Escitalopram reversibility of the impacts following chronic stress on central 5-HT profiles - Implications to depression and anxiety.

Stress is considered a crucial determinant influencing health capacity in modern society. Long-term stress makes individuals more susceptible to mental dysfunctions, among which depression and anxiety are two major mental disorders. The success of using selective serotonin reuptake inhibitors (SSRIs) to treat these two disorders highlights the involvement of the central serotonergic (5-HT) system. Later studies suggest both presynaptic and postsynaptic 5-HT profiles should be considered for the effects of SSRIs, making it difficult to interpret the etiological and therapeutic mechanisms underlying depression and anxiety. The present study aims to examine whether the intervention of escitalopram (Es, 5 mg/kg daily for 14 days) can reverse the behavioral phenotypes of both depression-like [by sucrose preference test (SPT) and forced swim test (FST)] and anxiety-like [by avoidance latency and escape latency in elevated-T maze (ETM)] behaviors, and the brain area-dependent neurochemical changes of 5-HT profiles of the terminal regions regarding both synaptic efflux and tissue levels in rats of chronic mild stress (CMS). Our results showed that: (i) Even mild stresses when presented in an unpredictable and long-term manner, can induce both depression-like and anxiety-like behaviors. (ii) Depressive profile indexed by SPT was more sensitive to reflect the Es effect than that of FST. (iii) Es did not significantly affect the CMS-induced anxiety-like symptoms indexed by ETM. (iv) Changes in the protein expression of 5-HT1A receptors in the prefrontal cortex and hippocampus were compatible with the treatment outcome. Our results contributed to the understanding of stress-induced mood dysfunction and the involvement of central 5-HT.

Time-Dependent Effects of Buspirone versus Desipramine on the 5-Choice Serial Reaction Time Task in Rats Reared in Social Isolation: Implication of Early Life Experience and Motoric Impulsivity.

BACKGROUND: Early life social experience and the function of the central serotonin (5-Hydroxytryptophan, 5-HT) system are involved in development of behavioral impulsivity in which individuals act without forethought or before all necessary information is available. However, most of the evidence has been obtained from acute 5-HT manipulation, whereas, the present study aimed to investigate the effects of subchronic regimen targeting of 5-HT1A receptors on motoric waiting impulsivity in socially isolated rats. METHODS: A two-week protocol of buspirone (0.5 mg/kg/day) and desipramine (2.5 mg/kg/day) was employed for rats following social isolation rearing (IR) to examine their behavioral performance in a 5-choice serial reaction time task (5-CSRTT) during the treatment regimen. Responses in any one of the apertures prior to an informative signal were recorded as a premature response. RESULTS: IR rats presented with more locomotor activity than socially reared (SR) rats. Buspirone progressively increased the baseline level of premature responding in a time-dependent manner that was not observed in IR rats. Both IR and SR rats exhibited less premature responding following acute buspirone challenge. For a subchronic desipramine regimen, IR rats followed the same trend of SR controls to increase the prematurity of baseline response. CONCLUSIONS: Buspirone but not desipramine-induced time-dependent effects of motoric waiting impulsivity can be reversed by IR, indicating a role for early life social experience on 5-HT1A receptor-associated ability to control impulsiveness.

Effects of Early Risperidone Treatment on Metabolic Parameters in Socially Isolated Rats-Implication of Antipsychotic Intervention across Developmental Stages of Schizophrenia.

