, may thus be of relatively little importance for immune-related health.

Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

AIM: To compare short-term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. METHODS: A retrospective study was performed in two centres using a tapering course of either 5 to 1 mg kg(-1) hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg(-1) dexamethasone (DEX; 21 d). In both centres glucocorticoid-treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular-intraventricular haemorrhage. The following short-term glucocorticoid-induced effects were investigated in 25 HC-treated and 25 control patients in centre A, and in 23 DEX-treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5-7 y of age was evaluated in all groups. RESULTS: HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX-treated children needed special school education significantly more often (p < 0.01) than controls at 5-7 y of age. No differences between neonatally HC-treated children and controls on neurodevelopmental outcome were found at 5-7 y of age. CONCLUSION: Neonatal HC therapy has fewer short- and long-term adverse effects than neonatal DEX therapy.

Individual differences in behavioral and physiological responses to restraint stress in pigs.

Several recent studies on pigs have demonstrated a relationship between the degree of resistance displayed early in life in a so-called backtest and a variety of behavioural and physiological responses in piglets and young fattening pigs. To study whether pigs with diverging responses in the backtest, i.e., high-resisting (HR) and low-resisting (LR) pigs, differ also in adulthood in their responses to an acute stressor, adult nulliparous HR (n=36) and LR gilts (n=36) housed in groups or stalls were challenged by 5-min fixation with a nose sling. During the first minute of restraint, HR gilts vocalised significantly more than LR gilts. Over the whole 5-min period, HR gilts tended to vocalise more than LR gilts. Housing or backtest type did not affect immediate cortisol increase (Delta(-5 min; 15 min)). At t=45 min, cortisol concentrations in HR gilts but not in LR gilts were still higher than at t=-5 min. Heart rate quickly decreased during the first min of restraint and remained fairly constant thereafter. Estimated heart rate after 5 min of nose sling was significantly lower in HR gilts compared to LR gilts. Housing or backtest type did not affect heart rate variability indices. The results support the idea that the backtest relates to individual characteristics, which at an adult age also seem to play a role in the regulation of certain behavioral and physiological responses to short-term stress.

Brain opioid receptor density reflects behavioral and heart rate responses in pigs.

Results from our previous research indicate that long-term tether-housed pigs with high and low levels of stereotypies show differences in the density of endogenous opioid receptors in the hippocampus and hypothalamus. It was not clear whether differences in opioid receptor density were induced by the chronic stress of tether housing or stereotypy performance, or were already present before the animals were tethered. The latter possibility was tested in the present experiment. We used a group of 18 nonstereotyping pigs that had no experience with tether housing and investigated whether the animals differed in the density of endogenous opioid receptors in the brain and, if so, whether these differences were related to the animals' reactions to acute challenges. The pigs were subjected to two tests: an open field test and a tethering test. Behavioral reactions as well as heart rate responses were measured. Opioid receptor densities were determined postmortem in the hippocampus and hypothalamus using a membrane binding assay with [(3)H]naloxone as a ligand. Animals differed widely in their responses to the two tests. In support of our hypothesis, we found a relationship between behavioral and heart rate responses and densities of naloxone binding sites in the hippocampus and hypothalamus. The data suggest that endogenous opioid systems in the brain contribute to differences in stress responding between individual pigs.

Opioid activity in behavioral and heart rate responses of tethered pigs to acute stress.

In a longitudinal experiment, effects of long-term tether housing on heart rate and behavioral responses to an acute stressor (a 15-min challenge with a nosesling) were investigated in pigs. The animals were challenged during loose housing and again after 10-11 weeks of tether housing. To detect possible changes in endogenous opioid systems modifying these responses, the pigs were pretreated with the opioid receptor antagonist naloxone (0.5 mg/kg body weight, iv). In response to the nosesling challenge, the animals showed pronounced resistance behavior and a sharp rise in heart rate. Following this initial phase of resistance, the heart rate dropped to prechallenge levels or below this line, and the pigs seemed to become sedated. Pretreatment with naloxone increased the heart rate response in animals that were long-term tether housed (n=12). No such effect was found in the control group (n=5) that was loose-housed during the entire experiment, indicating that the impact of endogenous opioid systems mitigating heart rate responses to acute stress had increased as a result of long-term tether housing. Changes in the effect of naloxone on the behavioral response were not found. Adaptive changes in opioid systems may prevent excessive physiological reactions to acute stress and, thus, may serve as a coping mechanism.

