Increased depressive-like behaviour of postpartum Flinders sensitive and resistant line rats is reversed by a predictable postpartum stressor.

During the peripartum period, women are at an increased risk to develop perinatal distress, presenting as symptoms of depression and/or anxiety. Yet, due to practical and ethical restrictions, our understanding of this condition remains limited. Animal studies that focus on the neuropsychiatric mechanisms associated with the postpartum period, often ignore the genetical predisposition factor. We therefore investigated whether pregnancy could alter the bio-behavioural profile of the Flinders sensitive and resistant line rats, and whether these effects are exacerbated by a postpartum stressor. Postpartum dams were compared to nulliparous controls in behavioural tests, analysing depressive- and anxiety-like behaviours. Next, postpartum dams were subjected to a maternal separation and early weaning (MSEW) regimen, with their behaviour and serotonergic and noradrenergic concentrations compared to rats not separated from their pups. Regardless of strain, pregnancy decreased time spent in the open arms of the elevated plus maze and hippocampal serotonin concentrations. Time spent immobile in the forced swim test was also increased, with a significant effect in the FRL and a strong trend in the FSL rats. MSEW reversed these behaviours in both strains and increased social interaction with a male counterpart in the FSL rats, without influencing hippocampal or cortical serotonin or norepinephrine. Taken together, these results suggest that pregnancy influences postpartum behaviour, in a strain-dependent manner. Contrary to what we expected, MSEW overall decreased depressive- and anxiety-like behaviours, with strain specific differences, indicating that a chronic, predictable stressor may not necessarily adversely affect postpartum behaviour.

Long-term effects of pre-pubertal fluoxetine on behaviour and monoaminergic stress response in stress-sensitive rats.

OBJECTIVE: Although prescription rates of antidepressants for children and adolescents have increased, concerns have been raised regarding effects on neurodevelopment and long-term outcome. Using a genetic animal model of depression, this study investigated the long-term effects of pre-pubertal administration of fluoxetine (FLX) on depressive-like behaviour in early adulthood, as well as on central monoaminergic response to an acute stressor. We postulated that pre-pubertal FLX will have lasting effects on animal behaviour and monoaminergic stress responses in early adulthood. METHODS: Flinders sensitive line (FSL) rats received 10 mg/kg/day FLX subcutaneously from postnatal day 21 (PnD21) to PnD34 (pre-pubertal). Thereafter, following normal housing, rats were either subjected to locomotor testing and the forced swim test (FST) on PnD60 (early adulthood), or underwent surgery for microdialysis, followed on PnD60 by exposure to acute swim stress and measurement of stressor-induced changes in plasma corticosterone and pre-frontal cortical monoamine concentrations. RESULTS: Pre-pubertal FLX did not induce a late emergent effect on immobility in FSL rats on PnD60, whereas locomotor activity was significantly decreased. Acute swim stress on PnD60 significantly increased plasma corticosterone levels, and increased pre-frontal cortical norepinephrine (NE) and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations. Pre-pubertal FLX significantly blunted the pre-frontal cortical NE and 5-HIAA response following swim stress on PnD60. Baseline dopamine levels were significantly enhanced by pre-pubertal FLX, but no further changes were induced by swim stress. CONCLUSION: Pre-pubertal FLX did not have lasting antidepressant-like behavioural effects in genetically susceptible, stress-sensitive FSL rats. However, such treatment reduced locomotor activity, abrogated noradrenergic and serotonergic stressor responses and elevated dopaminergic baseline levels in adulthood.

Reappraisal of spontaneous stereotypy in the deer mouse as an animal model of obsessive-compulsive disorder (OCD): response to escitalopram treatment and basal serotonin transporter (SERT) density.

Obsessive-compulsive disorder (OCD) is characterized by recurrent thoughts and repetitive motor actions. Hyposerotonergic signalling in the cortico-striatal circuitry is believed to be central to the pathology of OCD, while many patients only respond to chronic treatment with high dose selective serotonin (5HT) reuptake inhibitors (SSRIs). Confined deer mice spontaneously develop two forms of stereotypy, namely vertical jumping and pattern running. The purpose of this investigation was to reappraise these behaviours and strengthen the validity of deer mouse stereotypy as an animal model of OCD within a framework of three study questions: (1) can the time spent executing stereotypical behaviours be employed as a measure of extent of stereotypy, (2) does deer mouse stereotypy only respond to chronic, but not sub-chronic treatment with a high-dose SSRI, and (3) is deer mouse stereotypy associated with altered cortico-striatal 5HT transporter (SERT) binding? The current study demonstrates that treatment naïve high stereotypical (HS) deer mice spend significantly more time executing stereotypical behaviours while significantly less time is spent indulging in stereotypy following chronic, but not sub-chronic, treatment with escitalopram. Furthermore, HS deer mice present with a significant decrease in striatal SERT density compared to non-stereotypical (NS) controls. Building on previous validation studies, we conclude that deer mouse stereotypy is a valid naturalistic animal model of OCD with robust face, construct and predictive validity.

