Academic literature on the topic 'PTSD animal model'

Introduction: Posttraumatic stress disorder (PTSD) represents a mental disorder that occurs after life threatening situations. Animal models in psychiatry studies represent a base from which results and conclusions can be translated to human population. Amygdala and hippocampus are important neuroanatomical substrates possibly relevant to PTSD pathogenesis. Aim: The aim of study was to investigate volumetric changes that occur in hippocampus and amygdala related to PTSD animal model. Material and methods: Experiment was conducted on adult male Wistar rats. They were two groups, experimental and control. Experimental paradigm lasted for 31 days during which animals were exposed to acute and chronic stress. Acute stress was performed on the first day and ten days later. In between, animals were exposed to chronic social stress by pair rotations. Before second acute stress exposure, experimental group was divided in two subgroups from which one received dexamethasone dose. After the experiment ended, animals were sacrificed and the brain was extracted. Following the freezing process, brain tissue samples were cut and prepared for microscopy using. This was followed by volumetric analysis of hippocampus and amygdala. Measurements were performed bilaterally using Image Tool 3.0 Software. Results: Results showed volumetric changes in these structures. Hippocampus had smaller volume in the experimental subgroup without dexamethasone (x̄ = 0.6144) compared to the control group (x̄ = 0.9688). Amygdala, as well, had smaller volumes in same subgroup compared to the control (x̄ = 10.0156 compared to x̄ = 11.5041). Conclusion: Our study provided results in agreement with several previous studies on rodents and contributes to the assumption that hippocampus and amygdala have significance in PTSD etiology. Further goal is to expand our study which will help us to better understand the disorder itself.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalent neuropsychiatric disorders and frequently co-occur concomitantly. Individuals suffering from this dual diagnosis often exhibit increased symptom severity and poorer treatment outcomes than those with only one of these diseases. Lacking standard preclinical models limited the exploration of neurobiological mechanisms underlying PTSD and AUD comorbidity. In this review, we summarize well-accepted preclinical model paradigms and criteria for developing successful models of comorbidity. We also outline how PTSD and AUD affect each other bidirectionally in the nervous nuclei have been heatedly discussed recently. We hope to provide potential recommendations for future research.

Epidemiological studies report higher prevalence rates of stress-related disorders such as acute stress disorder and post-traumatic stress disorder (PTSD) in women than in men following exposure to trauma. It is still not clear whether this greater prevalence in woman reflects a greater vulnerability to stress-related psychopathology. A number of individual and trauma-related characteristics have been hypothesized to contribute to these gender differences in physiological and psychological responses to trauma, differences in appraisal, interpretation or experience of threat, coping style or social support. In this context, the use of an animal model for PTSD to analyze some of these gender-related differences may be of particular utility. Animal models of PTSD offer the opportunity to distinguish between biological and socio-cultural factors, which so often enter the discussion about gender differences in PTSD prevalence.In this review, we present and discuss sex-differences in behavioral, neurochemical, neurobiological and pharmacological findings that we have collected from several different animal studies related to both basal conditions and stress responses. These models have used different paradigms and have elicited a range of behavioral and physiological manifestations associated with gender. The overall data presented demonstrate that male animals are significantly more vulnerable to acute and chronic stress, whereas females are far more resilient. The stark contradiction between these findings and contemporary epidemiological data regarding human subjects is worthy of further study. The examination of these gender-related differences can deepen our understanding of the risk or the pathophysiology of stress-related disorders.

Aim: To further examine the neurobiological mechanisms and their outcomes responsible for the PTSD sequelae induced by laboratory animal model and to explore the effects of chronic psychosocial paradigm. We tested the hypothesis that our animal model of PTSD would display abnormalities in glucocorticoid levels that are manifest in people with PTSD and that psychosocially stressed rats exhibit a significantly greater suppression of corticosterone levels than control rats following the administration of dexamethasone.Methods: Animals were divided into two groups. The experimental group was scheduled to exposure to two types of stressors: double exposure to acute immobilization stress, and combined predator-threat stress and daily social stress. There was also administration of dexamethasone in combination with stress exposure.Results: There was a statistical difference between masses of thymus in the stress group and stress group with dexamethasone appliance (p=0.024). We found statistical significance between baseline cortisol and stress induced levels of cortisol and between stress induced group and return to baseline group.Conclusion: Significant changes in HPA activity, reductions in basal glucocorticoid levels and enhanced dexamethasone induced inhibition of glucocorticoid levels have been manifested. All of this is manifested in PTSD patients also as many other stress induces changes.

ObjectiveCo-morbid depression with post-traumatic stress disorder (PTSD) is often treatment resistant. In developing a preclinical model of treatment-resistant depression (TRD), we combined animal models of depression and PTSD to produce an animal with more severe as well as treatment-resistant depressive-like behaviours.MethodsMale Flinders sensitive line (FSL) rats, a genetic animal model of depression, were exposed to a stress re-stress model of PTSD [time-dependent sensitisation (TDS)] and compared with stress-naive controls. Seven days after TDS stress, depressive-like and coping behaviours as well as hippocampal and cortical noradrenaline (NA) and 5-hydroxyindoleacetic acid (5HIAA) levels were analysed. Response to sub-chronic imipramine treatment (IMI; 10 mg/kg s.c.×7 days) was subsequently studied.ResultsFSL rats demonstrated bio-behavioural characteristics of depression. Exposure to TDS stress in FSL rats correlated negatively with weight gain, while demonstrating reduced swimming behaviour and increased immobility versus unstressed FSL rats. IMI significantly reversed depressive-like (immobility) behaviour and enhanced active coping behaviour (swimming and climbing) in FSL rats. The latter was significantly attenuated in FSL rats exposed to TDS versus unstressed FSL rats. IMI reversed reduced 5HIAA levels in unstressed FSL rats, whereas exposure to TDS negated this effect. Lowered NA levels in FSL rats were sustained after TDS with IMI significantly reversing this in the hippocampus.ConclusionCombining a gene-X-environment model of depression with a PTSD paradigm produces exaggerated depressive-like symptoms that display an attenuated response to antidepressant treatment. This work confirms combining FSL rats with TDS exposure as a putative animal model of TRD.