Effect of a benzodiazepine receptor agonist and corticotropin-releasing hormone receptor antagonists on long-term foot-shock-induced increase in defensive withdrawal behavior.

RATIONALE: Traumatic life events can induce long-term alterations in neuronal substrates, which may ultimately lead to the development of anxiety disorders. It has been postulated that corticotropin-releasing hormone (CRH) plays an important role in anxiety-like behavior. OBJECTIVES: (1) To study the long-term effects of a single foot-shock experience on defensive withdrawal (DW) behavior in rats. (2) To examine the effects of the benzodiazepine anxiolytic drug chlordiazepoxide on the behavior of preshocked and control rats in the DW test. (3) To study the role of endogenous CRH in the long-term stress-induced increase in DW behavior. METHODS: (1) Rats were exposed to a single session of foot shocks or exposed to the grid cage without receiving any shocks. Two, six and ten weeks later, rats were tested in the DW tests (2, 3). In subsequent experiments, rats were exposed to foot shocks or exposed to the grid cage without receiving any shocks, and 2 weeks later the effect of pharmacological treatments on the behavioral response in the DW test was investigated. Chlordiazepoxide (1, 5, 10 mg/kg BW, i.p.) and the CRH antagonists D-Phe CRH(12-41) (0.2, 1, 5 microg per rat, i.c.v.) and alpha-helical CRH(9-41) (5 microg per rat, i.c.v.) were injected 30 min before the test. RESULTS: A single session of foot shocks induced a long-term increase in DW behavior, which persisted after repeated testing for at least 10 weeks. Chlordiazepoxide decreased the latency but did not affect time spent in light, distance moved, or the number of entries in the open field. D-Phe CRH(12-41) had no behavioral effects. alpha-Helical CRH(9-41) increased the time spent outside the box, primarily as a result of effects of alpha-helical CRH(9-41) in controls. CONCLUSION: These data demonstrate that preshocked rats display long-term increased anxiety-like behavior in the DW test but that CRH is unlikely to be involved in its expression.

LY354740 attenuates the expression of long-term behavioral sensitization induced by a single session of foot shocks.

Exposure of rats to a single session of foot shocks sensitizes behavioral responses to novel stimuli. There is evidence that metabotropic glutamate (mGlu) receptors play a role in sensitization processes. In the present study, we investigated the role of mGlu(2/3) receptors in the long-term (14 days) increase in defensive withdrawal behavior after a single session of foot shocks. Exposure to foot shocks increased defensive withdrawal behavior. The mGlu(2/3) receptor agonist LY354740 ((1S,2S,5R,6S)-(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 0.1 mg/kg, i.p.) normalized the increased latency and the decreased time in the light of the preshocked rats. We conclude that activation of mGlu(2/3) receptors attenuates the foot shock-induced expression of behavioral sensitization.

Stress-induced sensitization of CRH-ir but not P-CREB-ir responsivity in the rat central nervous system.

There is some evidence that a traumatic life event can induce long-term alterations in corticotropin-releasing hormone (CRH) producing neurons in humans, which may play a role in the pathophysiology of anxiety disorders, including post-traumatic stress disorder (PTSD). To study the long-term effects of a traumatic event on brain CRH-immunoreactivity (CRH-ir) and phospho-cAMP response element binding protein-immunoreactivity (P-CREB-ir), rats were exposed to a single session of foot shocks (preshocked) or no shocks (control). Two weeks later half of the control rats and half of the preshocked rats received an electrified prod in the home cage for 15 min and behavior was recorded. Fifteen minutes after the removal of the prod rats were perfused and brain sections were stained for CRH-ir and P-CREB-ir. There was no basal difference between preshocked and control rats in brain CRH-ir and P-CREB-ir. Exposure to the electrified prod induced a significant increase in CRH-ir in the paraventricular nucleus of the hypothalamus, the median eminence and the central amygdala in preshocked rats, but not in control rats. The electrified prod increased the number of P-CREB-ir neurons in the paraventricular nucleus of the hypothalamus and the locus coeruleus, but the preshock experience did not affect this response. In an additional experiment with a similar design plasma hormone levels were measured 14 days after the foot shocks. The preshock experience sensitized the shock prod-induced ACTH and corticosterone response. No behavioral differences between preshocked and control rats were found during the shock prod tests. We suggest that long-term stress-induced changes in neuropeptide dynamics of CRH-ir neurons may play a role in long-term stress-induced neuroendocrine sensitization.

