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Essential tremor (ET) is one of the most prevalent movement disorders and the most common cause of abnormal tremors. However, it cannot be treated efficiently with the currently available pharmacotherapy options. The pathophysiology of harmaline-induced tremor, most commonly used model of ET, involves various neurotransmitter systems including glutamate as well as ion channels. Agmatine, an endogenous neuromodulator, interacts with various glutamate receptor subtypes and ion channels, which have been associated with its’ beneficial effects on several neurological disorders. The current study aims to assess the effect of agmatine on the harmaline model of ET. Two separate groups of male rats were injected either with saline or agmatine (40 mg/kg) 30 min prior to single intraperitoneal injection of harmaline (20 mg/kg). The percent duration, intensity and frequency of tremor and locomotor activity were evaluated by a custom-built tremor and locomotion analysis system. Pretreatment with agmatine reduced the percent tremor duration and intensity of tremor induced by harmaline, without affecting the tremor frequency. However, it did not affect the decreased spontaneous locomotor activity due to harmaline. This pattern of ameliorating effects of agmatine on harmaline-induced tremor provide the first evidence for being considered as a treatment option for ET.

Erectile dysfunction (ED) has been reported to be associated with inflammation. This study investigated the effects of tumor necrosis factor alpha (TNF-α) inhibitor etanercept on penile neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) expressions, testosterone concentrations, neurogenic and endothelium-dependent relaxations of corpus cavernosum (CC), and circulating and cavernosal levels of inflammatory markers in aged rats. Animals were separated into control, aged, and etanercept-treated aged groups. Aged rats displayed significantly increased serum and cavernosal TNF-α, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule (ICAM–1) levels, and decreased penile nNOS and eNOS expressions and serum testosterone levels compared with controls. In etanercept-treated aged group, NOS expressions were similar to that of the control group. The circulating and cavernosal concentrations of TNF-α, CRP, MCP-1, ICAM-1, and testosterone were also normalized by etanercept. Neurogenic and endothelium-dependent relaxant responses significantly decreased in aged rats and etanercept treatment markedly improved these relaxation responses. Our findings indicate that aging decreases penile NOS expression, neurogenic and endothelium-dependent relaxations of CC, and also suppresses serum testosterone levels by inducing inflammatory response that may contribute to the development of ED. TNF-α antagonism may be a novel strategy to treat aging-associated ED.

Chronic stress is an important public health problem known as a risk factor for depression, cognitive deficits, and also erectile dysfunction (ED). Resveratrol, a plant polyphenol, was reported to activate constitutive endothelial nitric oxide synthase (eNOS). Although resveratrol has been proven to exert beneficial effects on the unpredictable chronic mild stress (UCMS)-induced decline in cognitive functions, its potential protecting effect on the penile tissue subjected to UCMS was in fact not investigated. Therefore, restorative effects of resveratrol on neurogenic and endothelium-dependent relaxations were evaluated in the corpus cavernosum of rabbits exposed to UCMS. Eighteen male New Zealand white rabbits were assigned into three groups (n = 6 in each group): controls; UCMS; and UCMS rabbits treated with resveratrol (20 mg/kg/day, i.p.) for 12-week period of stress induction. UCMS was induced by a couple of defined adverse conditions applied in a shuffled order for 12 weeks. Neurogenic and endothelium-dependent relaxations of corpus cavernosum were assessed by using organ bath studies. Both the electrical field stimulation (EFS)-induced neurogenic and carbachol-induced endothelium-dependent relaxant responses significantly decreased in physiological stress and resveratrol treatment exhibited a marked improvement in these relaxation responses in vitro. Our results indicated that chronic psychological stress could lead to ED by reducing neurogenic and endothelium-dependent relaxations and resveratrol prevents impairment of the functional responses, suggesting a potential new treatment approach for treatment of ED during psychological stress.