BACKGROUND: Second-generation antipsychotics (SGAs) is thought responsible for the metabolic abnormalities of schizophrenic patients, however, some untreated schizophrenic patients had already developed problems with glucose metabolism. The present study examined the hypothesis that schizophrenia itself but not risperidone, an extensively employed SGA, is accountable for metabolic abnormalities. METHODS: A 56-day risperidone regimen (1 mg/kg/day) was employed for rats of social isolation rearing (SIR) beginning at different developmental stage (28 or 56 days after weaning, i.e., adolescent and young adulthood, respectively). Metabolic parameters including body weight, systolic blood pressure (SBP), triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and plasma glucose were measured at baseline, 28, and 56 days of the regimen. Oral glucose tolerance test (OGTT) was performed at the end of the regimen. Insulin function was evaluated by area under the curve (AUC) of OGTT, homeostasis model assessment-insulin resistance (HOMA-ir), and Matsuda index. RESULTS: Our results demonstrated that: (i) SIR rats presented higher body weight, plasma triglyceride, and HOMA-ir than social controls. (ii) Higher insulin resistance was specifically presented in young adult rather than adolescent SIR rats. (iii) Adolescent drugged rats showed a lower level of LDL in day 28 of the regimen than young adult. Risperidone led to a lower LDL level in only young adult IR rats in day 56 than undrugged rats. (iv) SIR-induced dysregulation of insulin can be reversed by chronic risperidone treatment beginning at adolescence but not young adulthood. CONCLUSIONS: Our findings support the primary role of schizophrenia in metabolic abnormalities and risperidone appear beneficial when administered earlier.

Spectral analysis of cardiovascular oscillations in the 7-day regimen of losartan administration with and without cold stress.

Spectral analysis of heart rate (HR) and blood pressure (BP) variabilities (BPV and HRV) is widely available and utilized in understanding the dynamic cardiovascular autonomic regulation in a variety of pathophysiological conditions. In conscious cold-stressed (CS) rats, we examined the effect of a 7-day regimen administration of losartan, a selective nonpeptide angiotensin AT1 receptor blockade, on BPV and HRV at three frequency components: very-low frequency (VLF), low frequency (LF), and high frequency (HF). Key findings in changes of systolic BP (SBP), HR, and spectral power densities for cardiopulmonary oscillations (HF), sympathetic oscillations (LF), cardiovascular myogenic oscillations (VLF), and overall autonomic activity total power (TP) showed: (I) In the resting PreCS trial, compared with the saline, losartan increased HFBPV, TPHRV, all three HRV frequency powers, and the occurrence of the dicrotic notch (DN). However, it decreased SBP, HR, and the LFBPV frequency power. (II) In the CS trial, losartan significantly decreased SBP and DN occurrence and HR and LF/HFHRV but significantly increased HFHRV, TPBPV, and all three BPV frequency powers. In addition, similar to the saline, losartan showed positively correlated LFBPV and VLFBPV. Conversely, losartan converted the original inverse correlations between LFHRV and LFBPV of CS to a positive correlation. (III) Compared with saline in PreCS and CS trials, losartan detached the corresponding sympathetic oscillations between LFBPV and LFHRV. The overall result indicates that endogenous angiotensin II, through stimulation of the AT1 receptor, augments sympathetic tone but attenuates sympathetic oscillations in rats, particularly under the stressful cooling impacts.

Pharmacological Implications of Adjusting Abnormal Fear Memory: Towards the Treatment of Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a unique clinical mental abnormality presenting a cluster of symptoms in which patients primarily experience flashbacks, nightmares and uncontrollable thoughts about the event that triggered their PTSD. Patients with PTSD may also have comorbid depression and anxiety in an intractable and long-term course, which makes establishing a comprehensive treatment plan difficult and complicated. The present article reviews current pharmacological manipulations for adjusting abnormal fear memory. The roles of the central monoaminergic systems (including serotonin, norepinephrine and dopamine) within the fear circuit areas and the involvement of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) are explored based on attempts to integrate current clinical and preclinical basic studies. In this review, we explain how these therapeutic paradigms function based on their connections to stages of the abnormal fear memory process from condition to extinction. This may provide useful translational interpretations for clinicians to manage PTSD.

Effects of sinoaortic denervation on hemodynamic perturbations of prolonged paradoxical sleep deprivation and rapid cold stress in rats.