Thesis (PhD)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Posttraumatic stress disorder (PTSD) is a severe, chronic and debilitating psychiatric disorder that can present after the experience of a life-threatening traumatic event. D-cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist, has been found to augment cognitive behavioural therapy by facilitating fear extinction; however, the precise mechanisms whereby DCS ameliorates fear triggered by a traumatic context remains to be fully elucidated. This study aimed to (i) identify the molecular mechanisms of intrahippocampally administered DCS in facilitating fear extinction in a rat model of PTSD by investigating gene expression profiles in the left dorsal hippocampus (LDH) of male Sprague Dawley rats and (ii) determine whether microRNA (miRNA) expression and DNA methylation mediated these gene expression changes. An adapted version of the PTSD animal model described by Siegmund and Wotjak (2007) was utilised. The total number of 120 rats were grouped into four experimental groups (of 30 rats per group) based on fear conditioning and the intrahippocampal administration of either DCS or saline: (1) fear conditioned + intrahippocampal saline administration (FS), (2) fear conditioned + intrahippocampal DCS administration (FD), (3) control + intrahippocampal saline administration (CS) and (4) control + intrahippocampal DCS administration (CD). Behavioural tests (the light/dark [L/D] avoidance test, forced swim test and open field test) were conducted to assess anxiety and PTSD-like behaviours. The L/D avoidance test was the most sensitive behavioural test of anxiety and was subsequently used to differentiate maladapted (animals that displayed anxiety-like behaviour) and well-adapted (animals that did not display anxiety-like behaviour) subgroups. In order to identify genes that were differentially expressed between FS maladapted (FSM) (n = 6) vs. FD well-adapted (FDW) (n = 6) groups, RNA sequencing was performed on the Illumina HiSeq 2000 which generated more than 60 million reads per sample. This was followed by subsequent bioinformatics analyses (using the software programs TopHat, Bowtie, Cuffdiff and Bio-Ontological Relationship Graph (BORG) database (that identifies genes that may be biologically relevant) to identify biologically relevant differentially expressed genes between the treatment groups. Epigenetic mechanisms mediating observed differences in gene expression were investigated by conducting DNA methylation and miRNAseq analyses in the FDW and FSM experimental groups. DNA methylation was investigated using real-time quantitative PCR (qPCR) amplification followed by high resolution melt analysis on the Rotor-GeneTM 6000. Differences in miRNA expression levels between the FDW and FSM groups were investigated by sequencing the miRNA fraction on the MiSeq platform. The bioinformatics pipeline used to analyse the RNAseq data identified 93 genes that were significantly downregulated in the FDW group compared to the FSM group. Forty-two of these genes were predicted to be biologically relevant (based on BORG analysis). Integrative network analyses revealed subsets of differentially expressed genes common across biological functions, pathways and disorders. The co-administration of DCS and behavioural fear extinction downregulated immune system genes and genes that transcribe proinflammatory and oxidative stress molecules. These molecules mediate neuroinflammation and subsequently cause neuronal damage. DCS also regulated genes involved in learning and memory processes. Additionally, a subset of the genes, which have been found to be associated with disorders that commonly co-occur with PTSD (such as cardiovascular disease, metabolic disease, Alzheimer‘s and Parkinson‘s disease), was downregulated by the co-administration of DCS and behavioural fear extinction. In order to determine whether real-time qPCR analysis would be sensitive enough to detect differential expression in those genes found to be differentially expressed in RNAseq analysis, the expression of nine genes was analysed using SYBR Green qPCR technology. In the LDH, six of the nine genes were found to be differentially expressed between FDW and FSM groups and one gene, matrix metallopeptidase 9 (MMP9), was observed to be differentially expressed between these two groups in the blood. Three of the nine genes for which differential expression levels were investigated using SYBR Green real-time qPCR, contained CpG islands and were used for CpG island DNA methylation analysis. Results indicated that CpG island DNA methylation did not mediate differential gene expression of TRH, NPY or MT2A. Bioinformatics analysis of miRNAseq data identified 23 miRNAs that were differentially expressed between the FDW and FSM groups. Several of these miRNAs have previously been found to be involved in brain development and behavioural measures of anxiety. Furthermore, functional luciferase analysis indicated that the upregulation of rno-mi31a-5p could have facilitated the downregulation of interleukin 1 receptor antagonist gene (IL1RN) as detected in RNAseq. RNAseq and miRNAseq analyses in this PTSD animal model identified differentially expressed genes and miRNAs that serve to broaden our understanding of the mechanism whereby DCS facilitates fear extinction. To this end, immune system genes and genes transcribing proinflammatory and oxidative stress molecules were among the genes that were found to be differentially expressed between the FDW and FSM groups. Based on the results obtained, it can be hypothesised that DCS attenuates neuroinflammation and subsequent neuronal damage, and also regulates genes involved in learning and memory processes. Concomitantly, these gene expression alterations mediate optimal neuronal functioning, plasticity, learning and memory (such as fear extinction memory) which contribute to the fear extinction process. Furthermore, biologically relevant differentially expressed genes that were associated with DCS facilitation of fear extinction and with other chronic medical conditions, such as cardiovascular disease and metabolic diseases, might help to explain the co-occurrence of these disorders with PTSD. In conclusion, Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction and could, in future work be used to explore novel therapeutic targets to effectively treat PTSD and related disorders.
AFRIKAANSE OPSOMMING: Posttraumatiese stressindroom is 'n ernstige, kroniese aftakelende psigiatriese toestand wat kan ontwikkel na 'n lewensgevaarlike traumatiese gebeurtenis. Daar is bevind dat die gesamentlike toediening van D-sikloserien (DCS), 'n N-metiel-D-aspartaat (NMDA) reseptor agonis, en kognitiewe gedragsterapie effektief is in die bemiddeling van vrees uitwissing; maar die presiese meganisme waar deur DCS die vrees wat deur 'n traumatiese konteks ontlok word verminder, is egter onduidelik. Hierdie studie het beoog om (i) die molekulêre meganismes te identifiseer waardeur intra-hippokampaal toegediende DCS vrees uitwissing fasiliteer, in 'n rot model van posttraumatiese stressindroom, deur geen uitdrukkingsprofiele in the linker dorsale hippokampus (LDH) van manlike Sprague Dawley rotte te ondersoek en (ii) om te bepaal of mikroRNA (miRNA) uitdrukking en DNA metilering die veranderinge in geen uitdrukking bemiddel het. 'n Gewysigde weergawe van die posttraumatiese stressindroom diere model, beskryf deur Siegmund en Wotjak (2007), was gebruik tydens die studie. Rotte was in vier groepe verdeel, vrees kondisionering + soutwater (FS), vrees kondisionering + DCS (FD), kontrole + soutwater (CS) en kontrole + DCS (CD). Gedragstoetse was uitgevoer om angstige, vreesvolle en posttraumatiese stressindroom-tipe gedrag te evalueer. Gedurende die lig/donker (L/D) vermydingstoets het die FS groep aansienlik meer tyd in die donker kompartement deurgebring ('n indikasie van vreesvolle gedrag) in vergelyking met die CS en die FD groepe wat meer tyd in die verligte kompartement deurgebring het ('n indikasie van vreeslose gedrag). Die L/D toets was die mees sensitiewe gedragstoets vir angstige en vreesvolle gedrag en was gevolglik gebruik om die diere te sub-groepeer in wanaangepaste (diere wat angstige en vreesvolle gedrag vertoon het) en goedaangepaste (diere wat nie angstige en vreesvolle gedrag vertoon het nie) subgroepe. Nuwe generasie RNA volgordebepaling (RNAseq) van die LDH RNA en daaropvolgende bioinformatiese analise was uitgevoer om gene te identifiseer wat differensieel uitgedruk is tussen die twee behandelingsgroepe van belang in die betrokke studie, naamlik FS wanaangepaste (FSM) teenoor FD goedaangepaste (FDW) groepe. Epigenetiese analises was uitgevoer om te bepaal of differensieel uitgedrukte miRNAs of CpG-eiland DNA metilasie die differensiële geenuitdrukking bemiddel het. Bioinformatiese analises van die RNAseq data het 93 gene geïdentifiseer waarvan die geen uitdrukking beduidend onderdruk was in die FDW groep in vergelyking met die FSM groep; 42 van hierdie gene was voorspel om biologies relevant te wees. Geïntegreerde netwerk analise het onthul dat sekere van die differensieel uitgedrukte gene gemeenskaplik was tussen verskeie biologiese funksies, padweë en versteurings. DCS het die uitdrukking van immuun-sisteem gene en pro-inflammatoriese en oksidatiewe stres gene verlaag. Hierdie molekules medieer neuro-inflammasie wat gevolglik tot neurale skade lei. DCS het ook gene gereguleer wat betrokke is by leer en geheue prosesse. DCS het onder meer ook die geenuitdrukking verlaag van 'n sub-groep van gene wat voorheen geassosier is met komorbiede versteurings van PTSD. SYBR Green real-time qPCR (werklike tyd kwantitatiewe polimerase ketting reaksie) analise was ondersoek om te bepaal of hierdie metode sensitief genoeg sou wees om die verlaagde geen-uitdrukking van verskeie van die biologies relevante differensieel uitgedrukte gene te identifiseer, in dieselfde LDH komplementêre DNA (cDNA) monsters as wat in die RNAseq gebruik is, asook in die bloed cDNA monsters. SYBR Green real-time qPCR was in staat om ses, van die nege, differensieel uitgedrukte gene in die LDH cDNA monsters en een geen, matriks metallopeptidase 9 (MMP9), in die bloed cDNA monsters op te tel. Drie van die gene waarvoor SYBR Green real-time qPCR gebruik is om differensiële geenuitdrukking te toets, het CpG eilande bevat en was gevolglik gebruik in CpG eiland DNA metilering analises. Resultate het getoon dat CpG eiland DNA metilering nie die differensiële geenuitdrukking van TRH, NPY of MT2A gedryf het nie. Bioinformatiese analises van die miRNAseq data het 23 miRNAs geïdentifiseer wat differensieël uitgedruk was tussen die FDW en FSM groepe. Verskeie van hierdie miRNAs is reeds voorheen beskryf om betrokke te wees in brein ontwikkeling en angs gedrags metings. Funksionele luciferase analises het verder aangedui dat die verhoogde uitdrukking van rno-mi31a-5p moontlik die verlaagde geen uitdrukking van IL1RN, soos waargeneem in die RNAseq data, kon bewerkstellig het. RNAseq en miRNAseq analises in hierdie posttraumatiese stressindroom dieremodel het differensieël uitgedrukte gene en miRNAs geïdentifiseer wat dien om die verstaanswyse te verbreed van hoe DCS die vrees uitwissings proses fasiliteer. Die meganismes waardeur DCS vrees uitwissings bewerkstellig het sluit die verlaging van immuun-sisteem geen-uitdrukking in, sowel as verlaagde uitdrukking van gene wat pro-inflammatoriese en oksidatiewe stress gene transkribeer. DCS het daardeur neuro-inflammasie en gevolglike neurale skade voorkom. DCS het daarmee saam ook gene gereguleer wat betrokke is by leer en geheue prosesse. Hierdie gesamentlike veranderings in geen uitdrukking het gelei tot die uiteindelike bewerkstelling van optimale neurale funksionering, plastisiteit, leer en geheue prosesse wat uiteindelik bygedra het tot vrees uitwissing. Biologies relevante differensieël uitgedrukte gene wat ook geassosieer was met ander kondisies, soos middel verwante versteurings en metaboliese versteurings, kan help om die komorbiditeit met posttraumatiese stressindroom te verklaar. Identifisering van die molekulêre grondslae van DCS bemiddelde vrees uitwissing verbreed ons begrip en verstaan van vrees uitwissing en kan moontlik, in toekomstige navorsing gebruik word om nuwe innoverende terapeutiese teikens te verken om sodoende posttraumatiese stressindroom meer effektief te kan behandel.