ß-Catenin, Cox-2 and p53 immunostaining in colorectal adenomas to predict recurrence after endoscopic polypectomy.

BACKGROUND: Endoscopic polypectomy significantly reduces the incidence of colorectal cancer, but recurrence rates are high, especially for adenomas with advanced histology. The present guidelines recommend re-colonoscopy 3 to 5 years later. Due to limited resources, more precise predictions of adenoma recurrence are required. DESIGN: Lesions from 109 patients with colorectal adenomas recruited into a randomized, placebo-controlled chemoprevention trial with mesalazine were included. Formalin-fixed paraffin-embedded tissue sections were stained for ß-catenin, cyclooxygenase-2 (Cox-2), and p53 and scored. Adenoma recurrence rates were recorded after 3 years and associated with clinical and immunohistochemical parameters by contingency table analysis. RESULTS: After 3 years, adenomas recurred in 51.4% of patients. Out of 109 adenomas, 95 met at least one criterion of advanced adenoma (size >1 cm, villous histology, high-grade intraepithelial neoplasia). There was no influence of age, sex, size or villous histology on adenoma reappearance, whilst the number of adenomas at baseline was positively associated with recurrence (p = 0.003). In contrast, ß-catenin nuclear localisation, Cox-2 expression and p53 nuclear expression were significantly associated with adenoma recurrence after 3 years (ß-catenin: p = 0.002; Cox-2: p = 0.001; p53: p = 0.001). Combining these three markers led to a negative predictive value of 88.5% and a sensitivity of 94.6%. (OR = 13.54) CONCLUSIONS: Scoring each single parameter and, more strongly, the combination of all three parameters of the expression of ß-catenin, Cox-2 and p53 in colorectal adenoma tissue may be a useful negative predictor for adenoma recurrence in patients with advanced colorectal adenomas.

Managing asthma in primary care through imperative outcomes.

RATIONALE, AIMS AND OBJECTIVES: To evaluate asthma management and control in primary care clinics so as to design improvements based on guideline-directed outcomes. METHODS: In this study, all medical records of asthma-diagnosed patients (children as well as adults, entire lifespan, asthma-related visits or not) were retrospectively reviewed as a basis for assessing the level of guideline adherence and asthma control. Six primary health care clinics were visited in the Dr Kenneth Kaunda Municipal District, Potchefstroom, South Africa during May to July 2008, 2009 and 2010. RESULTS: A total of 323 asthma patient records were reviewed over the three time slots, resulting in 125, 87, and 111 patients respectively. A suboptimal clinical asthma control picture, with a mere 16% (n = 20) of females and 2% (n = 3) of males with Peak Expiratory Flow (PEF) percentages above 60%, were observed in the initial assessment. Improvement in control was observed during the following time slot, but with an end result in 2010 of no PEF percentages above 60% for males and only 9% (n = 7) for females. CONCLUSION: Over all three of the data collection periods adherence to effectively applied management of asthma guidelines proved to be below the minimum recommended clinical evaluation work-up as set out by the Expert Panel Report 3 (EPR3) of the National Asthma Education and Prevention Program (NAEPP). Applying a greater focus on essential outcomes through different disease management documents resulted in an improved quality of managed care, but still requires dedicated and continuous education and motivation. (NWU-0052-08-A5).

Chronic treatment with the phosphodiesterase type 5 inhibitors sildenafil and tadalafil display anxiolytic effects in Flinders Sensitive Line rats.

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolytic-like behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood-brain barrier to elicit central effects.

The influence of 5-aminosalicylic acid on the progression of colorectal adenomas via the ß-catenin signaling pathway.