BACKGROUND: Sleep disturbances and aversive cold stress (CS) are cardiovascular risk factors. This study investigates how homeostatic control autonomic baroreflex influences the hemodynamic perturbations evoked by paradoxical sleep deprivation (PSD) and CS. METHODS: Conscious adult male rats were randomly divided into four groups (Sham/CON [control], Sham/PSD, sinoaortic denervation [SAD]/CON, and SAD/PSD). Spectral analysis and SAD were employed to evaluate the effects of a 72-hr PSD with 10-min CS on blood pressure variability and heart rate variability (BPV and HRV) at total power (TP) and three frequency power densities, very-low-frequency (VLF), low frequency (LF), and high frequency (HF). RESULTS: Key findings showed: (I) Compared with the control sham surgery (Sham/CON), in the natural baseline (PreCS) trial, SAD surgery (SAD/CON) causes high systolic blood pressure (SBP), heart rate (HR), increases LFBPV (low-frequency power of BPV), LF/HFHRV (the ratio LF/HF of HRV), and TPBPV (the total power of BPV), but decreases HFHRV (high-frequency power of HRV) and VLFHRV (very-low-frequency power of HRV) than the Sham/CON does. In the CS trial, SAD/CON increases the CS-induced pressor, increases the CS-elicited spectral density, LF/HFHRV, but decreases HFBPV than the Sham/CON does. (II) Compared with SAD/CON and Sham/PSD (PSD under sham surgery), in both PreCS and CS trials, SAD/PSD (PSD under SAD) causes high SBP and HR than both SAD/CON and Sham/PSD their SBP and HR. In PreCS, SAD-PSD also changes the spectral density, including increasing Sham-PSD's LFBPV, LF/HFHRV, VLFBPV, and TPBPV but decreasing Sham-PSD's VLFHRV and TPHRV. However, in CS, SAD-PSD changes the CS-elicited spectral density, including increasing Sham-PSD's VLFBPV, LF/HFHRV, and TPHRV but decreasing Sham-PSD's HFBPV and LFBPV. CONCLUSION: The results suggest baroreflex combined with other reflex pathways, such as inhibitory renorenal reflex, modulates the vascular and cardiorespiratory responses to PSD under PreCS and subsequent CS trials.

Effects of RU486 in Treatment of Traumatic Stress-Induced Glucocorticoid Dysregulation and Fear-Related Abnormalities: Early versus Late Intervention.

Central glucocorticoid receptor (GR) activity is enhanced following traumatic events, playing a key role in the stress-related cognitive abnormalities of posttraumatic stress disorder (PTSD). GR antagonists are expected to have potential as pharmacological agents to treat PTSD-related symptoms such as anxiety and fear memory disruption. However, an incubation period is usually required and stress-induced abnormalities do not develop immediately following the trauma; thus, the optimal intervention timing should be considered. Single prolonged stress (SPS) was employed as a rodent PTSD model to examine the effects of early or late (1-7 versus 8-14 days after the SPS) sub-chronic RU486 (a GR antagonist) administration. Behaviorally, fear conditioning and anxiety behavior were assessed using the fear-conditioning test and elevated T-maze (ETM), respectively. Neurochemically, the expressions of GR, FK506-binding proteins 4 and 5 (FKBP4 and FKBP5), and early growth response-1 (Egr-1) were assessed in the hippocampus, medial prefrontal cortex (mPFC), amygdala, and hypothalamus, together with the level of plasma corticosterone. Early RU486 administration could inhibit SPS-induced behavioral abnormalities and glucocorticoid system dysregulation by reversing the SPS-induced fear extinction deficit, and preventing SPS-reduced plasma corticosterone levels and SPS-induced Egr-1 overexpression in the hippocampus. Early RU486 administration following SPS also increased the FKBP5 level in the hippocampus and hypothalamus. Finally, both early and late RU486 administration inhibited the elevated hippocampal FKBP4 level and hypothalamus GR level in the SPS rats. Early intervention with a GR antagonist aids in the correction of traumatic stress-induced fear and anxiety dysregulation.