Regulation of cholecystokinin release from central nerve terminals.

The high abundance of the cholecystokinin octapeptide in various brain regions is expressed by involvement of this neuropeptide in diverse brain functions. This peptide is mostly, if not always, co-localized with classic transmitters in central nerve terminals. Since the functions of the coexisting transmitters are often different, differential regulation of their release is obvious. This differentiation is realized by differences in presynaptic localization, release dynamics, and calcium regulation. In addition, CCK release is locally modulated by receptors, kinases and phosphatases. The regulatory mechanisms of CCK release are placed into physiological perspective.

Long-term sensitization of cardiovascular stress responses after a single stressful experience.

There is evidence that the experience of traumatic events may play a role in the pathogenesis of somatic diseases, including cardiovascular disorders. In this study, telemetry was used to investigate the long-term effects of a single stressful experience on cardiovascular and behavioral responses to novel challenges 2 weeks later. Rats were exposed to footshocks and tested for sensitization using the following challenges: novel cylinder (Day 14); shock prod acquisition test (Day 15); and shock prod retention test (Day 16). No difference in basal somatomotor activity (SA), heart rate (HR) and blood pressure between preshocked rats and control rats was found. However, preshocked rats displayed an enhanced blood pressure response compared to controls during the shock prod acquisition test and the shock prod retention test. No differential increase in HR response between both groups was found. During the novel cylinder test, the preshocked rats displayed less SA while no behavioral differences were found in the shock prod acquisition test and the shock prod retention test. We conclude that a single stressful experience induces long-term sensitization of blood pressure responses to novel challenges that are not necessarily linked to sensitized behavioral responses. The footshock model may be a useful model to study autonomic hyperresponsivity found in posttraumatic stress disorder (PTSD).

The stimulatory effect of vasopressin on the luteinizing hormone surge in ovariectomized, estradiol-treated rats is time-dependent.

The luteinizing hormone surge in the female rat is not only induced by the positive feedback of estradiol, but also by circadian signals originating in the suprachiasmatic nucleus (SCN). In a previous study we showed that administration of vasopressin, an SCN transmitter present in preoptic projections, induced an LH surge in animals bearing complete lesions of the SCN. This strongly suggests vasopressin as a stimulatory circadian signal for the timing of the LH surge. In the present study we investigated during which time window vasopressin may act in the medial preoptic area to stimulate LH secretion in SCN-intact female rats. Vasopressin or a specific V1a receptor antagonist was administered into the MPO by a reverse microdialysis technique during different time windows, and plasma LH concentrations were measured. Vasopressin stimulated the LH surge in 30% of the animals, when administered during the second half of the light period, but during the first half of the light period no effects were observed. Administration of the V1a receptor antagonist, however, did not affect the LH surge. These data confirm our previous results that vasopressin is a stimulatory factor for the LH surge also in SCN-intact animals, and indicate that a certain time window is available for such stimulation. We hypothesize that vasopressin in the SCN-intact animal may act as a circadian signal during a specific time window to induce the LH surge. The time window is the result of other SCN regulatory systems that are involved in the preparation of the LH surge.

Control of the estradiol-induced prolactin surge by the suprachiasmatic nucleus.