Surveillance colonoscopy is an important strategy for prevention of colorectal cancer. 5-aminosalicylate (ASA) (mesalazine) is discussed as a chemopreventive agent as it reduces the cancer risk in ulcerative colitis patients. The current study analyses the effect of 5-ASA on Wnt/ß-catenin signaling in vitro and in vivo in colon epithelial cells. The effect of 5-ASA was determined using a ß-catenin/T-cell factor (TCF)-reporter assay and by western blotting in cultured colon cancer cells. Formalin fixed paraffin embedded material from 227 polyps removed from a subgroup of 56 patients, who participated in a randomized placebo-controlled 3-year prevention trial with 5-ASA was evaluated according to histomorphological characteristics and expression of ß-catenin and target genes Cox2, cyclin D1 and E-cadherin as well as ornithine decarboxylase (ODC). Patients were grouped into a low-risk and a high-risk group according to the number of adenomas at initial colonoscopy. ß-catenin/TCF signaling activity was significantly reduced by 5-ASA treatment possibly through a reduction in ß-catenin levels. Moreover, 5-ASA significantly reduced ß-catenin levels and nuclear localization in patients' adenomas. In addition, 5-ASA also significantly changed expression of the downstream targets Cox2, cyclin D1 and E-cadherin, correlating with ß-catenin status. Moreover, 5-ASA significantly reduced levels of ODC in vivo. Expression of p53 was unaltered by the 5-ASA treatment. Our study shows a significant in vitro and long-term in vivo effect of 5-ASA on ß-catenin signaling as a key signaling pathway in the development of colorectal adenoma. Therefore, we suggest the use of 5-ASA as a promising drug for prevention of sporadic colorectal carcinoma.

Severe hypoalbuminemia at day 90 predicts worse nonrelapse mortality and overall survival after allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome.

Because patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) remain in the vicinity of the transplant center for approximately 90 days posttransplantation, identifying prognostic factors to determine those at immediate higher risk of mortality is essential. A normal serum albumin level generally denotes healthiness. We evaluated the prognostic significance of day 90 hypoalbuminemia (and other clinical, pharmacologic, and laboratory variables) in 163 patients, median age 48 years (range, 19-69 years), who underwent allo-HCT for acute myelogenous leukemia (n = 124) or myelodysplastic syndrome (n = 39). Day 90 hypoalbuminemia (serum albumin <3.0 g/dL) was associated with worse nonrelapse mortality (NRM) and poor overall survival (OS). The estimated 1- and 2-year cumulative incidence rates of NRM were 48% and 52%, respectively, and the corresponding OS rates were 7% and 3%. Serum albumin level <3.0 g/dL and Karnofsky score <80 at day 90 were strong independent predictors of worse NRM and OS in multivariate analysis. These results support day 90 hypoalbuminemia as an adverse prognostic marker for NRM and OS after allo-HCT for acute myelogenous leukemia and myelodysplastic syndrome.

Antidepressant-like properties of phosphodiesterase type 5 inhibitors and cholinergic dependency in a genetic rat model of depression.

We explored the antidepressant-like properties of two phosphodiesterase type 5 (PDE5) inhibitors in a genetic animal model of depression, namely Flinders sensitive line rats. We investigated the dose-dependency of the antidepressant-like action of sildenafil, and its interaction with the cholinergic system and behavioural correlates of monoaminergic neurotransmission, in the forced swim test. Antidepressant-like properties of tadalafil (a structurally distinct PDE5 inhibitor) were also evaluated. Flinders sensitive line rats were treated for 14 days with vehicle, fluoxetine, atropine or PDE5 inhibitors+/-atropine. Immobility, swimming and climbing behaviours were assessed in the forced swim test. In combination with atropine (1 mg/kg), both sildenafil (10, 20 mg/kg) and tadalafil (10 mg/kg) decreased immobility while increasing swimming (serotonergic) and climbing (noradrenergic) behaviours. Interestingly, sildenafil (3 mg/kg) decreased immobility while selectively increasing climbing behaviour in the absence of atropine. These results suggest that the antidepressant-like activity of PDE5 inhibitors involve alterations in monoaminergic neurotransmission, but involve a dependence on inherent cholinergic tone so that the final response is determined by the relative extent of activation of these systems. Furthermore, the behavioural profile of sildenafil alone, and its observed antidepressant-like properties, shows strict dose-dependency, with only higher doses showing an interaction with the cholinergic system.

The ampakine, Org 26576, bolsters early spatial reference learning and retrieval in the Morris water maze: a subchronic, dose-ranging study in rats.