Pharmacology
Ph.D.
Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship remains largely unknown. Identifying mechanisms that underlie this association is necessary, and recognizing pathologies shared by these disorders may provide pertinent information in understanding their functional relationship. Separate lines of evidence suggest that PTSD and drug addiction may share a common feature, that is, dysregulation of the brain's reward circuitry. We hypothesize that PTSD results in reduced dopaminergic neurotransmission which may contribute to deficient reward function and vulnerability to drug-seeking behavior. To address this hypothesis, we combined single-prolonged stress (SPS), a rodent model of PTSD, with a series of behavioral and neuropharmacological assays to assess dopaminergic reward function and cocaine intake. The results of the studies presented herein extend our understanding of the effects of severe stress on drug reinforcement and consumption, and establish a potential mechanism by which PTSD produces deficient reward function through alterations in the dopamine system. A modified SPS procedure consisting of 2 hours of restraint, 20 minutes of group swimming, isoflurane exposure until loss consciousness, and 7 days of isolation was used to induce severe stress in our studies. Initial studies were conducted to examine the effect of SPS on cocaine-conditioned reward and anhedonia-like behavior in adult male Sprague-Dawley rats. Using a biased conditioned place preference paradigm, unstressed controls demonstrated a significant preference for the cocaine-paired context following four pairings with cocaine (5-20 mg/kg, i.p.). Preference for the cocaine-paired side was significantly lower in rats exposed to SPS, suggesting a deficit in the rewarding properties of cocaine following exposure to severe stress. Anhedonia-like behavior was assessed by a two-bottle choice sucrose preference test. Robust consumption of sucrose solution (0.25-1%) was observed in rats that underwent control handling, however, SPS significantly reduced sucrose intake compared to controls. These results suggest an increase in anhedonia-like behavior or a reduction in the rewarding effects of sucrose as a non-drug reinforcer. Finally, basal behavioral activity in SPS rats was compared to unstressed controls in a 24-hour test. Results indicate a significant reduction in spontaneous nocturnal activity following SPS versus control handling. In contrast, hyperlocomotion induced by an acute cocaine injection (5-20 mg/kg, i.p.) was unaltered between rats that underwent SPS or control handling. These data suggest that deficient behavioral activity may be specific to voluntary movements or behavior, and support an increase in anhedonia following exposure to SPS. Intravenous cocaine self-administration was conducted to examine the effect of SPS on the acquisition, motivation, and escalation of cocaine intake. Acquisition of cocaine self-administration was studied using an escalating dose regimen in which rats had sequential access to 0.1875, 0.375, and 0.75 mg/kg/infusion on a fixed-ratio 1 schedule of reinforcement. Rats exposed to SPS did not significantly differ from control handled animals in the latency to meet acquisition criteria (consumption of 6.75 mg/kg/day for 3 consecutive days) or the general pattern and level of cocaine intake at each dose. A subsequent study assessing the breakpoint for cocaine self-administration using a progressive-ratio schedule of reinforcement determined a dose-dependent increase in motivation to work for cocaine (0-1.5 mg/kg/infusion) across both experimental groups. However, motivation to obtain cocaine was similar between SPS and unstressed rats, as there was no significant difference in breakpoint for cocaine self-administration at any dose of cocaine tested. To evaluate potential differences in the transition to escalated cocaine intake, self-administration was measured using an extended-access procedure in which unlimited cocaine (0.375 mg/kg/infusion) was available for six hours daily. Upon extended-access to cocaine, SPS significantly attenuated cocaine intake compared to control handling over 14 sessions. Despite a significant reduction in cocaine intake, rats exposed to SPS still significantly escalated their cocaine intake over the course of 14 days. These results suggest that escalation of cocaine intake occurred in the presence of lower total doses of cocaine in the SPS exposed animals compared to controls. In addition, SPS rats demonstrated a greater percent increase in cocaine consumption compared to controls. This finding suggests that rats exposed to SPS compensated for a decrease in cocaine reinforcement by escalating their intake to a greater magnitude than controls. These studies indicate that SPS may not alter the acquisition of cocaine self-administration or motivation for cocaine. However, the finding of reduced cocaine intake upon extended-access in SPS rats is consistent with a deficit in cocaine-induced reward. The ability of SPS rats to escalate cocaine intake in the presence of less cocaine, or a greater magnitude of escalated cocaine intake than controls, may reflect mechanisms leading to enhanced vulnerability to cocaine abuse. To understand the mechanisms of reduced reward and behavior in the SPS model of PTSD, a series of neurochemical assays was used to assess the ability of SPS to induce dysfunction of dopaminergic neurotransmission. Using high performance liquid chromatography, tissue levels of dopamine and the dopamine metabolites DOPAC and HVA were measured immediately and one week following SPS or control handling. Tissue obtained from SPS rats demonstrated significant decreases in dopamine, DOPAC, and HVA content in both the nucleus accumbens and caudate putamen immediately following SPS and one week later, suggesting a potential deficit in dopaminergic tone. Quantitative autoradiography was used measure the density of dopamine transporters and dopamine D1 and D2 receptors. [3H]WIN35428 binding to dopamine transporters was higher in the nucleus accumbens of SPS rats compared to controls, suggesting an increase in dopamine transporter density following severe stress. The level of [3H]WIN35428 binding in the caudate putamen was not different between groups. [3H]Raclopride binding to D2 receptors was significantly reduced in both the nucleus accumbens and caudate putamen following SPS versus control handling. These results suggest a decrease in the density of striatal D2 receptors. D1 receptor expression was not significantly altered by SPS, as no significant difference in [3H]SCH23390 binding was detected in SPS rats compared to controls. A preliminary functional assessment of dopamine transporters revealed a significant increase in dopamine uptake in the nucleus accumbens of SPS rats compared to controls, whereas uptake in the caudate putamen was unaltered between groups. Enhanced dopamine uptake following SPS is consistent with the increase in dopamine transporter density observed in the nucleus accumbens of SPS rats. Activation of D1 receptors and G-protein mediated transduction was assessed using an adenylyl cyclase assay with the D1 agonist SKF82958. In the caudate putamen, a significant decrease in D1 receptor-stimulated cAMP production was revealed in SPS rats compared to controls, whereas SKF82958-induced cAMP was unchanged in the nucleus accumbens. Finally, the function of D2 dopamine receptors was assessed by D2 receptor-stimulated [35S]GTPγS binding using quinpirole. In the caudate putamen, [35S]GTPγS binding following stimulation of D2 receptors was enhanced by SPS compared to control handling, whereas no difference was observed between groups in the nucleus accumbens. These results indicate increased D2 receptor-mediated activation of G-proteins in the caudate putamen following SPS. In summary, the studies described herein tested the hypothesis that reduced dopaminergic function may be a mechanism for deficient reward and heightened susceptibility to drug use in PTSD. Results demonstrated a significant reduction in cocaine-conditioned reward, as well as attenuated sucrose preference and spontaneous activity in rats exposed to SPS. These findings are consistent with the presence of a dysfunctional reward system which may contribute to anhedonia-like behavior in PTSD. Furthermore, reward deficits may promote altered patterns of cocaine taking behavior and vulnerability to substance abuse. Results demonstrated significant escalation of drug intake following exposure to SPS, which occurred in the presence of less cocaine than controls. A greater increase in cocaine intake was observed in SPS rats over the course of escalation, which may reflect a mechanism for enhanced vulnerability to the development of a substance use disorder in PTSD. Dopaminergic dysfunction may contribute to deficient reward capacity and an altered pattern of cocaine intake in SPS. SPS-induced alterations in dopamine function included a reduction in striatal dopamine content alongside enhanced dopamine transporter levels and function. Mild alterations in D2 receptor density and the function of D1 and D2 receptors were also observed. These findings support the hypothesis that PTSD results in reduced dopaminergic neurotransmission, which may contribute to deficient reward function and altered drug-seeking behavior. Identifying the pathology of PTSD, such as altered dopamine neurotransmission, may lead to enhanced treatment strategies and interventions to prevent substance abuse in persons with PTSD.
Temple University--Theses