In the present study we investigated how the suprachiasmatic nucleus (SCN) controls the E(2)-induced PRL surge in female rats. First, the role of vasopressin (VP), a SCN transmitter present in medial preoptic area (MPO) projections and rhythmically released by SCN neurons, as a circadian signal for the E(2)-induced PRL surge was investigated. Using a reverse microdialysis technique, VP was administered in the MPO during the PRL surge, resulting in a suppression of the surge. VP administration before the surge did not affect PRL secretion. Also, administration of a V1a receptor antagonist before the surge was ineffective. Second, lesions of the SCN were made that resulted in constant basal PRL levels, suggesting that with removal of the SCN a stimulatory factor for PRL secretion disappeared. Indeed, the PRL secretory response to blockade of pituitary dopamine receptors was significantly reduced in SCN-lesioned animals. These data suggest that the afternoon decrease of VP release in the MPO by SCN terminals enables the PRL surge to occur, and may thus be a circadian signal for the PRL surge. Simultaneously the SCN is involved in the regulation of the secretory capacity of the pituitary, possibly via specific PRL-releasing factors.

Weak 24-h periodicity of body temperature and increased plasma vasopressin in melancholic depression.

Earlier work has shown that plasma vasopressin levels of depressed patients were higher than those of healthy controls. The aim of the present study was to determine whether plasma vasopressin levels were correlated to parameters of the circadian rhythm. Forty-one patients with major depression and twenty-five controls participated in a case-control design under natural circumstances in a field study to investigate plasma vasopressin levels three times daily, circadian motor activity, and the 24-h periodicity of body temperature for five consecutive 24-h periods. Temperature measurements consisted of at least five, but mostly six or more measurements every 24 h. Twenty-two percent of the patients, but none of the controls lacked 24-h periodicity of body temperature. In melancholic patients increased vasopressin levels in plasma correlated with a weak 24-h periodicity of body temperature. The role of vasopressin is discussed in the light of the present findings.

CRH signalling in the bed nucleus of the stria terminalis is involved in stress-induced cardiac vagal activation in conscious rats.

The bed nucleus of the stria terminalis (BNST) is involved in autonomic and behavioral reactions to fearful stimuli and contains corticotropin-releasing hormone (CRH) fibers and terminals. The role of CRH in the medial part of the BNST in the regulation of heart rate (HR) and PQ interval of the electrocardiogram was studied under resting conditions and conditioned fear stress in freely moving rats. Microinfusion of CRH (0.2 microg/0.6 microl) in the medial BNST under resting conditions significantly enhanced HR as compared to saline treatment, but did not reduce the PQ interval, indicating that exogenous CRH in the medial BNST can activate both the sympathetic and parasympathetic cardiac outflow. In addition, CRH induced a slight increase in gross locomotor activity, an effect that succeeded the tachycardiac response, indicating that the HR response was not a consequence of increased locomotor activity, but likely a direct effect of CRH. CF was induced by 10-min forced exposure to a cage in which the rat had experienced footshocks (5 x 0.5 mA x 3s) the day before. alpha-helical CRH(9-41) (alphahCRH; 5 microg/0.6 microl), a non-selective CRH receptor antagonist, or saline was infused into the medial BNST of rats prior to CF. CF induced freezing behavior, associated with an increase in HR and PQ interval, indicating activation of sympathetic and vagal outflow to the heart. alphahCRH significantly reduced the PQ response, but enhanced the tachycardia, suggesting inhibition of vagal activity. In addition, alpha-helical CRH(9-41) reduced the freezing response. Taken together, the data provide first evidence that CRH, released in the medial BNST during stress, contributes to cardiac stress responses, particularly by activating vagal outflow.

Long-lasting stress sensitisation.

Stressful experiences in humans can result in a spectrum of long-term changes in behavioural, autonomic and hormonal responsivity. An extreme form of such alterations is found in patients with post-traumatic stress disorder (PTSD). A number of animal models has been developed in which intense stressful experiences (shocks, social confrontations) result in longterm altered responsivity of behavioural, autonomic and hormonal responses to aversive challenges which mimic many of the changes seen in PTSD. These models of stress-induced sensitisation are beginning to generate a better understanding of the vulnerability factors, time-course and underlying neuronal substrates of the long-term disturbances experienced by humans as a result of stressful life events.