Ampakines have shown beneficial effects on cognition in selected animal models of learning. However, their ability to modify long-term spatial memory tasks has not been studied yet. This would lend credence to their possible value in treating disorders of cognition. We evaluated the actions of subchronic Org 26576 administration on spatial reference memory performance in the 5-day Morris water maze task in male Sprague-Dawley rats, at doses of 1, 3 and 10 mg/kg twice daily through intraperitoneal injection over 12 days. Org 26576 exerted a dose and time-dependent effect on spatial learning, with dosages of 3 and 10 mg/kg significantly enhancing acquisition on day 1. Globally, escape latency decreased significantly as the training days progressed in the saline and Org 26576-treated groups, indicating that significant and equal learning had taken place over the learning period. However, at the end of the learning period, all doses of Org 26576 significantly improved spatial memory storage/retrieval without confounding effects in the cued version of the task. Org 26576 offers early phase spatial memory benefits in rats, but particularly enhances search accuracy during reference memory retrieval. These results support its possible utility in treating disorders characterized by deficits in cognitive performance.

Stress and re-stress increases conditioned taste aversion learning in rats: possible frontal cortical and hippocampal muscarinic receptor involvement.

Symptoms of posttraumatic stress disorder are often precipitated by sensory cues in the form of visual, auditory, olfactory and gustatory "flashbacks" resulting in enhanced fear-memory consolidation and the characteristic symptoms of re-experiencing, avoidance and hyper-arousal. Single prolonged stress with and without re-stress have been used to explore the neurobiology of this disorder, particularly with respect to contextual conditioning and spatial memory impairment. However, less work has been done regarding associative sensory-related memories linked to aversive events. Although growing evidence supports a role for cholinergic pathways in stress, this has not been studied in the above animal models. We studied the effects of single prolonged stress with and without re-stress on conditioned taste aversion learning in rats, together with differential analysis of frontal cortical and hippocampal [3H]-quinuclidinyl benzylate ([3H]-QNB) muscarinic receptor binding. Single prolonged stress with and without re-stress both enhanced associative sensory aversion learning 7 days after stressor-taste pairing, although re-stress did not strengthen this response. Increased cortical and hippocampal muscarinic receptor density (Bmax) was found 7 days after single prolonged stress with re-stress, although receptor affinity remained unaltered. Frontal cortical and hippocampal muscarinic receptor changes may thus underlie conditioned taste aversion learning in rats exposed to stress and re-stress. These data suggest that it may be useful to study the role of cholinergic pathways in mediating associative memory in psychiatric disorders such as posttraumatic stress disorder.

Psychopharmacology of maternal separation anxiety in vervet monkeys.

Maternal separation in non-human primates has been proposed as a model of early adversity. The symptoms of separation anxiety were studied in vervet monkeys, during the weaning period, when psychotropic medications were administered. The control group received a normal diet and treatment groups received citalopram, reboxetine or lamotrigine in their food daily. Treatment was given for 7 weeks starting 1 month prior to weaning. Behavior was recorded twice weekly for 8 weeks, and was rated for anxiety and depression. Cerebrospinal fluid was collected at the beginning and end of the trial and analyzed for monoamines and metabolites using High Performance Liquid Chromatography. Citalopram pretreatment prevented the reduction of affiliation behavior and reduced stereotypies after weaning, and both citalopram and reboxetine abolished the increase in activity seen in control monkeys after weaning, but no statistically significant differences were found between groups. Citalopram pretreatment also significantly increased noradrenaline and 5-hydroxyindolacetic acid (5-HIAA) levels and reboxetine significantly decreased dopamine levels over time. The 5-HIAA levels of reboxetine and lamotrigine treated monkeys were significantly lower than that of the control group at the end of the trial. Although limited by a small sample size, this study demonstrates the possibility of investigating the psychopharmacology of early adversity in a non-human primate model.

Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is characterized by monoaminergic and hypothalamic-pituitary-adrenal (HPA)-axis abnormalities. Understanding monoamine-HPA-axis responses following stress and restress may provide a greater understanding of the neurobiology of PTSD and of its treatment. Hippocampal and frontal cortex serotonin, noradrenaline and dopamine, plasma corticosterone and aversive behavior were studied in rats on day 1 and day 7 post acute stress (AS = sequential restraint stress, swim stress and halothane exposure), and on day 1 and day 7 post restress (RS = swim stress). After AS, there was an early increase in both avoidant behavior and corticosterone (1 h after stress), with subsequent normalisation (day 7), suggesting an adequate adaptive response to the stressor. However, restress (RS) evoked a significant early HPA-axis hyporesponsiveness (1 h after RS) and a later significant increase in avoidant behavior on day 7 post RS. Hippocampal serotonin, noradrenaline and dopamine concentrations were unchanged 1 h post AS, but were significantly raised on day 7 post AS. Restress, however, reduced serotonin and noradrenaline levels 1 h after and on day 7 post RS, respectively, while dopamine was unchanged. In the frontal cortex only dopamine levels were altered, being significantly elevated 1 h after AS, and reduced on day 7 post RS. AS and RS thus differently effect the HPA-axis, evoking regional-specific brain monoamine changes that underlie maladaptive behavior and other post stress-related sequelae.

Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression.

Tianeptine, an atypical antidepressant patented and developed by Servier, enhances the synaptic reuptake of serotonin, without affecting norepinephrine and dopamine uptake, while it lacks affinity for neurotransmitter receptors. This mechanism for an antidepressant is apparently paradoxical, since the currently employed antidepressants enhance serotonin by inhibiting its breakdown or by inhibiting monoaminergic reuptake. Although tianeptine has been shown to reduce central 5HT availability and to indirecty modulate central adrenergic and dopaminergic systems and to indirectly inhibit cholinergic hyperactivity, its antidepressant action is believed to be more directly related to central neuronal remodeling and restoration of neuronal plasticity. In reliable animal models of depression tianeptine has been shown to prevent neurodegeneration and decreases in hippocampal volume in response to chronic stress. These effects on neuroplasticity are suspected to involve the normalization of the hypothalamic-pituitary-adrenal axis and modulatory effects on excitatory amino acids and N-methyl-D-aspartate receptors. Together with a body of related studies, these data provide further support for the hypothesis that depression may involve dysregulation of pathways controlling cellular resilience and that treatment should be directed towards the reversal thereof. Importantly, tianeptine is not anxiogenic and has also been shown to be effective in treatment-resistant depression, which may lead the way to a major breakthrough in the treatment of depression.

Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus.

RATIONALE: Stress-related glucocorticoid and glutamate release have been implicated in hippocampal atrophy evident in patients with post-traumatic stress disorder (PTSD). Glutamatergic mechanisms activate nitric oxide synthase (NOS), while gamma-amino-butyric acid (GABA) may inhibit both glutamatergic and nitrergic transmission. Animal studies support a role for NOS in stress. OBJECTIVES: We have studied the role of NOS and glucocorticoids, as well as inhibitory and excitatory transmitters, in a putative animal model of PTSD that emphasizes repeated trauma. METHODS: Hippocampal NOS activity, N-methyl-D-aspartate (NMDA) receptor binding characteristics and GABA levels were studied in Sprague-Dawley rats 21 days after exposure to a stress-restress paradigm, using radiometric analysis, radioligand studies and high-performance liquid chromatography (HPLC) analysis with electrochemical detection, respectively. The NOS isoform involved, and the role of stress-mediated corticosterone release in NOS activation, was verified with the administration of selective iNOS and nNOS inhibitors, aminoguanidine (50 mg/kg/day i.p.) and 7-nitroindazole (12.5 mg/kg/day i.p.), and the steroid synthesis inhibitor, ketoconazole (24 mg/kg/day i.p.), administered for 21 days prior to and during the stress procedure. RESULTS: Stress evoked a sustained increase in NOS activity, but reduced NMDA receptor density and total GABA levels. Aminoguanidine or ketoconazole, but not 7-nitroindazole or saline, blocked stress-induced NOS activation. CONCLUSIONS: Stress-restress-mediated glucocorticoid release activates iNOS, followed by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. The role of NO in neuronal toxicity, and its regulation by glutamate and GABA has important implications in stress-related hippocampal degeneration.

Serotonin and stress: protective or malevolent actions in the biobehavioral response to repeated trauma?