Post-traumatic stress disorder (PTSD) is a severe anxiety disorder affecting cognitive function. 1 in 4 individuals exposed to a life-threatening event may develop PTSD, which is characterised by symptoms of hyperarousal, avoidance and intrusions. Although treatment is effective in most cases, the response is far from satisfactory. It is now clear that novel drug treatment and a better understanding of the neurobiology of PTSD are necessary if we are to realise a better response and treatment outcome in these patients. Glutamatergic pathways play an important role in cognition, while recent studies have emphasized a causal role for glutamate in PTSD, and of the potential value of glutamate receptor modulators in treating the disorder. Stress-related elevation in glutamate exerts detrimental effects on cognition, especially via activation of the N-methyl-D-aspartate (NMDA) receptor, and has been implicated in PTSD associated cognitive deficits. Recently, the cr-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor has been found to exert a modulatory action on NMDA receptor function. Ampakines are positive allosteric modulators of the AMPA receptor, and have demonstrated beneficial effects in animal models of learning as well as antidepressant action, and to improve short-term memory in humans. The aims of this study were firstly to study the effects of the ampakine, Org 26576, on spatial memory performance in healthy male Sprague-Dawley rats. Secondly, since PTSD is associated with pronounced deficits in cognition, we studied the ability of Org 26576 to modify stress-evoked spatial memory deficits in rats subjected to single prolonged stress (SPS), a putative animal model of PTSD. In both cases, neuroreceptor studies were performed to determine any relationship between hippocampal and cortical NMDA receptor binding characteristics and effects on spatial memory performance. After exposure of the animals to either normal handling or SPS conditions, spatial memory performance was assessed using a 5 day memory acquisition and consolidation protocol in a modified version of the Morris water maze (MWM). Experimental and control groups both received either saline (1 ml/kg i.p.) or Org 26576 at incremental doses of 1, 3 or 10 mg/kg intraperitoneally twice daily for 12 days. Separate groups of animals were used for the neuroreceptor studies, except that behavioural testing was not performed. 24hrs after drug treatment discontinuation, the animals were sacrificed and frontal cortex and hippocampus removed for NMDA receptor binding analysis. In normal rats, Org 26576 3 mg/kg and 10 mg/kg exerted a short-lasting reduction in escape latency on day 1, but which lost prominence over the subsequent training days. Org 26576 1, 3 and 10 mg/kg, however, significantly improved spatial memory retrieval on day 5. No changes in frontal cortical or hippocampal NMDA receptors were observed. Contrary to expected, rats subjected to SPS failed to express noteworthy deficits in spatial memory as previously described. Treatment of SPS-exposed animals with Org 26576 did not significantly alter spatial learning evident in SPS animals on day 1 of acquisition training, as well as on subsequent training days. Org 26576 1 mg/kg increased spatial memory retrieval compared to the unstressed saline control, but not compared to the SPS group. Org 26576 only at a dose of 1 mg/kg decreased cortical, but not hippocampal NMDA receptor density (Bmax) in SPS animals versus unstressed but not saline treated SPS animals. No changes in receptor affinity (Kd) were noted. Org 26576 therefore improves early initial spatial learning in healthy rats, but exerts a lesser effect on memory consolidation over the remainder of the training period. However, Org 26576 significantly improves retrieval of spatial memory without simultaneous changes in frontal cortical and hippocampal NMDA receptor binding. Org 26576 thus may benefit both short-term and long-term memory processes in normal animals without effects on limbic NMDA receptor binding, and provides a rationale for testing in conditions that present with cognitive disturbances. However, the SPS model failed to engender marked deficits in spatial memory performance; this result ultimately complicated the interpretation of the combined stress-drug treatment studies. Studies in healthy animals therefore conclude that Org 26576 is an effective agent to enhance long-term memory processes and should be investigated further for its possible application in disorders of cognition. Although the value of Org 26576 in an animal model of PTSD were inconclusive, further studies in SPS and other PTSD models, as well as models of relevance for schizophrenia, Alzheimer's disease and depression, are encouraged.
Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2009.