Chronic stress is associated with male sexual problems including ejaculatory dysfunctions. The aim of this study was to determine whether resveratrol (RS) or quercetin (QE) has protective effects on vas deferens (VD) contractility in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were separated into six groups: control, control + RS and control + QE, stress, stress + RS, and stress + QE. Stress groups were subjected to UCMS procedure for 5 weeks. Animals in treatment groups were injected intraperitoneally with RS (20 mg/kg) or QE (30 mg/kg) for 5 weeks during UCMS period. UCMS caused depressive-like behaviors and enhanced systemic levels of corticosterone. The nerve-evoked contractile responses of VD significantly impaired and, noradrenaline- and ATP-induced contractile responses of VD significantly increased in stressed rats. UCMS exposure also markedly enhanced oxidative stress and inflammation in VD tissues. Treatment with RS or QE significantly ameliorated all the aforementioned parameters. The current study demonstrated that RS or QE protected against chronic stress-induced VD dysfunction by their antioxidant and anti-inflammatory effects on VD, suggesting that oxidative stress and inflammation may be synergistic parts in the development of VD dysfunction associated with chronic stress-induced depression.

Objective NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictable mild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated with suppression of NLRP1.Methods Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronic ketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test were performed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissected and prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemical analysis.Results CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment ameliorated them. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB, endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba- 1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment.Conclusion In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shown to be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.

31st Congress of the European-College-of-Neuropsychopharmacology (ECNP) -- OCT 06-09, 2018 -- Barcelona, SPAIN WOS:000458400500354 Background: Diabetes mellitus (DM) is associated with modest impairments in cognition. Common molecular pathways to cellular and metabolic dysfunction have been implicated in both DM and cognitive dysfunctions. It has been shown in rodent models that cognitive impairment might be an adverse effect of diabetes. These models are being increasingly used to study pathogenesis and to develop new treatments [1,2]. Agmatine is an endogenous guanidoamine produced from L-arginine in many organs, including brain. Studies suggest that agmatine could be regarded as a neurotransmitter and shown to facilitate memory and learning in rats, in scopolamine-induced amnesia, streptozotocin (STZ)-induced Alzheimer model and chronic stress-induced depression [3]. Hence, the present study was conducted to examine the effect of agmatine as a possible antidiabetic agent in STZ-induced diabetes mellitus (DM) model in rats by evaluating cognitive functions, molecular mechanisms of neuroinflammation and neuroplasticity besides histological changes due to astrosit/microglial activation. European Coll Neuropsychopharmacol

Aksöz, Elif (Balikesir Author), Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. One of the most commonly prescribed oral antidiabetic drug, metformin, has been shown to have beneficial effects on restoring impaired cognitive function. In the present study, we investigated the effects of metformin on spatial memory in terms of alleviating scopolamine-induced learning and memory impairments in rats by using the Morris water maze (MWM) test and the modified elevated plus-maze (mEPM) test. Furthermore, we investigated the possible mechanisms of action of metformin in preventing cognitive dysfunction. Methods: Male Wistar rats received metformin (50, 100, or 200 mg/kg/day) via gavage feeding for three weeks. Scopolamine was administered intraperitoneally before the probe step of the MWM test or the acquisition session of the mEPM test. Results: The learning and memory impairment induced by scopolamine was reversed by metformin. In addition, metformin improved the level of phosphorylated AMP-activated protein kinase and cAMP responsive element binding protein. However, metformin pretreatment had no impact on inhibiting the scopolamine-induced changes in acetylcholine levels. Furthermore, metformin exerted its antioxidant effect by significantly reversing scopolamine-induced changes in malondialdehyde, total antioxidant status, and superoxide dismutase levels in the hippocampus. Conclusion: Our results indicate that one of the most commonly used antidiabetic drug, metformin, has the potential to prevent the development of dementia and be a novel therapeutic drug for the amelioration of cognitive dysfunction in AD., Balikesir University

Psychological stress may lead to erectile dysfunction (ED), and inflammation has been evaluated as a major contributing factor. The goal of this study was to investigate the effects of etanercept (ETN), an anti-tumor necrosis factor α (TNF-α) protein, on cavernosal function in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were divided into 4 groups: animals not exposed to UCMS, animals not exposed to UCMS and treated with ETN, animals exposed to UCMS, and animals treated with ETN while exposed to UCMS. UCMS significantly impaired the neurogenic and endothelium-dependent relaxation responses; reduced cavernosal endothelial nitric oxide (NO) synthase (eNOS) and neuronal NO synthase (nNOS) expressions; decreased testosterone levels; enhanced systemic levels of corticosterone, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1); and also increased cavernosal levels of TNF-α, IL-1β, and IL-6 in rats. ETN administration restored NO-mediated neurogenic and endothelium-dependent relaxation responses of the corpus cavernosum, increased cavernosal eNOS and nNOS expressions, enhanced testosterone levels, and decreased corticosterone levels in UCMS-exposed rats. Also, systemic inflammatory markers and cavernosal proinflammatory cytokine levels were reduced by ETN. Our results demonstrate the role of TNF-α-mediated inflammation in the development of depression and ED in rats exposed to chronic stress.

