Stress-related Neuropeptide Research Articles

Association between RMTg Neuropeptide Genes and Negative Effect during Alcohol Withdrawal in Mice.

Alcohol use disorders (AUDs) frequently co-occur with negative mood disorders, such as anxiety and depression, exacerbating relapse through dopaminergic dysfunction. Stress-related neuropeptides play a crucial role in AUD pathophysiology by modulating dopamine (DA) function. The rostromedial tegmental nucleus (RMTg), which inhibits midbrain dopamine neurons and signals aversion, has been shown to increase ethanol consumption and negative emotional states during abstinence. Despite some stress-related neuropeptides acting through the RMTg to affect addiction behaviors, their specific roles in alcohol-induced contexts remain underexplored. This study utilized an intermittent voluntary drinking model in mice to induce negative effect behavior 24 h into ethanol (EtOH) abstinence (post-EtOH). It examined changes in pro-stress (Pnoc, Oxt, Npy) and anti-stress (Crf, Pomc, Avp, Orx, Pdyn) neuropeptide-coding genes and analyzed their correlations with aversive behaviors. We observed that adult male C57BL/6J mice displayed evident anxiety, anhedonia, and depression-like symptoms at 24 h post-EtOH. The laser-capture microdissection technique, coupled with or without retrograde tracing, was used to harvest total ventral tegmental area (VTA)-projecting neurons or the intact RMTg area. The findings revealed that post-EtOH consistently reduced Pnoc and Orx levels while elevating Crf levels in these neuronal populations. Notably, RMTg Pnoc and Npy levels counteracted ethanol consumption and depression severity, while Crf levels were indicative of the mice's anxiety levels. Together, these results underscore the potential role of stress-related neuropeptides in the RMTg in regulating the negative emotions related to AUDs, offering novel insights for future research.

Increased pituitary adenylate cyclase-activating peptide genes expression in the prefrontal cortex in schizophrenia in relation to suicide.

Pituitary adenylate cyclase-activating peptide (PACAP) is a stress-related neuropeptide that is produced in several brain areas. It acts by 3 receptors: PACAP type-1 (PAC1), vasoactive intestinal peptide (VIP) -1 and -2 (VPAC1 and 2). Data on polymorphisms in PACAP and PAC1 indicate a relationship of the PACAP system with schizophrenia (SCZ). The prefrontal cortex was chosen to measure PACAP-gene related expression changes, since this is a central structure in the symptoms of schizophrenia (SCZ). We investigated alterations in the expression of the PACAP-related genes by qPCR in the human dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) of 35 SCZ patients and 34 matched controls in relation to SCZ, suicide, gender and medication. The ACC revealed an upregulation in PACAP, PAC1, VPAC1 and VPAC2 in SCZ suicide (S) completers compared to controls. An increase in PACAP, VPAC1 and VPAC2 expression was also present in the ACC in SCZ-S compared to SCZ patients who died naturally (SCZ-N). In the DLPFC, an increase in PAC1 was found in SCZ-N patients compared to SCZ-S and controls. Moreover, an increase in all PACAP-related genes was present in SCZ-N male patients compared to SCZ-N females. Concluding, expression changes were found in PACAP-related genes in relation to SCZ, suicide and gender. In particular, there was a higher PACAP-related gene expression in SCZ patients in the ACC in relation to suicide and in DLPFC in relation to SCZ. These findings suggest a potential link between PACAP and the pathophysiology of SCZ and suicide. Further research is needed to understand the functional significance and potential clinical applications of these changes.

Yokukansan, a Traditional Japanese Medicine, Suppresses Stress-Induced Sympathetic Activation via Central Responses in Rats