Does positive feeling lead to more impulsiveness? - Implication of previous rewarded experience on location-dependent motoric impulsivity.

Positive feeling or rewarding experience is crucial for individuals to operative their cognitive activities via an outcome evaluation of incentive reinforcement. For a long time, rewarding process or outcome evaluation is assumed greatly influenced by neuronal construct that holds individuals' impulsiveness, a capacity to inhibit unwanted behaviors provoked in a given situation. In the present study, we proposed that the outcome evaluation or rewarding experience can influence the occurrence of impulsiveness too. We hypothesized that animals would be more likely to deliver impulsive action in the place where it was previously associated with reinforcing process, in which central dopamine may play an important role. By employing five-choice serial reaction time task (5-CSRTT), we examined whether one of the five holes where rats made a correct response to get the reward would gain a higher probability to deliver premature or perseverative activities than other holes in the next trial of 5-CSRTT under baseline or longer waiting period condition. The effects of D1 receptor antagonist SCH23390 were also evaluated in the above paradigm. We demonstrated that (i) the influence on motoric impulsive response from previous rewarded experience can be described in a behavioral paradigm such as the 5-CSRTT, (ii) both prematures and perseverations at the hole associated with previous rewarding were about one-fifth of probability, however were statistically not correlated unless the interventions of inter-trial interval = 7 plus SCH23390, and (iii) the hole associated with the positive reinforcement of the 5-CSRTT appears more likely for rats to carry out an intuitive impetus under SCH23390 in a longer waiting condition. Our results may shed some insight toward the role of rewarding process in impulsive behavior.

Effects of early life social experience on fear extinction and related glucocorticoid profiles - behavioral and neurochemical approaches in a rat model of PTSD.

People may agonize over an intrusive fear-inducing memory even when the traumatic event has passed, which is the principle manifestation of posttraumatic stress disorder (PTSD). However, many traumatized people do not present symptoms of PTSD, implying that certain hidden factors help those individuals to cope with the traumatic stress. Increasing evidence suggests that early life experience may serve as a predisposing factor in the development of PTSD. For example, early life social deprivation disrupts the glucocorticoid system, one of the biological abnormalities of PTSD. By employing isolation rearing (IR) with a subsequent single prolonged stress (SPS) paradigm, we examined the hypothesis that early-life social experience may change the outcome of traumatic stress in both behavioral and neurochemical profiles. Behaviorally, the performance of rats on a Pavlovian fear conditioning test was measured to evaluate their retrieval ability of fear memory extinction. Neurochemically, plasma corticosterone levels and glucocorticoid receptor (GR), FK506-binding proteins 4 and 5 (FKBP4 and FKBP5) and early growth response-1 (Egr-1) expression were measured in GR-abundant brain areas, including the hypothalamus, medial prefrontal cortex, and hippocampus. Our results demonstrated an area-dependent IR effect on the SPS outcomes. IR prevented the SPS-impaired fear extinction retrieval ability and averted the SPS-elevated expression of GR, FKBP4, and Egr-1 in the hippocampus, whereas it did not change the SPS-reduced plasma corticosterone levels and SPS-enhanced GR activity in the mPFC and hypothalamus. The present study provides some new insights to support the hypothesis that early-life experience may play a role in the occurrence of PTSD.

Early life social experience affects adulthood fear extinction deficit and associated dopamine profile abnormalities in a rat model of PTSD.