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder characterised by hypothalamic-pituitary-adrenal (HPA)-axis abnormalities, hyperarousal, anxiety, flashbacks of trauma memories and avoidance. Increasing evidence is now accumulating that the disorder is also associated with shrinkage of the hippocampus and cognitive dysfunction that may have its origin in stress-induced excitotoxicity. Animal studies have indeed highlighted a potential role of the excitotoxic glutamatenitric oxide (NO) pathway in the stress response. Since PTSD appears to be an illness that progresses and worsens over time after an initial severe traumatic event, this study has used an animal model that emphasises repeated trauma to investigate the effect of stress on hippocampal NO synthase (NOS) activity, the release of the nitrogen oxide metabolites of NO (NOx), and also the evoked release of cGMP. Furthermore, the modulation and dependency of these responses on glutamate, NO and cGMP activity using drugs selective for these targets, will also be investigated. Rats (n=10/group) were exposed to repeated stress together with saline or drug administration immediately after the stress procedure and continuing for one week post-stress. The animals were then sacrificed for assay of hippocampal NOS activity, NO, and cGMP accumulation. Animals received either the glutamate-NMDA receptor antagonist, memantine (MEM;5mg/kg ip/d), the neuronal NOS selective inhibitor, 7- nitroindazole monosodium salt (7-NINA;20mg/kg ip/d), the cGMP-specific PDE inhibitor, sildenafil (SIL;10mg/kg ip/d) or the NFkb antagonist, pyrollidine dithiocarbamate (PDTC;70mg/kg ip/d). The latter inhibits the nuclear transcription factor, NFkb, responsible for inducing the expression of iNOS, while it also appears to mediate the glutamatergic actions on NOS expression, Stress significantly increased hippocampal NOS activity, as well as significantly increased hippocampal cGMP and NO, levels. These increases were blocked by pretreatment with either PDTC or 7-NINA, while memantine was without effect. Sildenafil significantly augmented stress induced NO, accumulation, as well as cGMP. although the latter failed to reach significance. 7-NINA and memantine significantly blocked the increase in cGMP evoked by time-dependent sensitisation (TDS)-stress, with PDTC attenuating this response, but not significantly. Additionally, administration of each drug separately for seven days without exposure to stress, did not evoke significant changes in NOx levels, compared to the control group. However, significant increases in cGMP levels, compared to the control group, were found with all four drugs. Repeated trauma therefore activates the NO-cGMP pathway, possibly involving actions on both nNOS and iNOS. The NMDA receptor appears less involved after chronic repeated stress, and may have limited therapeutic implications. Sub-cellular NO-modulation, however, may represent an important therapeutic strategy in preventing the effects of severe stress and in treating PTSD.
Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may result from an exposure to a severely traumatic life-event. It is characterised by a delayed onset of psychological and physical symptoms including re-experiencing the event, avoidance of reminders associated with the trauma, increased autonomic arousal and distinct memory deficits. This disorder is also characterised by a maladaptive hypothalamic-pituitary-adrenal (HPA)-axis response and altered monoamine concentrations in the hippocampus and pre-frontal cortex. The Time Dependent Sensitization (TDS) model is a putative animal model of PTSD that is based on the concept of repeated trauma, using three acute stressors (TS) of intense severity followed by a mild situational reminder (RS) on day 7 subsequent to the acute stressors. The aims of this study were to determine if the Triple Stressor (TS) induces stress and if the situational reminder (RS) is necessary for the maintenance of the stress response over time and whether these two stress responses are qualitatively and quantitively different. This was done to further validate the TDS model and to characterize the development and progression of the stress-related pathology of PTSD. Methods used were High Performance Liquid Chromatography (HPLC) with electrochemical detection (biochemical correlates) for quantifying the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) concentrations in the hippocampus and pre-frontal cortex (PFC); radio immuno assay (RIA) for the determination of plasma corticosterone concentrations (neuroendocrine parameter) and the use of the Elevated Plus Maze (EPM) to detect anxiety-like behaviour (behavioural analyses). The study was subdivided into an Acute and Re-Stress study (n = 10). In the Acute Study rats were exposed to TS as the only stressor. Group 1 was sacrificed immediately after TS, Group 2 was sacrificed 3 days post TS and Group 3 on day 7 post TS. In the Re-Stress Study both TS and RS were used as stressors. Group 4 was sacrificed immediately after the situational reminder, Group 5 was sacrificed 3 days post RS and Group 6 on day 7 post RS. A group of unstressed rats were used as Control. The results of this study found corticosterone concentrations elevated immediately after the TS (p<0.05). Exposure to the RS resulted in a profound hypocortisolism (p<0.05). These results indicate a possible disturbance in the regulation of the HPA-axis, which manifests as an enhanced negative feed-back upon re-introduction of the stressful situation. Changes in MA concentrations were evident. Although no definite fixed trend is apparent in this study, it is evident that the TDS model does induce monoamine dysregulation. Hippocampal NA. DA and 5-HT concentrations were noted to be elevated on day 7 post TS (p<0.05). On day 7 post RS only hippocampal 5HT was decreased significantly (p<0.05). Behavioural analyses indicate that stress related anxiety was not sustained after the TS but 7 days after the exposure to the RS rats were most anxious (p<0.05). The results confirm that the TDS model does induce PTSD-like symptoms in rats and that the situational reminder (RS) is necessary for the maintenance of the stress response. This model may be useful in the investigation of future experimental pharmacological interventions in the management of PTSD.
Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