Since the discovery of nitric oxide (NO) as a neuronal messenger, its way to modulate learning and memory functions is subject of intense research. NO is an intercellular messenger in the central nervous system and is formed on demand through the conversion of L-arginine to L-citrulline via the enzyme nitric oxide synthase (NOS). Neuronal form of nitric oxide synthase may play an important role in a wide range of physiological and pathological conditions. Therefore the aim of this study was to investigate the effects of chronic 3-bromo 7-nitroindazole (3-Br 7-NI), specific neuronal nitric oxide synthase (nNOS) inhibitor, administration on spatial learning and memory performance in rats using the Morris water maze (MWM) paradigm. Male rats received either 3-Br 7-NI (20mg/kg/day) or saline via intraperitoneal injection for 5days. Daily administration of the specific neuronal nitric oxide synthase (nNOS) inhibitor, 3-Br 7-NI impaired the acquisition of the MWM task. 3-Br 7-NI also impaired the probe trial. The MWM training was associated with a significant increase in the brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. BDNF mRNA expression in the hippocampus did not change after 3-Br 7-NI treatment. L-arginine significantly reversed behavioural parameters, and the effect of 3-Br 7-NI was found to be NO-dependent. There were no differences in locomotor activity and blood pressure in 3-Br 7-NI treated rats. Our results may suggest that nNOS plays a key role in spatial memory formation in rats.

Objective: Biological aging has been recognized to cause impairment of memory and the development of vascular dementia. Based on our previous work, agmatine has been shown to have a beneficial effect and might have therapeutic potential on cognitive functions, including learning and memory. The aim of the present study was to examine the possible effect of agmatine on biological aging-induced vascular endothelial dysfunction and associated dementia in rats. Methods: We used three different age groups (4-month-olds, 18-month-olds and 24-montholds; n = 12 in each group) of control and agmatine-treated rats. Control animals received physiological saline for 8 weeks. Agmatine sulfate (40 mg/kg, twice daily) was given to the agmatine groups orally for 8 weeks. Herein, we investigated the effects of agmatine on systolic blood pressure (SBP), nitric oxide (NO)-mediated endothelium-dependent and - independent vasorelaxant responses in thoracic aorta, cognitive performance (passive avoidance test; PAT, and Morris water maze test; MWMT), endothelial nitric oxide synthase (eNOS) expression and both hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression in aged rats. Results: We found cognitive decline, endothelial dysfunction and reduced eNOS and BDNF expression in aged rats. All these changes may result from aging-induced vascular dementia. We also found that chronic treatment with agmatine may improve amygdala-dependent emotional and spatial learning and memorial performance, and endothelial function, and may regulate eNOS and BDNF protein expression in aged rats. Conclusion: Results of the current study point out that chronic agmatine treatment may prevent endothelial dysfunction associated with vascular dementia through eNOS and BDNF expression in aged rats. Gazi Universitesi Research Fund [01/2010-80] This study was supported by the Grant from the Gazi Universitesi Research Fund [project number: 01/2010-80] and presented at the 27th European College of Neuropsychopharmacology Congress, 18- 21 October 2014, Berlin, Germany. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. WOS:000403941900002 Q4

Sexual dysfunction is a common and underestimated effect of antidepressants. However, the mechanism by which these drugs cause erectile dysfunction is unclear. We investigated the reactivity of the corpus cavernosum of rabbits that were treated with either chronic imipramine, which is a tricyclic agent; agomelatine, which is a melatonergic agonist and serotonin 5HT(2c) antagonist; or moclobemide, which is a reversible inhibitor of monoamine-oxidase A. Twenty rabbits were randomly divided into four groups: the control group (n=5), the imipramine-treated group (n=5), which received i.p. injections of 10 mg/kg/day of imipramine, the moclobemide-treated group (n=5), which received i.p. injections of 20 mg/kg/day of moclobemide, and the agomelatine-treated group (n=5), which was orally administered 10 mg/kg/day of agomelatine. The reactivities of corpus cavernosum tissue obtained from the antidepressant-treated and the control groups were studied in organ chambers after the animals were subjected to 21 days of drug administration. The acetylcholine-induced endothelium-dependent and the electrical field stimulation (EFS)-induced neurogenic relaxation of the corpus cavernosum of the imipramine-treated group was significantly decreased compared with the control group. However, neither the acetylcholine- nor EFS-induced relaxation was changed in the moclobemide- or agomelatine-treated groups. There were no change in the relaxant response to the nitric oxide (NO) donor sodium nitroprusside and contractile response to KCl between the groups. This study suggests that chronic imipramine treatment but not agomelatine and moclobemide treatments causes significant functional changes in the penile erectile tissue of rabbits and that these changes may contribute to the development of impotence.