Individuals may develop fear extinction deficits after life-threatening traumatic events; such deficits indicate posttraumatic stress disorder (PTSD). Because the occurrence of this disorder differs among people who have experienced trauma, hidden underlying factors should be determined. Increasing evidence suggests the involvement of neuronal dysregulation of information processes or cognitive function during development. This neuronal dysregulation is caused by disturbances in dopamine (DA) transmission within the fear circuit, which comprises the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Single prolonged stress (SPS) combined with an isolation rearing (IR) paradigm was used to randomly assign rats to four groups [social rearing-no SPS (SR-NS), SR-SPS, IR-NS, and IR-SPS], and their performance in prepulse inhibition (PPI) and on Pavlovian fear conditioning tests was assessed. Tissue DA levels and the expression of DA receptors (D1R and D2R) in the fear circuit were measured at the end of the experiment. Our results indicated that PPI deficits and fear extinction problems were specific to rats subjected to IR and SPS, respectively. Furthermore, IR-induced PPI deficits were not influenced by SPS, but SPS-induced fear extinction retrieval impairment could be adjusted according to previous IR experiences. Neurochemically, tissue DA levels and D1R expression in the mPFC and amygdala were nonspecifically reduced by IR and SPS, whereas D2R expression in the mPFC and amygdala was higher in IR-SPS than in SR-SPS rats. These findings suggest that early life experiences may influence fear responses in adulthood through a change in DA profiles within the fear circuit.

Effects of oxytocin on prosocial behavior and the associated profiles of oxytocinergic and corticotropin-releasing hormone receptors in a rodent model of posttraumatic stress disorder.

BACKGROUND: Traumatic experience may lead to various psychological sequelae including the unforgettable trauma-associated memory as seen in posttraumatic stress disorder (PTSD), with a mechanism of impaired fear extinction due to biological imbalance among hypothalamic-pituitary-adrenal (HPA) axis and fear circuit areas such as medial prefrontal cortex (mPFC), hippocampus, and amygdala. Recently the impaired sociability seen in PTSD patients received great attention and the involvement of oxytocin (OXT) mediation is worth being investigated. This study examined whether the trauma-altered prosocial behavior can be modulated by OXT manipulation and its relationship with corticotropin-releasing hormone (CRH) signaling. METHODS: Male rats previously exposed to a single prolonged stress (SPS) were evaluated for their performance in social choice test (SCT) and novel object recognition test (NORT) following the introduction of intranasal oxytocin (OXT) and OXT receptor antagonist atosiban (ASB). OXT receptors (OXTR) and CRH receptors (CRHR1, CRHR2) were quantified in both protein and mRNA levels in medial prefrontal cortex (mPFC), hippocampus, and amygdala. RESULTS: SPS reduced inclination of rats staying at the sociable place with performing less prosocial contacts. OXT can amend the deficit but this effect was blocked by ASB. Expression of OXTR became reduced following SPS in mPFC and amygdala, the latter exhibited higher therapeutic specificity to OXT. Expression of CRHR1 appeared more sensitive than CRHR2 to SPS, higher CRHR1 protein levels were found in mPFC and amygdala. CONCLUSION: Psychological trauma-impaired sociability is highly associated with OXT signaling pathway. Intranasal OXT restored both the SPS-impaired prosocial contacts and the SPS-reduced OXTR expressions in mPFC and amygdala. OXT may have therapeutic potential to treat PTSD patients with impaired social behaviors.

Subchronic administration of aripiprazole improves fear extinction retrieval of Pavlovian conditioning paradigm in rats experiencing psychological trauma.

People may suffer from an intruded fear memory when the attributable traumatic events no longer exist. This is of highly clinical relevance to trauma-induced mental disorders, such as posttraumatic stress disorder (PTSD). Mechanism underlying PTSD largely lies in the abnormal process of fear extinction and a functional imbalance within amygdala associated fear circuit areas. Previous evidence suggested central dopamine plays a key role in the regulation of the fear memory process, yet it remains unclear whether the intervention of dopamine modulators would be beneficial for the fear extinction abnormalities. The present study examined the performance of Pavlovian conditioned fear and the changes of dopamine profiles following a subchronic 14-day regimen of aripiprazole (a partial agonist of dopamine D2 receptors to normalize the condition caused by dopamine imbalance) in rats previously experienced a psychologically traumatic procedure of single prolonged stress (SPS). The results demonstrated that aripiprazole at 5.0 mg/kg reversed the SPS-impaired fear memory dysfunction and the SPS-reduced dopamine efflux in the amygdala. The present study suggests a therapeutic potential of subchronic treatment with aripiprazole in managing patients suffered from fear extinction problem.