碩士
國防醫學院
生物及解剖學研究所
104
Post-traumatic stress disorder (PTSD) is a complex disease that is defined by individual experience to intense, life-threatening trauma then lead to various physical and psychological abnormalities. The re-experiencing and avoidance symptoms of the disorder may hinder daily life in PTSD patients, and they develop additional debilitating symptoms, including persistent anxiety, exaggerated startle, and cognitive impairments. Environmental enrichment has been showed to enhance learning and memory, improve neurological diseases and anxiety behavior. Furthermore, previous research also found that estrogen may correlate with the stress response. In the present study, we want to investigate the effects of environmental enrichment on anxiety and depress behavior before or after survival stress in male rats. Furthermore, the concentrations of estradiol during experiments were detected. In this study, we breed rats in different environment and observe the effect of PTSD related symptoms. Therefore we use eight-week-old SD male rats expose to survival pressure, and then divided into three groups: control, isolate feeding (ISO) and enrich environment (EE). We use the behavioral tests (open field test and tail suspension test) to determine the level of anxiety and depress in animals. Serum samples of all animals were also collected through tail vein for hormone analysis (estrogen) before and after survival stress. From our results in tail suspension test and open field test, the animals of EE before stress and Continue EE could resistant to stress. However, the group of Continue ISO showed more depress in tail suspension test. On the other hand, the group of EE before stress showed more anxiety in open field test. In the results of hormone test, we found survival stress enhances E2 level in male rats, and animals of EE group in second bitch showed less enhanced. Therefore, our result showed enhanced anxiety, depress and serum estradiol levels after survival stress. Environmental enrichment could constant these change. Finally, we purpose environmental enrichment may be one of the improved ways for PTSD.