article i nfo Our aim was to investigate the effects of acute harmane administration upon learning and memory perfor- mance of rats using the three-panel runway paradigm and passive avoidance test. Male rats received harmane (2.5, 5, and 7.5 mg/kg, i.p.) or saline 30 min. before each session of experiments. In the three panel runway paradigm, harmane did not affect the number of errors and latency in reference memory. The effect of harmane on the errors of working memory was significantly higher following the doses of 5 mg/kg and 7.5 mg/kg. The latency was changed significantly at only 7.5 mg/kg in comparison to control group. Animals were given pre-training injection of harmane in the passive avoidance test in order to deter- mine the learning function. Harmane treatment decreased the retention latency significantly and dose de- pendently, which indicates an impairment in learning. In this study, harmane impaired working memory in three panel runway test and learning in passive avoidance test. As an endogenous bioactive molecule, harmane might have a critical role in the modulation of learning and memory functions.

Objective: Agmatine, the decarboxylation product of arginine produced by arginine decarboxylase, is a novel neurotransmitter and exists in the mammalian brain. Agmatine has been reported to modulate cognitive functions, including learning and memory. Methods: In the present study, we evaluated the effects of agmatine on cognitive performance and oxidative damage in intracerebroventricular (i.c.v.) streptozotocin (STZ) model of Alzheimer's disease (AD). Adult male Sprague-Dawley rats were injected STZ (3mg/kg, i.c.v, bilaterally) on days 1 and 3. The learning and memory patterns were assessed by using passive avoidance, Morris water maze, and closed field activity tests. Also, malondialdehyde (MDA), glutathione (GSH) levels and myeloperoxidase (MPO) activity have been determined as the parameters of oxidative damage. The behavioral tests were performed after 14 days from the first injection of STZ. Rats with impaired learning and memory performance were treated with intraperitoneal (i.p.) agmatine (40 mg/kg) twice daily for 7 days. After agmatine treatment, rats were subjected to the aforementioned behavioral tests again. Immediately after decapitation of the rats, the brains were collected and analyzed for oxidative damage parameters. Results: Agmatine improved the STZ-induced both spatial and emotinal memory impairment and oxidative damage. Findings of the study demonstrated the effectiveness of agmatine in reversing the cognitive deficits as well as the oxidative damage caused by i.c.v STZ. Conclusion: Taken together, our results have provided experimental evidence suggesting a possible therapeutic potential of agmatine as a regulator in etiopathogenesis of neurodegenerative diseases such as Alzheimer's disease.

Agmatine (l-amino-4-guanidino-butane), a metabolite of L-arginine through the action of arginine decarboxylase, is a novel neurotransmitter. In the present study, effects of agmatine on cognitive functions have been evaluated by using one trial step-down passive avoidance and three panel runway task. Agmatine (20, 40, 80 mg/kg i.p.) was administered either in the presence or absence of a cholinergic antagonist, scopolamine (1 mg/kg i.p.). Scopolamine significantly impaired learning and memory in both passive avoidance and three panel runway test. Agmatine did not affect emotional learning, working and reference memory but significantly improved scopolamine-induced impairment of learning and memory in a dose dependent manner. Our results indicate that agmatine, as an endogenous substance, may have an important role in modulation of learning and memory functions.

The aim of this study was to compare the effects of both neuronal NOS (nNOS) and inducible NOS (iNOS) inhibitor 2-iminobiotin, with the more selective nNOS inhibitor N(ω)-propyl-L-arginine (NPLA) and selective inducible NOS (iNOS) inhibitor aminoguanidine, on emotional learning, working memory and reference memory, by using three panel runway and passive avoidance paradigm in order to clarify the role of distinct isoforms of NOS in the regulation of learning and memory functions. NPLA and 2-iminobiotin significantly increased the number of errors and latency of working and reference memory performances of rats in three panel runway paradigm and impairs retention for the passive avoidance task. However, aminoguanidine did not affect cognitive functions in three panel runway and passive avoidance test. The effect of NPLA and 2-iminobiotin was reversed by pretreatment with a NOS substrate L-arginine. In conclusion, NPLA and 2-iminobiotin impaired cognitive functions in different kind of tasks used in this study and the effect of NPLA and 2-iminobiotin was found to be NO-dependent. Our results may confirm that nNOS plays the key role on emotional learning, working memory and reference memory in rats.