Objectives: Yokukansan (YKS) is a traditional Japanese Kampo medicine approved by the Ministry of Health, Labour and Welfare of Japan. Recently, in addition to its indications as a drug treatment, YKS has been shown to have ameliorative effects on various psychological and behavioral responses such as anxiety, aggression, and stress responses. Stress exposure activates not only the hypothalamic–pituitary–adrenal axis but also the sympathetic nervous system. Sympathetic activation in brain regions such as the paraventricular hypothalamic nucleus (PVN) stimulates elevation of plasma catecholamine (noradrenaline and adrenaline) levels. We previously reported that various stress-related neuropeptides and several kinds of stressors, such as restraint stress (RS), increase plasma catecholamine and that brain prostanoids and their synthases mediate these responses in rats. In the present study, to determine if YKS treatment can affect stress-induced sympathetic activation, we examined the effects of YKS treatment on the RS-induced elevation of plasma catecholamine levels and related prostanoid production in the PVN of rats. Methods: YKS (1000 mg/10 mL/kg, p.o.) or vehicle was administered to rats daily for 14 days, and all rats were exposed to RS for 60 min on day 14. Before and during stress exposure on day 14, blood samples and PVN dialysates were collected and analyzed by high-performance liquid chromatography and liquid chromatography-ion trap tandem mass spectrometry, respectively. Results: Our results showed that repeated administration of YKS suppressed the RS-induced increase in plasma adrenaline but not noradrenaline. Furthermore, YKS administration also suppressed the RS-induced elevation of both prostaglandin E2 and thromboxane B2 levels in the PVN. In addition, we found that repeated administration of YKS suppressed the RS-induced increase in serotonin, gamma-aminobutyric acid, and acetylcholine in the PVN. Conclusion: Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.

Increased pituitary adenylate cyclase-activating polypeptide in the central bed nucleus of the stria terminalis in mood disorders in men

The mood disorders major depressive disorder (MDD) and bipolar disorder (BD) are highly prevalent worldwide. Women are more vulnerable to these psychopathologies than men. The bed nucleus of the stria terminalis (BNST), the amygdala, and the hypothalamus are the crucial interconnected structures involved in the stress response. In mood disorders, stress systems in the brain are put into a higher gear. The BNST is implicated in mood, anxiety, and depression. The stress-related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is highly abundant in the central BNST (cBNST). In this study, we investigated alterations in PACAP in the cBNST of patients with mood disorders. Immunohistochemical (IHC) staining of PACAP and in situ hybridization (ISH) of PACAP mRNA were performed on the cBNST of post-mortem human brain samples. Quantitative IHC revealed elevated PACAP levels in the cBNST in both mood disorders, MDD and BD, but only in men, not in women. The PACAP ISH was negative, indicating that PACAP is not produced in the cBNST. The results support the possibility that PACAP innervation of the cBNST plays a role in mood disorder pathophysiology in men.

Alcohol dependence interactions with sex-specific stress-related neuropeptide and alcohol CeA synaptic effects

Alcohol dependence interactions with sex-specific stress-related neuropeptide and alcohol CeA synaptic effects

Stress-related neuropeptide systems as targets for treatment of alcohol addiction: A clinical perspective.

Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic relapsing condition characterized by increased motivation to use alcohol, choice of alcohol over healthy, natural rewards, and continued use despite negative consequences. Available pharmacotherapies for alcohol addiction are few, have effect sizes in need of improvement, and remain infrequently prescribed. Research aimed at developing novel therapeutics has in large part focused on attenuating pleasurable or "rewarding" properties of alcohol, but this targets processes that primarily play a role as initiation factors. As clinical alcohol addiction develops, long-term changes in brain function result in a shift of affective homeostasis, and rewarding alcohol effects become progressively reduced. Instead, increased stress sensitivity and negative affective states emerge in the absence of alcohol and create powerful incentives for relapse and continued use through negative reinforcement, or "relief." Based on research in animal models, several neuropeptide systems have been proposed to play an important role in this shift, suggesting that these systems could be targeted by novel medications. Two mechanisms in this category, antagonism at corticotropin-releasing factor type 1, and neurokinin 1/substance P receptors, have been subject to initial evaluation in humans. A third, kappa-opioid receptor antagonism, has been evaluated in nicotine addiction and could soon be tested for alcohol. This paper discusses findings with these mechanisms to date, and their prospects as future targets for novel medications.

Modulatory effect of long-term treatment with escitalopram and clonazepam on the expression of anxiety-related neuropeptides: neuromedin U, neuropeptide S and their receptors in the rat brain