Hyperbaric oxygen therapy restored traumatic stress-induced dysregulation of fear memory and related neurochemical abnormalities.

Individuals with posttraumatic stress disorder (PTSD) are characterized by fear memory problems and hypocortisolemia of which traumatic stress-induced monoaminergic disruption over infralimbic (IL) cortex is considered the key mechanism. Hyperbaric oxygen therapy (HBOT) has recently proven its utility in treating several mental disorders but remains unexplored for PTSD. The present study aimed to examine the effects of 5-day HBO paradigm on traumatic stress (single prolonged stress, SPS, an animal model of PTSD)-induced dysregulation of fear memory/anxiety profiles and related abnormalities in IL monoamines and plasma corticosterone. Rats were randomly assigned to four groups (CON-sham, CON-HBOT, SPS-sham, and SPS-HBOT) and received Pavlovian fear conditioning test or elevated-T maze (ETM). The extracellular and tissue levels of monoamines over the IL cortex and the activity of the hypothalamus-pituitary-adrenal axis (i.e., the plasma corticosterone level and expression of the glucocorticoid receptor (GR) in the IL, hippocampus, amygdala, and hypothalamus) were measured. The results demonstrated that HBOT restored behaviorally the SPS-impaired fear extinction retrieval ability and SPS-induced conditioned anxiety, and neurochemically the SPS-reduced IL monoamines efflux level, and the corticosterone profiles. The present study shows some positive effects of HBOT in both behavioral and neurochemical profiles of PTSD outcomes.

Effects of Oxytocin on Fear Memory and Neuroinflammation in a Rodent Model of Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterized by fear extinction abnormalities, which involve biological dysfunctions among fear circuit areas in the brain. Oxytocin (OXT) is a neuropeptide that regulates sexual reproduction and social interaction and has recently earned specific attention due to its role in adjusting neurobiological and behavioral correlates of PTSD; however, the mechanism by which this is achieved remains unclear. The present study aimed to examine whether the effects of OXT on traumatic stress-induced abnormalities of fear extinction (specifically induced by single prolonged stress (SPS), an animal model of PTSD) are associated with pro-inflammatory cytokines. Seven days after SPS, rats received intranasal OXT 40 min before a cue-dependent Pavlovian fear conditioning-extinction test in which rats' freezing degree was used to reflect the outcome of fear extinction. We also measured mRNA expression of IL-1ß, IFN-γ, and TNF-α in the medial prefrontal cortex (mPFC), hippocampus, and amygdala at the end of the study, together with plasma oxytocin, corticosterone, IL-1ß, IFN-γ, and TNF-α, to reflect the central and peripheral changes of stress-related hormones and cytokines after SPS. Our results suggested that intranasal OXT effectively amends the SPS-impaired behavior of fear extinction retrieval. Moreover, it neurochemically reverses the SPS increase in pro-inflammatory cytokines; thus, IL-1ß and IFN-γ can be further blocked by the OXT antagonist atosiban (ASB) in the hippocampus. Peripheral profiles revealed a similar response pattern to SPS of OXT and corticosterone (CORT), and the SPS-induced increase in plasma levels of IL-1ß and TNF-α could be reduced by OXT. The present study suggests potential therapeutic effects of OXT in both behavioral and neuroinflammatory profiles of PTSD.

Effects of 5HT1A Activation on Depression Profile Following 5-HT Depletion in Rats Lacking Social Attachment Since Weanling.