The effects of dextromethorphan (DM, CAS 6700-34-1), a common over-the-counter cough suppressant, on the reference memory have been investigated by a three-panel runway setup in rats. This study was designed by using a repeated acquisition procedure such as a radialarm maze task or a water maze task. DM (20-40 mg/kg i.p.) produced a significant decrease in the number of errors (pushes made on the two incorrect panels of the three panel gates at four choice points) and latency. Systemically administered scopolamine (CAS 114-49-8) (1 mg/kg i.p.) impaired the performance on both parameters. DM (40 mg/kg i.p.) was effective in reversing the reference memory deficit induced by administration of scopolamine. DM acts as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors. Our results suggest that inhibition of NMDA receptors by DM supports its potential positive properties. This finding might present an oppurtunity for the evaluation of this old antitussive drug.

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.

Antidepressant therapy is considered as one of the factors leading to male infertility. In this study, the effects of long-term treatment with fluoxetine or venlafaxine were investigated on electrical field stimulation (EFS, 1-64 Hz), noradrenaline (10(-8) to 10(-4) M), serotonin (10(-8) to 10(-4) M), adenosine 5'-triphosphate [ATP (10(-8) to 10(-4) M)] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of rat isolated vas deferens strips. Serotonin-induced contractile responses were significantly increased in the epididymal portion of the vas deferens obtained from the fluoxetine-treatment group, whereas in the prostatic portion there was no change. However, venlafaxine treatment had no effect on serotonin responses in the either portion of the vas deferens. Both fluoxetine and venlafaxine treatment significantly inhibited ATP-evoked contractions of the prostatic and epididymal portions of the rat vas deferens, but had no effect on EFS, noradrenaline- and KCl-evoked contractions of the vas deferentia in both portions. In conclusion, these results suggest that chronic treatment with fluoxetine and venlafaxine affects vas deferens motility. Purinoceptors may, at least in part, responsible for the impaired motility in chronic treatment of venlafaxine and fluoxetine.

Summary 1 Nicotine, which is tobacco alkaloid, still induces interests for researchers because of smokers addiction to nicotine. Nicotine having influence on the neuronal acetylcholine receptors (nAChRs) increases release of most certain neurotransmitters from the nerve endings. Also, nicotine, affecting the mitochondrial respiratory chains, contributes to the formation of reactive oxygen species. 2 In the present study, we investigated the effects of nicotine on smooth muscles of gastric fundus on the electrical field stimulation (EFS) that induces transition contraction via stimulation nAChRs. In addition, we aimed to investigate the interaction between release of acetylcholine, induced by nicotine, and the effects of reactive oxygen species. 3 Therefore, the effects of allopurinol (10 )6 ‐10 )5 M), deferoxamine (10 )4 M) and mannitol (10 )4 ‐5 · 10 )3 M) were tested on the transient contraction induced by nicotine. 4 In conclusion, mannitol (5 · 10 )3 M) significantly reduced contractile response to nicotine on EFS only in high concentration. Whereas in small concentrations mannitol (10 )4 M)

The role of nitric oxide (NO) on cognitive performance in a modified elevated plus-maze (mEPM) and passive-avoidance (PA) task was investigated by using the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI) and an NO precursor l -arginine. The interaction between the activation of N -methyl- d -aspartate (NMDA) receptors and NO synthesis on memory retention was also studied. 7-NI, l -arginine or MK-801, a non-competitive NMDA receptor antagonist were injected intraperitoneally (i.p) to male Wistar rats 30 min before the first training session of the PA test or 30 min before on the first day testing (acquisition session) of mEPM task. Transfer latency, the time rat took to move from the open arm to the enclosed arm, was used as an index of learning and memory in a mEPM test. The retention session was performed 24 h after the acquisition one. In the PA task, the retention test was carried out 24 h after training and reduction of retention latency was used to evaluate the acquisition of learning and memory. Blood glucose level and locomotor activity of the rats was also evaluated. 7-NI (10, 20, 25, 50 mg/kg) and MK-801 (0.15 mg/kg) significantly prolonged the transfer latency on retention session in a mEPM test and shortened step-through latency in PA test. 7-NI-induced impairment in memory and learning was partly reversed by l -arginine (200 mg/kg), a competitive substrate for NOS. However subeffective doses of 7-NI (5 mg/kg) and MK-801 (0.075 mg/kg) given in combination significantly impaired plus-maze and PA performances in rats. Thus NMDA receptor mediated NO pathways may be implicated in the PA and mEPM behaviours in rats. Since 7-NI does not affect blood pressure and did not alter blood glucose level and locomotor activity in conscious rats, 7-NI-induced impairment of memory is not due to either hypertension, changes in blood glucose level or effects on locomotor activity.