Structural hippocampus and prefrontal cortex changes occur in patients with posttraumatic stress disorder (PTSD) that appears correlated with cognitive dysfunction. In these brain regions, serotonin (5HT) plays a prominent role in symptom presentation and treatment of PTSD. However, 5HT is both anxiogenic and anxiolytic, and while 5HT reuptake inhibitors are effective in treatment, the role of 5HT in the development of PTSD remains uncertain. Using a model of repeated trauma in rats, we observed significant spatial memory impairment together with significantly increased 5HT(1A) receptor density (B(max)), decreased 5HT(1A) receptor affinity (K(d)), and significantly increased 5HT(2A) receptor affinity on day 7 poststress. The serotonergic agent fluoxetine (FLX; 10 mg/kg/d ip) administered 1 week before stress and continuing throughout the stress procedure, but not the 5HT depleter p-chloro-phenylalanine (PCPA; 300/100/50 mg/kg/d ip), prevented stress-induced cognitive dysfunction. PCPA, however, reversed stress-induced hippocampal 5HT(1A) receptor affinity changes, with FLX narrowly missing significance. Neither drug reversed stress effects on 5HT(2A) receptor affinity. Thus, 5HT plays an important part in the cognitive-behavioral changes evoked by repeated trauma. That raised 5HT activity may mediate hippocampal 5HT(1A) receptor changes evoked by stress suggests a bidirectional role for 5HT in the development of PTSD.

Endocrine, cognitive and hippocampal/cortical 5HT 1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats.

Post traumatic stress disorder (PTSD) is characterised by hyperarousal, anxiety and amnesic symptoms. Deficits in explicit memory recall have been causally related to volume reductions of the hippocampus and prefrontal cortex. While stress-related glucocorticoid secretion appears involved in this apparent atrophy, there is also evidence for low plasma cortisol in PTSD. Prior exposure to trauma is an important risk factor for PTSD, suggesting a role for sensitisation. Using Sprague-Dawley rats, we studied the effects of a time-dependent sensitisation (TDS) model of stress on spatial memory deficits, 1 week post-stress, using the Morris water maze. Basal and 7-day post-stress plasma corticosterone levels were also determined. Due to the putative role of serotonin in anxiety and stress, and in the treatment of PTSD, hippocampal 5HT(1A) and prefrontal cortex 5HT(2A) radioligand binding studies were performed. TDS stress evoked a marked deficit in spatial memory on day 7 post TDS stress, coupled with significantly depressed plasma corticosterone levels. Cognitive and endocrine changes at day 7 post stress were associated with a significant increase in receptor density (B(max)) and a significant decrease in receptor affinity (K(d)) for hippocampal 5HT(1A) receptors. The B(max) of prefrontal cortex 5HT(2A) receptors were unaffected, but K(d) was significantly increased. We conclude that TDS stress evokes cognitive and endocrine changes characteristic of PTSD. Moreover, TDS stress induces diverse adaptive 5HT receptor changes in critical brain areas involved in emotion and memory that may underlie the effect of stress on cognitive function.

NMDA receptor involvement in imipramine withdrawal-associated effects on swim stress, GABA levels and NMDA receptor binding in rat hippocampus.

Abrupt antidepressant withdrawal after chronic treatment is associated with a stress response that may negatively affect the long-term outcome of depression, the neurochemical correlates, of which, remain undetermined. Prolonged depression involves the stress-related release of glucocorticoids and glutamate, while response to antidepressants involves gamma-amino butyric acid (GABA) and the glutamate N-methyl-D-aspartate (NMDA) receptor. Here, imipramine (IMI) was administered to rats for three weeks followed by acute withdrawal for seven days. Levels of GABA in the hippocampus (HC), and effects on swim stress immobility (SSI), were determined. Furthermore, glutamate/NMDA receptor binding properties were determined using [(3)H]-CGP-39653. Finally, the ability of dizocilpine (MK801), a glutamate NMDA antagonist, to reverse IMI withdrawal was determined. Chronic IMI (15 mg/kg ip) significantly reduced SSI together with a slight but insignificant decrease in HC GABA levels. However, IMI significantly reduced specific binding (B(max)) of [(3)H]-CGP-39653. Withdrawal of IMI for 7 days resulted in a loss of efficacy on SSI, a slight increase in GABA and a significant reversal of IMI effects on [(3)H]-CGP-39653 binding. MK801 (0.2 mg/kg ip) alone for seven days caused a significant decrease in SSI, a significant suppression of HC GABA, and significantly decreased [(3)H]-CGP-39653 B(max). MK801 during IMI-withdrawal significantly decreased GABA, prompted recovery on SSI, though not significantly, but significantly reversed withdrawal effects on [(3)H]-CGP-39653 B(max). In conclusion, acute antidepressant discontinuation is associated with subtle changes on HC GABA, a resurgence of NMDA receptor density and a loss of its anti-immobility response. These responses are reversed by a NMDA antagonist suggesting that abrupt antidepressant discontinuation mobilises glutamate activity.