OBJECTIVE: Post weanling isolation-reared (IR) rats are featured with depressive phenotype, yet its mechanism is not clearly defined particularly in terms of the involvement of central 5-HT1A receptors. The present study aims to examine the effects of 5HT1A activation on forced swim test (FST) in IR rats following 5-HT depletion. METHODS: Social control (SOC) and IR rats received an intracerebraoventricular (ICV) injection of 5-HT depletion agent, 5,7-DHT. 14 days after the surgery, rats were assessed their performance in FST with or without the challenge with a 5-HT1A agonist, 8-OH-DPAT. Rats were then sacrificed for analyzing their 5-HT tissue levels and the expressions of their 5-HA1A receptors in prefrontal cortex (PFC), hippocampus (HPX), and amygdala (AMY). RESULTS: 5,7-DHT decreased the tissue concentration of 5-HT in both IR and SOC rats. IR rats were more immobile and less sensitive to the lesion-induced immobility, however this effect was reversed by acute challenge of 8-OH-DPAT. 5,7-DHT lesion increased the expression of PFC 5-HT1A receptors. CONCLUSION: The integrity of central 5-HT system is developmentally crucial for the 5-HT1A-relevant depression profile in rats of social isolation.

Effects of 5HT1A Activation on Gating Profile Following 5HT Depletion in Rats Lacking Social Attachment Since Weanling.

OBJECTIVE: Central 5-HT1A receptor is involved in the modulation of sensorimotor gating function. However, its precise role is not clearly defined in developmentally social deprived (isolation rearing, IR) rats featured with impaired sensorimotor gating ability. We therefore aimed to examine the effects of 5HT1A activation on acoustic startle response (ASR) and prepulse inhibition (PPI) in IR rats in a condition of compromised presynaptic 5-HT functions. METHODS: Social control (SOC) and IR rats received an intracerebraoventricular (ICV) injection of 5-HT depletor, 5,7-DHT. Seven days later rats entered a protocol of 8-OH-DPAT, a 5-HT1A agonist, in which locomotor activity, ASR and PPI and their tissue levels of 5-HT were measured. RESULTS: Our results found that both IR and 5,7-DHT decreased the tissue concentration of 5-HT. IR-induced hyperactivity and gating impairment were unaffected by 5-HT depletion. 8-OH-DPAT strengthened the ASR in IR but not SOC rats and the drug-reduced PPI could be adjusted by 5,7-DHT pretreatment. 8-OH-DPAT at 100 µg/kg enhanced PPI in 5-HT-depleted SOC rats. However for IR rats, 8-OH-DPAT strengthened PPI in sham rats but downgraded it in depletion condition. CONCLUSION: The integrity of central 5-HT system is important to 5-HT1A-modulated sensorimotor gating in isolation-reared rats.

Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder.

Central catecholamines regulate fear memory across the medial prefrontal cortex (mPFC), amygdala (AMYG), and hippocampus (HPC). However, inadequate evidence exists to address the relationships among these fear circuit areas in terms of the fear symptoms of posttraumatic stress disorder (PTSD). By examining the behavioral profile in a Pavlovian fear conditioning paradigm together with tissue/efflux levels of dopamine (DA) and norepinephrine (NE) and their reuptake abilities across the fear circuit areas in rats that experienced single prolonged stress (SPS, a rodent model of PTSD), we demonstrated that SPS-impaired extinction retrieval was concomitant with the changes of central DA/NE in a dissociable manner. For tissue levels, diminished DA and increased NE were both observed in the mPFC and AMYG. DA efflux and synaptosomal DA transporter were consistently reduced in the AMYG/vHPC, whereas SPS reduced NE efflux in the infralimbic cortex and synaptosomal NE transporter in the mPFC. Furthermore, a lower expression of synaptosomal VMAT2 was observed in the mPFC, AMYG, and vHPC after SPS. Finally, negative correlations were observed between retrieval freezing and DA in the mPFC/AMYG; nevertheless, the phenomena became invalid after SPS. Our results suggest that central catecholamines are crucially involved in the retrieval of fear extinction in which DA and NE play distinctive roles across the fear circuit areas.

Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory.