Newly identified multifunctional peptidergic modulators of stress responses: neuromedin U (NMU) and neuropeptide S (NPS) are involved in the wide spectrum of brain functions. However, there are no reports dealing with potential molecular relationships between the action of diverse anxiolytic or antidepressant drugs and NMU and NPS signaling in the brain. The present work was therefore focused on local expression of the aforementioned stress-related neuropeptides in the rat brain after long-term treatment with escitalopram and clonazepam. Studies were carried out on adult, male Sprague-Dawley rats that were divided into 3 groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 5mg/kg daily), and clonazepam (at single dose 0.5mg/kg). All individuals were sacrificed under anaesthesia and the whole brain excised. Total mRNA was isolated from homogenized samples of amygdala, hippocampus, hypothalamus, thalamus, cerebellum and brainstem. Real time-PCR method was used for estimation of related NPS, NPS receptor (NPSR), NMU, NMU and receptor 2 (NMUR2) mRNA expression. The whole brains were also sliced for general immunohistochemical assessment of the neuropeptides expression. Chronic administration of clonazepam resulted in an increase of NMU mRNA expression and formation of NMU-expressing fibers in the amygdala, while escitalopram produced a significant decrease in NPSR mRNA level in hypothalamus. Long-term escitalopram administration affects the local expression of examined neuropeptides mRNA in a varied manner depending on the brain structure. Pharmacological effects of escitalopram may be connected with local at least partially NPSR-related alterations in the NPS/NMU/NMUR2 gene expression at the level selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.

Escitalopram alters local expression of noncanonical stress-related neuropeptides in the rat brain via NPS receptor signaling.

Neuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular relationships between the anxiolytic activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in the context of novel stress-related neuropeptides action. The present work therefore focused on gene expression of novel stress neuropeptides in the rat brain after acute treatment with escitalopram and in combination with neuropeptide S receptor (NPSR) blockade. Studies were carried out on adult, male Sprague-Dawley rats that were divided into five groups: animals injected with saline (control) and experimental rats treated with escitalopram (at single dose 10mg/kg daily), escitalopram and SHA-68, a selective NPSR antagonist (ata single doseof 40mg/kg), SHA-68 alone and corresponding vehicle (solvent SHA-68) control. To measure anxiety-like behavior and locomotor activity the open field test was performed. All individuals were killed under anaesthesia and the whole brainwas excised. Total mRNA was isolated from homogenized samples ofthe amygdala, hippocampus, hypothalamus, thalamus, cerebellum, and brainstem. Real-time PCR was used for estimation of related NPS, NPSR, neuromedin U (NMU), NMU receptor 2 (NMUR2) and nesfatin-1 precursor nucleobindin-2 (NUCB2) gene expression. Acute escitalopram administration affects the local expression of the examined neuropeptides mRNA in a varied manner depending on brain location. An increase in NPSR and NUCB2 mRNA expression in the hypothalamus and brainstem was abolished by SHA-68 coadministration, while NMU mRNA expression was upregulated after NPSR blockade in the hippocampus and cerebellum. The pharmacological effects of escitalopram may be connected with local NPSR-related alterations in NPS/NMU/NMUR2 and nesfatin-1 gene expression at the level of selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.

Effect of Escitalopram on the Number of DCX-Positive Cells and NMUR2 Receptor Expression in the Rat Hippocampus under the Condition of NPSR Receptor Blockade.

Background: Neuropeptide S (NPS) is a multifunctional regulatory factor that exhibits a potent anxiolytic activity in animal models. However, there are no reports dealing with the potential molecular interactions between the activity of selective serotonin reuptake inhibitors (SSRIs) and NPS signaling, especially in the context of adult neurogenesis and the expression of noncanonical stress-related neuropeptides such as neuromedin U (NMU). The present work therefore focused on immunoexpression of neuromedin U receptor 2 (NMUR2) and doublecortin (DCX) in the rat hippocampus after acute treatment with escitalopram and in combination with selective neuropeptide S receptor (NPSR) blockade. Methods: Studies were carried out on adult, male Sprague-Dawley rats that were divided into five groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 10 mg/kg daily), escitalopram + SHA-68, a selective NPSR antagonist (at single dose 40 mg/kg), SHA-68 alone, and corresponding vehicle control. All animals were sacrificed under halothane anaesthesia. The whole hippocampi were quickly excised, fixed, and finally sliced for general qualitative immunohistochemical assessment of the NPSR and NMUR2 expression. The number of immature neurons was enumerated using immunofluorescent detection of doublecortin (DCX) expression within the subgranular zone (SGZ). Results: Acute escitalopram administration affects the number of DCX and NMUR2-expressing cells in the adult rat hippocampus. A decreased number of DCX-expressing neuroblasts after treatment with escitalopram was augmented by SHA-68 coadministration. Conclusions: Early pharmacological effects of escitalopram may be at least partly connected with local NPSR-related alterations of neuroblast maturation in the rat hippocampus. Escitalopram may affect neuropeptide and DCX-expression starting even from the first dose. Adult neurogenesis may be regulated via paracrine neuropeptide S and NMU-related signaling.