Antidepressants inhibiting the reuptake of both serotonin and norepinephrine may exhibit efficacy superior to that of selective serotonin reuptake inhibitors (SSRIs). Since the clinical effects of antidepressants appear gradually following weeks of treatment, the present study was designed to investigate if there is a benefit to long-term administration of the SSRI, fluoxetine, in comparison with venlafaxine, a 5-HT/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI; both 20 mg/kg ip, once a day for 14 days) in a one-trial step-through passive avoidance task in rats. Locomotor activity was evaluated to assess the effects of the drugs on the motility of the animals. The comparison of training latencies versus test latencies showed inhibition of passive avoidance learning in fluoxetine- or venlafaxine-treated rats (e.g., no significant difference between training and test latencies) in a step-through test. There was no significant difference between fluoxetine- and venlafaxine-induced reduction of latency in rats in this test. Drug Dev. Res. 67:456–461, 2006. © 2006 Wiley-Liss, Inc.

Studies on the occurrence and properties of b-carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds play a role in processes of substance abuse and dependence. This study investigates the effects of harmane on naloxone-precipitated withdrawal syndrome in morphine-dependent guinea pig ileum. Segments of ilea from starved male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ bath containing 10(-6) M morphine in Tyrode solution at 37 degrees C, which was bubbled with 95% O(2) and 5% CO(2). Tissues were incubated in 10(-6) M morphine containing Tyrode solution for 4 hours before harmane was added. Naloxone and harmane had no effect on naive ilea. Naloxone (10(-6) M) contracted morphine-dependent ilea. Harmane significantly inhibited the contractile response to naloxone in a dose-dependent manner (10(-7) M = 24%; 10(-6) M = 49.3%; 10(-5) = 70%). These results suggest that harmane may have beneficial effects on morphine withdrawal syndrome.

ObjectiveHarmane is a beta-carboline, which binds to imidazoline receptors and it has been previously shown that it may have an antidepressant effect when administered acutely. This study is planned to investigate the effect of harmane on chronic unpredictable mild stress (CUMS) model and microglial (Iba-1) immunoreactivity in the same model as markers of neuroinflammation.MethodsMale Wistar Albino rats (290–360 g) were divided into groups such as control (saline), CUMS, CUMS + Imipramine (20 mg/kg; i.p.), CUMS + Harmane5 (5 mg/kg; i.p.), CUMS + Harmane10 (10 mg/kg; i.p.) groups (n = 10–12 in each). In CUMS model, various stressors were applied for 40 days. On day 20, harmane administration was started for 20 days. At the end, sucrose preference and forced swimming tests were performed. Then, brains were removed with paraformaldehyde perfusion for Iba-1 immunohistochemical analysis in hippocampus. One-way analysis of variance and Tukey's test were used for statistical analysis.ResultsThe time of immobility in forced swim test was significantly reduced while sucrose preference was increased in Imipramine and CUMS + harmane10 groups. In immunohistochemical experiments, Iba-1 were overexpressed in CUMS group and Harmane significantly reduced the overexpression of Iba-1.ConclusionOur results suggest that chronic administration of harmane has an antidepressant-like activity in chronic stress model of depression. These results support the notion of imidazoline receptors involvement in depression by modulating neuroinflammation and at least a part of its antidepressant effect might be through modulating microglial activation as a reflection of neuroinflammation.This research was supported by Marmara University, Scientific Research Projects – SAG-C-YLP-110915-0415 and SAG-E-120613-0233.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Effects of agmatine, an endogenous metabolite formed by decarboxylation of L-arginine, on ethanol-induced gastric mucosal injury were investigated in rats. Agmatine at 1 and 10 mg/kg i.p doses significantly increased ethanol-induced gastric mucosal injury. This effect of agmatine was abolished completely by pretreatment with idazoxan, an imidazoline receptor-antagonist and alpha2 receptor- antagonist, (0.5 mg/kg i.p), partly by yohimbine, an alpha2 receptor- antagonist, (1 mg/kg i.p) but not by L-arginine, a precursor of nitric oxide, (500 mg/kg i.p). Our results suggest that agmatine had a potent ulcerogenic effect mediated, at least in part, by both alpha2-adrenoceptors and imidazoline receptors.