RATIONALE: Posttraumatic stress disorder (PTSD) is a trauma-induced mental disorder characterised by fear extinction dysfunction in which fear circuit monoamines are possibly associated. PTSD often coexists with depressive/anxiety symptoms, and selective serotonin reuptake inhibitors (SSRIs) are recommended to treat PTSD. However, therapeutic mechanisms of SSRIs underlying the PTSD fear symptoms remain unclear. OBJECTIVES: Using a rodent PTSD model, we examined the effects of early SSRI intervention in mood and fear dysfunctions with associated changes of monoamines within the fear circuit areas. METHODS: A 14-day escitalopram (ESC) regimen (5 mg/kg/day) was undertaken in two separate experiments in rats which previously received a protocol of single prolonged stress (SPS). In experiment 1, sucrose preference and elevated T-maze were used to index anhedonia depression and avoidance/escape anxiety profiles. In experiment 2, the percentage of freezing time was measured in a 3-day fear conditioning paradigm. At the end of our study, tissue levels of serotonin (5-HT) in the medial prefrontal cortex, amygdala, hippocampus, and striatum were measured in experiment 1, and the efflux levels of infralimbic (IL) monoamines were measured in experiment 2. RESULTS: In experiment 1, ESC corrected both behavioural (depression/anxiety) and neurochemical (reduced 5-HT tissue levels in amygdala/hippocampus) abnormalities. In experiment 2, ESC was unable to correct the SPS-impaired retrieval of fear extinction. In IL, ESC increased the efflux level of 5-HT but failed to reverse SPS-reduced dopamine (DA) and noradrenaline (NA). CONCLUSIONS: PTSD-induced mood dysfunction is psychopathologically different from PTSD-induced fear disruption in terms of disequilibrium of monoamines within the fear circuit areas.

Role of Efferent Sympathoadrenal Effects in Cooling-Induced Hemodynamic Perturbations in Rats: An Investigation by Spectrum Analysis.

Cold stress may produce hemodynamic perturbations but the underlying mechanisms are still not clear. Spectral analysis was used in this study to explore that sympathoadrenal activation could be involved in mechanisms of hemodynamic perturbations to cooling. Conscious rats after treatment with a control vehicle (saline) compared with withdrawal of sympathetic influences by ganglion blocker hexamethonium (HEX) or chemical sympathectomy guanethidine (GUA) were challenged by stressful cooling as acute immersing all four extremities in ice water (4 ± 2°C) for 10 min. Plasma nitric oxide (NO) and the appearance of Dichroitic notch (DN) were measured in comparison between treatment groups throughout the experimental course. Hemodynamic indices were telemetrically monitored, and variability of blood pressure and heart rate (BPV; HRV) were assessed over a range of frequencies: very-low frequency (VLF: 0.02-0.2 Hz), low frequency (LF: 0.2-0.6 Hz), high frequency (HF: 0.6-3 Hz), normalized (n)LF, nHF, ratio LF/HF of HRV (LF/HF(HRV)), and total power (TP: ≤3 Hz). Results showed that the concomitant reciprocal changes of spectral powers existed between frequencies of BPV and HRV to the stressful cooling (i.e. VLF(BPV) versus VLF(HRV), LF(BPV) versus LF(HRV), and nLF(BPV) versus nLF(HRV)) which contribute to the underlying mechanisms of sympathetic efferent influences and myogenic cardiovascular responsiveness. Furthermore, compared with the control vehicle in the stressful cooling, HEX restrained the increase of the pressor, tachycardia and VLF(BPV), except that VLF(HRV) was reduced. GUA abolished pressor, however, restrained the increase of the tachycardia, VLF(BPV) and LF(BPV). In addition, GUA reversed the downward tendency of nLF(BPV) into an upward tendency and attenuated both nLF(HRV) and LF/HF(HRV). DN was virtually undetectable after HEX management but was apparently noticeable after GUA management. Finally, the increase of plasma NO after cooling was diminished after HEX or GUA management. Taken together, these results substantiate that the spectral changes during stressful cooling are highly relevant to the efferent sympathetic rhythmicity and subsequent NO production.