Animal models of post-traumatic stress disorder (PTSD) provide a wellspring of biological information about this complex condition by providing the opportunity to manipulate trauma exposure and measure biological outcomes in a systematic manner that is not possible in clinical studies. Symptoms of PTSD may be induced in animals by physical (immobilization, foot shock, underwater stress) and psychological stressors (exposure to predator, social defeat, early life trauma) or a combination of both. In addition, genetic, epigenetic and transgenic models have been created by breeding animals with a behavioral propensity for maladaptive stress response or by directly manipulating genes that have been implicated in PTSD. The effect of stressors in animals is measured by a variety of means, including observation of behavior, measurement of structural alterations in the brain and of physiological markers such as HPA axis activity and altered gene expression of central nervous system neurotransmitter system components including receptors. By comparing changes observed in stress exposed animals to humans with PTSD and by comparing animal response to treatments that are effective in humans, we can determine the validity of PTSD animal models. The identification of a reliable physiological marker of maladaptive stress response in animals as well as standard use of behavioral cutoff criteria are critical to the development of a valid animal model of PTSD.

This chapter provides a broad overview of the fear circuitry implicated in the development and maintenance of posttraumatic stress disorder. It begins by reviewing evidence from animal models of fear conditioning and extinction that unveiled the neural structures incorporated in the fear circuitry. Then it explores the translation of these findings to healthy human models of fear conditioning and finally examines the neural dysfunctions highlighted by neuroimaging studies of posttraumatic stress disorder (PTSD) in order to conceptualize mechanisms of fear extinction and the role of impaired fear extinction in contributing to the pathology of PTSD. The chapter ends with the potential therapeutic interventions for the treatment of PTSD in the scope of this model but with a note of caution regarding some of its limitations.