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.

The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.

An animal model was developed to elucidate the effect of chronic obstruction of the internal pudendal artery on the responsiveness of the corpus cavernosum. In male albino rabbits, the internal pudendal artery was chronically ligated unilaterally with a silk tie and the occlusion was maintained for 1 month. The control group was sham-operated. The reactivity of corpus cavernosum tissue from the ligated animals and the control animals was studied in organ chambers. Unilateral chronic ligation of the internal pudendal artery caused an impaired contractile response to α-adrenoceptor stimulation with decreased Em and pD2 values and an impaired relaxant response to electrical field stimulation but resulted in a marked increase in the endothelium-dependent relaxant response to carbachol with an increased pD2 value. However chronic obstruction of the pudendal artery had no effect on adenosine-, papaverine- and sodium nitroprusside-induced relaxant responses, and there was no change in agonist potency. These data indicate that altered penile hemodynamics have an effect on the reactivity of the corpus cavernosum and may contribute to the etiology of impotence.

Succinic acid monomethyl ester (SAM) was recently proposed as an insulinotropic tool in non-insulin-dependent diabetes mellitus. The present study was designed to define whether SAM has the vascular effect in thoracic aorta of streptozotocin (STZ)-diabetic rats. (1) Body weights of diabetic rats were significantly increased after SAM treatment (P0.05). (2) Ten-day SAM treatment did not significantly affect blood glucose levels in SAM-treated control and SAM-treated STZ-diabetic rats. (3) Maximum tension responses to noradrenaline and KCl (80 mmol l-1) were not significantly different among all the experimental groups. (4) pD2 (-log EC50) values for noradrenaline of untreated diabetic rats were significantly less than those of controls, SAM-treated control and SAM-treated diabetic rats (P0.01, P0.001 and P0.05, respectively). SAM treatment normalized the decreased sensitivity of noradrenaline response in diabetic rats. (5) Fast, slow and total components of responses to noradrenaline (10(-5) mol l-1 approximately equal to EC90) were not significantly different among all the experimental groups. (6) There were no significant differences between aorta precontracted with noradrenaline from controls and STZ-diabetic (untreated and SAM-treated) rats in pD2 values and the potency of maximum relaxation to acetylcholine or in pD2 values to sodium nitroprusside. In conclusion, 10-day SAM treatment increases the sensitivity of diabetic-aortic rings to noradrenaline compared to untreated diabetic control rats.

WOS: 000072668400005, PubMed ID: 9566022, It is known that diabetes mellitus alters the vascular responsiveness to several vasoconstrictors and vasodilators. Endothelium-derived nitric oxide is a potent endogenous nitrovasodilator, and endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor substance. They play a major role in the modulation of vascular tone. Selective impairment of endothelium-dependent relaxation and impaired vasoconstriction in response to ET-1 could result in vascular disorders. The purpose of our study was to determine whether vascular responses to ET-1 and endothelium-dependent relaxing substances are impaired in rats with streptozotocin-induced diabetes of 2 weeks duration. Endothelium-dependent relaxations produced by carbachol and ATP in aortic rings precontracted with phenylephrine were significantly attenuated in rings from diabetic rats, but the endothelium-independent relaxations produced by sodium nitroprusside and adenosine in diabetic preparations were not changed when compared to the corresponding controls. The ET-1-induced contractions were significantly attenuated with no change in agonist potency (pD(2) value) in aortae with and without endothelium obtained from diabetic rats when compared to those from controls. Mechanical removal of the endothelium did not significantly change ET-1 responses of aortae from either diabetic or control rats compared with responses of aortae with intact endothelium. These results suggest that, in this diabetic model, the contractile responsiveness of thoracic aortic muscles and the endothelial functions are significantly altered during 2 weeks of diabetes.