P612. Role of Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis in Modulating Anxiety-Like Behavior in Male and Female Rats

Corticotropin-releasing factor (CRF) is a stress-related neuropeptide that is produced in the dorsolateral bed nucleus of the stria terminalis (BNSTdl), a brain region that mediates behavioral responses to stressors.

Stimulation of brain corticotropin-releasing factor receptor type1 facilitates the rat micturition via brain glutamatergic receptors

Corticotropin-releasing factor (CRF), a representative stress-related neuropeptide, in the central nervous system reportedly both facilitates and suppresses the micturition, therefore, roles of central CRF in regulation of the micturition are still controversial. In this study, we investigated (1) effects of intracerebroventricularly (icv)-administered CRF on the micturition, and (2) brain CRF receptor subtypes (CRFR1/CRFR2) and glutamatergic receptors (NMDA/AMPA subtypes) involved in the CRF-induced effects in male Wistar rats under urethane anesthesia. Intercontraction intervals (ICI), and maximal voiding pressure (MVP), were evaluated by continuous cystometry 45 min before CRF administration or intracerebroventricular pretreatment with other drugs as follows and 3 h after CRF administration. Single-voided volume (Vv), post-voiding residual volume (Rv), bladder capacity (BC), and voiding efficiency (VE) were evaluated by single cystometry 60 min before CRF administration and 60–120 min after the administration. Icv-administered CRF reduced ICI, Vv, and BC without changing MVP, Rv, or VE. The CRF-induced ICI reduction was attenuated by icv-pretreated CP154526 (CRFR1 antagonist), MK-801 (NMDA receptor antagonist), and DNQX (AMPA receptor antagonist), but not by K41498 (CRFR2 antagonist). These results indicate that stimulation of brain CRFR1 can be involved in facilitation of the rat micturition via brain NMDA/AMPA receptors.

Yokukansan, a traditional Japanese medicine, suppresses stress-induced sympathetic activation and central responses to stress in rats

Stress exposure activates the sympathetic nervous system. We previously reported that restraint stress and stress-related neuropeptides increases plasma catecholamine levels and that brain prostanoids medicate these responses in rats. Yokukansan (YKS), a traditional Japanese medicine, has been used for neurosis, night crying and irritability. Additionally, it has been reported that YKS is also effective against the behavioral and psychological symptoms of dementia in patients with Alzheimer's disease, stress-related anxiety-like behavior and stress-induced increase in plasma corticosterone in rodents. These previous findings raise the possibility that YKS can exert its action in the brain and has suppressive effects on stress responses. In this study, we examined effects of YKS on stress-induced sympathetic activation and stress responses in the brain using rats. Repeated administration with YKS suppressed stress-induced increase in plasma adrenaline level. YKS also suppressed stress-induced elevation of prostaglandin E2 and thromboxane B2 levels in the paraventricular hypothalamic nucleus (PVN). In addition, YKS suppressed stress-induced increases of acetylcholine, GABA and serotonin in the PVN. Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain.

Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N6-methyladenosine (m6A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m6A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m6A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m6A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m6A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.

Corticotropin-Releasing Hormone from the Pontine Micturition Center Plays an Inhibitory Role in Micturition.

Lower urinary tract or voiding disorders are prevalent across all ages and affect >40% of adults over 40 years old, leading to decreased quality of life and high health care costs. The pontine micturition center (PMC; i.e., Barrington's nucleus) contains a large population of neurons that localize the stress-related neuropeptide, corticotropin-releasing hormone (CRH) and project to neurons in the spinal cord to regulate micturition. How the PMC and CRH-expressing neurons in the PMC control volitional micturition is of critical importance for human voiding disorders. To investigate the specific role of CRH in the PMC, neurons in the PMC-expressing CRH were optogenetically activated during in vivo cystometry in unanesthetized mice of either sex. Optogenetic activation of CRH-PMC neurons led to increased intermicturition interval and voided volume, similar to the altered voiding phenotype produced by social stress. Female mice showed a significantly more pronounced phenotype change compared with male mice. These effects were eliminated by CRH-receptor 1 antagonist pretreatment. Optogenetic inhibition of CRH-PMC neurons led to an altered voiding phenotype characterized by more frequent voids and smaller voided volumes. Last, in a cyclophosphamide cystitis model of bladder overactivity, optogenetic activation of CRH-PMC neurons returned the voiding pattern to normal. Collectively, our findings demonstrate that CRH from PMC spinal-projecting neurons has an inhibitory function on micturition and is a potential therapeutic target for human disease states, such as voiding postponement, urinary retention, and underactive or overactive bladder.SIGNIFICANCE STATEMENT The pontine micturition center (PMC), which is a major regulator of volitional micturition, is neurochemically heterogeneous, and excitatory neurotransmission derived from PMC neurons is thought to mediate the micturition reflex. In the present study, using optogenetic manipulation of CRH-containing neurons in double-transgenic mice, we demonstrate that CRH, which is prominent in PMC-spinal projections, has an inhibitory function on volitional micturition. Moreover, engaging this inhibitory function of CRH can ameliorate bladder hyperexcitability induced by cyclophosphamide in a model of cystitis. The data underscore CRH as a novel target for the treatment of voiding dysfunctions, which are highly prevalent disease processes in children and adults.