To elucidate the pathophysiology of post-traumatic stress disorder (PTSD), the establishment of an appropriate animal model is necessary. In a series of studies, the authors validated single prolonged stress (SPS) as a model for PTSD. SPS-treated rats mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced anxiety-like behavior, glucocorticoid negative feedback, and analgesia. In addition, the authors demonstrated enhanced freezing in response to contextual fear conditioning, and impaired extinction of fear memory, which was alleviated by D-cycloserine (DCS). In parallel, there was a decrease in extracellular glycine mediated by an increase in glycine transporter 1 in the hippocampus of SPS-treated rats after fear conditioning, which suggested that activation of N-methyl-D-asparate receptor by DCS during fear extinction training might alleviate the impaired fear extinction. This chapter summarizes PTSD-like symptoms in SPS and evaluates the validity of SPS as an animal model of PTSD.

Autonomic hyperarousal and avoidance in post-traumatic stress disorder (PTSD) can be triggered by a host of stimuli or situations that bear some similarity or association to the trauma event. As these triggers are often encountered in safe environments removed from the original trauma, this overgeneralization of fear and anxiety is a burden that can interfere with daily life. Recent efforts to understand the neurobiology of PTSD have relied on laboratory models of Pavlovian fear conditioning and extinction. This chapter reviews studies of fear generalization in animals and humans, which provide a valuable model to conceptualize the excessive fear generalization characteristic of PTSD.

Current therapeutic and preventive interventions for post-traumatic stress disorder (PTSD) have important limitations in terms of efficacy and tolerability. Translational research based on animal models of fear extinction and the stress response has yielded a number of new targets for investigation in clinical studies. Novel treatment approaches include new medications, psychotherapies, and the combination of exposure-based therapies with medications to enhance fear extinction. PTSD prevention represents a major opportunity, and preventive interventions can also be informed by basic neurobiology. Despite potentially useful new therapeutic and prevention approaches, the pace of clinical studies has been slow, and the evidence for most novel interventions is sparse. Given the urgent clinical need, more resources should be directed to clinical trials to fulfill the promise of translational research for this disorder.

This chapter examines the heterogeneity of posttraumatic stress disorder (PTSD), reviews the controversy over traumatic triggering events, and explores the complexities of the disease including clinical presentation, comorbidity, and the role of social support. Conceptual models for PTSD are also detailed. PTSD has a highly individualistic clinical presentation, which lends itself to the holistic nature of complementary and alternative medicine (CAM). In this chapter, CAM treatments that have demonstrated clinical utility and research support are reviewed. These approaches include mindfulness, Chinese medicine, the Neuro-Emotional Technique, biofeedback, animal-assisted therapy, yoga, plant-based medicines, and cannabis. The chapter addresses those who want to understand and treat PTSD.

Glucocorticoids (GCs) play a major role in orchestrating the complex physiological and behavioral reactions essential for the maintenance of homeostasis. These compounds enable the organism to prepare for, respond to, and cope with the acute demands of physical and emotional stressors and enable a faster recovery with passage of the threat. A timely and an appropriate GC release commensurate with stressor severity enables the body to properly contain stress responses so as to promote recovery by rapidly restoring homeostasis. Inadequate GC release following stress not only delays recovery by disrupting biological homeostasis but can also interfere with the processing or interpretation of stressful information that results in long-term disruptions in memory integration. A salient example of such an impaired post-traumatic process is post-traumatic stress disorder (PTSD). The findings from recent animal models and translational and clinical neuroendocrine studies summarized in this chapter provide insights shedding light on the apparently contradictory studies of the HPA-axis response to stress. Also included is a review of the basic facts about PTSD and biological data.

A large proportion of humans experienced a traumatic event in their lifetime, with more than 10% developing posttraumatic stress disorder (PTSD), panic disorder, phobias, and other fear/anxiety disorders. The neural circuitry of fear responses is highly conserved in humans as well as rodents, and this allows for translational research using animal models of fear. Fear/anxiety disorders in humans are most efficiently treated by exposure-based psychotherapy (i.e., cognitive behavioral therapy; CBT), the main aspects of which are closely modeled by extinction training in Pavlovian fear conditioning and extinction paradigms in rodents. To improve the efficacy of psychotherapy, pharmacological agents potent for enhancing learning and memory consolidation processing should be developed to combine with exposure-based therapy. The purpose of these adjunctive pharmacological agents is to promote fear memory erasure and the consolidation of extinction memories, thus providing a combined treatment of increased effectiveness. This review discusses established pharmacological adjuncts to behavioral therapeutic interventions for fear/anxiety disorders. The mechanisms of action of these adjuncts, as well as the evidence for and against the pharmacological treatment strategies and their limitations are discussed.

Traumatic brain injury due to blast exposure is quickly becoming the most frequently seen injury in today’s battlefields. Alterations in cognitive function, such as attention, memory, language and problem solving skills appear to occur as a result of blast-induced TBI. Furthermore, behavioral symptoms such as mood changes, depression, anxiety, impulsiveness and emotional outbursts are associated with blast-induced TBI (Okie et al, 2005). Observed overlaps between symptoms of post-traumatic stress disorder (PTSD) and TBI confound the differential diagnosis. Thus, soldiers with blast-induced TBI may be substantially under-diagnosed after exposure to blast waves. Animal models of blast-induced TBI are underdeveloped and there is a vital need for blast exposure biomarkers to help effectively diagnosis blast-induced TBI. In this study, we have investigated the mechanisms that underlie cognitive impairment of blast-induced neurotrauma. We have studied the cascade of neurochemical changes within the hippocampus of blast-exposed animals using 1H-Magnetic Resonance Spectroscopy (1HMRS). Furthermore, we examined changes in TBI protein markers using Western blotting and immunohistochemistry. Results suggest that exposure to blast waves has a significant effect on the hippocampus.