The analgesic effects of verapamil, a calcium channel blocker, and chloramphenicol, a phenicolated antibiotic, were compared using the test of acetic-acid-induced writhing and the hot-plate test in mice. The results suggest that both drugs have antinociceptive properties comparable to salicylate analgesia. No significant difference was found between verapamil- and chloramphenicol-induced analgesia (p < 0.05).

Stress has been recognized as a risk factor for cardiovascular disease and depression, but the correlation is not well understood. However, inflammation is known to have a crucial role in both cardiovascular disease and depression. Tumor necrosis factor alpha (TNF-α) is a major cytokine for the activation of neuroendocrine, immune and behavioral responses. Therefore, we aimed to explore the effects of etanercept, an anti-TNF-α fusion protein, on endothelium-dependent vascular reactivity, blood pressure and endothelial nitric oxide synthase (eNOS) immunoreactivity in a model of unpredictable chronic mild stress (UCMS). Male rats were exposed to UCMS for 8 weeks, and etanercept (0.8 mg/kg, weekly) was administered during UCMS induction. The systolic blood pressure was recorded by the tail cuff method, and the relaxant responses of the aorta induced by carbachol, sodium nitroprusside (SNP) and papaverine were evaluated in an isolated organ bath system. UCMS rats exhibited an impaired carbachol-induced relaxant response compared to control rats, but there were no significant differences in the SNP- and papaverine-induced relaxant responses between the control and stressed rats. Etanercept treatment improved the carbachol-induced endothelium dependent relaxations observed in rats that experienced UCMS. No significant change in the systemic blood pressure was observed, but decreased expression of eNOS was detected in the UCMS group. Moreover, there were no significant changes in the etanercept treatment group compared to the control rats. Our results suggest that TNF-α could be a mediator of vascular dysfunction associated with UCMS, which leads to decreased expression of eNOS.

Pro-inflammatory cytokines have been proposed to be associated with the pathogenesis of depression. Consistent with this notion, several clinical observations have suggested the antidepressant efficacy of TNF-α inhibitors in patients with chronic inflammatory diseases. In this study, we evaluated the antidepressant and anxiolytic effects of chronic TNF-α inhibitor (infliximab, 5 mg/kg, i.p., weekly) administration in the chronic mild stress (CMS) model of depression. Rats were divided into three groups: saline-control (no stress), saline-CMS, and infliximab-CMS. Rats in the latter two groups were exposed to CMS for 8 weeks. Saline (former two groups) or infliximab was injected weekly during this period. After CMS, total locomotor activity, anxiety-like behaviour and depression-like behaviours were evaluated using automated locomotor activity cage, elevated plus maze (EPM), and sucrose preference (SPT) and forced swimming (FS) tests, respectively. As expected, the saline-CMS group exhibited higher depression-like behaviours in FS and SPT tests compared with the saline-control group. There were no differences between these two groups in terms of the anxiety-like behaviour or total locomotor activity. Infliximab reduced the depression-like behaviour of CMS rats compared with saline-CMS group, and anxiety-like behaviour of CMS rats compared with saline-CMS and saline-control groups. Our findings suggest that chronic and systemic TNF-α inhibition reduced depression and anxiety-like behaviour in the CMS model of depression in rats.

Depression is the most common psychiatric disorder. It is well established that endogenous nitric oxide (NO) contributes to chronic unpredictable mild stress (CUMS)-induced depression. The aim of this study was to investigate brain-derived neurotropic factor (BDNF) expression in CUMS-induced depression-like behaviour in rats. Rats were exposed to CUMS for 5 weeks. A specific and selective nNOS inhibitor, 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg/day, i.p.), and a specific soluble guanylate cyclase (sGC) inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 mg/kg/day, i.p.), were administered during CUMS. The forced swimming test (FST) was used to assess despair and sucrose consumption, and sucrose preference test was used to assess anhedonia that are the main symptoms of the depression. We show that both 3-Br-7-NI and ODQ administration during CUMS suppressed CUMS-induced, depression-like behavioural changes, including reduced sucrose preference, body-weight and locomotor activity as well as increased immobility time in the FST. CUMS also significantly decreased BDNF protein levels in the CA1 and CA3 regions of the hippocampus, which was reversed by 3-Br-7-NI and ODQ administration. Our findings suggest a novel role for nNOS and sGC-cGMP in the development of the CUMS model of depression.