Corticotropin-Releasing Hormone Expressing Neurons of the Pontine Micturition Center Inhibit Volitional Micturition

Lower urinary tract or voiding disorders are prevalent across all ages and affect over 40% of adults over 40 years old leading to decreased quality of life and high healthcare costs. The pontine micturition center (PMC) contains a large population of neurons that co-localize the stress-related neuropeptide, corticotropin-releasing hormone (CRH) and project to neurons in the spinal cord to regulate micturition. How the PMC and CRH-expressing neurons in the PMC control volitional micturition is of critical importance for human voiding disorders. To investigate the specific role of these CRH-expressing PMC neurons, these neurons were optogenetically stimulated during in vivo cystometry in unanesthetized mice. Optogenetic activation of CRH-PMC neurons led to increased intermicturition interval and voided volume, similar to the altered voiding phenotype produced by social stress. These effects were eliminated by CRH-receptor 1 antagonist pretreatment. In a cyclophosphamide cystitis model of bladder overactivity, optogenetic stimulation of CRH-PMC neurons returned the voiding pattern to normal. Collectively, our findings demonstrate that CRH in PMC spinal projections has an inhibitory function on micturition and may be a potential therapeutic target for human disease states such as voiding postponement, urinary retention, and under- or over-active bladder.

Role of Corticotropin Releasing Factor in the Neuroimmune Mechanisms of Depression: Examination of Current Pharmaceutical and Herbal Therapies.

Approximately 3% of the world population suffers from depression, which is one of the most common form of mental disorder. Recent findings suggest that an interaction between the nervous system and immune system might be behind the pathophysiology of various neurological and psychiatric disorders, including depression. Neuropeptides have been shown to play a major role in mediating response to stress and inducing immune activation or suppression. Corticotropin releasing factor (CRF) is a major regulator of the hypothalamic pituitary adrenal (HPA) axis response. CRF is a stress-related neuropeptide whose dysregulation has been associated with depression. In this review, we summarized the role of CRF in the neuroimmune mechanisms of depression, and the potential therapeutic effects of Chinese herbal medicines (CHM) as well as other agents. Studying the network of CRF and immune responses will help to enhance our understanding of the pathogenesis of depression. Additionally, targeting this important network may aid in developing novel treatments for this debilitating psychiatric disorder.

Hypocretin in median raphe nucleus modulates footshock stimuli-induced REM sleep alteration

Stress is one of major factors that cause sleep problems. Hypocretin represents a stress-related neuropeptide and is well known in maintaining physiological wakefulness. The hypocretinergic neurons originate in the lateral hypothalamic area (LHA) and transmit to several brain regions, including the median raphe nuclei (MRNs). The MRNs modulate both fear responses and sleep-wake activity; however, it remains unclear whether stress alters the levels of hypocretin to regulate MRNs and consequently disrupt sleep. In this paper, we employed the inescapable footshock stimuli (IFS) as a stressor and hypothesized that the IFS-induced sleep disruption is mediated by increased hypocretins in the MRNs. Our results demonstrate that the concentrations of hypocretin in the hypothalamus increased after IFS. Rapid eye movement (REM) sleep was reduced after footshock, and microinjection of non-selective hypocretin receptor antagonist TCS-1102 into the MRNs blocked the IFS-induced decrease of REM sleep. Furthermore, administration of hypocretins into the MRNs mimicked the IFS-induced REM sleep reduction. These results conclude that the increased levels of hypocretins in the MRNs mediate the IFS-induced REM sleep reduction.

Effects of γ-aminobutyric acid on aggressive behaviour, jejunum villus morphology, serum biochemical indicators and hippocampal neuropeptide mRNA levels in piglets at weaning with mixing

The effects of γ-aminobutyric acid (GABA) on weanling piglets after mixing stress were investigated and the underlying molecular mechanism was analyzed. Sixty weaning piglets were randomly assigned to either the control group (weaning and mixing with a 3 : 3 sex ratio) or the GABA supplement group (30 mg GABA/kg body weight/day + weaning and mixing with a 3 : 3 sex ratio). Aggressive behaviours have been recorded for 2 days and the number of lesions for 3 days. The diarrhea rate on day 6 post-weaning and mixing was analyzed. Serum biochemical indicators, antioxidant variables, jejunum villus morphology and mRNA levels of stress-related neuropeptide genes of the hippocampus were investigated. The GABA addition decreased serum adrenocorticotropic hormone concentrations (P < 0.05), aggressive behaviours of weaned piglets 5 h after mixing (P < 0.05), lesion scores over the entire 3-day period (P < 0.01) and diarrhea rate (P < 0.01) and improved jejunum villus integrity. Serum neuropeptide Y (NPY) concentration (P < 0.05) and total superoxide dismutase activity (P < 0.01) were increased in the GABA supplement group, whereas serum malondialdehyde concentration had a decreasing tendency (0.05 < P < 0.1), and glutathione peroxidase activity had an increasing tendency (0.05 < P < 0.1). The GABA treatment group had increased mRNA levels of NPY (P < 0.05) and peptide YY (PYY) (P < 0.05) in the hippocampus, which may contribute to insights into the regulatory mechanism of GABA in weaning and mixing stress. The addition of GABA is beneficial to reduce weaning and mixing stress in piglets, and NPY and PYY may mediate the process.

Role of the Bed Nucleus of the Stria Terminalis in PTSD: Insights From Preclinical Models.

Post-traumatic stress disorder (PTSD) afflicts approximately 8% of the United States population and represents a significant public health burden, but the underlying neural mechanisms of this and other anxiety- and stressor-related disorders are largely unknown. Within the last few decades, several preclinical models of PSTD have been developed to help elucidate the mechanisms underlying dysregulated fear states. One brain area that has emerged as a critical mediator of stress-related behavioral processing in both clinical and laboratory settings is the bed nucleus of the stria terminalis (BNST). The BNST is interconnected with essential emotional processing regions, including prefrontal cortex, hippocampus and amygdala. It is activated by stressor exposure and undergoes neurochemical and morphological alterations as a result of stressor exposure. Stress-related neuro-peptides including corticotropin-releasing factor (CRF) and pituitary adenylate cyclase activating peptide (PACAP) are also abundant in the BNST, further implicating an involvement of BNST in stress responses. Behaviorally, the BNST is critical for acquisition and expression of fear and is well positioned to regulate fear relapse after periods of extinction. Here, we consider the role of the BNST in stress and memory processes in the context of preclinical models of PTSD.

MP11-13 CENTRALLY ADMINISTERED BOMBESIN INDUCES FREQUENT URINATION VIA BRAIN CORTICOTROPIN-RELEASING FACTOR RECEPTOR TYPE 1 IN RATS

INTRODUCTION AND OBJECTIVES:Psychological stress exacerbates bladder dysfunction such as overactive bladder (OAB) and bladder pain syndrome/interstitial cystitis (BPS/IC). We previously reported that bombesin (BB), a stress-related neuropeptide, centrally induces facilitation of the rat micturition reflex. Brain BB is reported to activate hypothalamo-pituitary-adrenal axis and sympathetic nerves, as representative responses to stressful conditions, via brain corticotropin-releasing factor (CRF), another stress-related neuropeptide. Therefore, we examined whether brain CRF is involved in the BB-induced frequent urination in rats.METHODS:(1) In urethane anesthetized (0.8 g/kg, ip) male Sprague-Dawley (SD) rats (300-400 g), a catheter was inserted into the bladder to perform cystometry (CMG, 12 ml/h saline infusion). Astressin (a non-selective CRF receptor antagonist, 1 or 3 nmol/rat) was intracerebroventricularly (icv) pretreated 60 min before BB administration (0.03 nmol/rat, icv). CMG was started 60 min b...