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Acute Administration (acute + administration)
Selected AbstractsResistin increases islet blood flow and decreases subcutaneous adipose tissue blood flow in anaesthetized ratsACTA PHYSIOLOGICA, Issue 2 2009T. Danielsson Abstract Aim:, Resistin is an adipokine which has been suggested to participate in the induction of insulin resistance associated with type 2 diabetes. The aim of the present study was to investigate whether acute administration of resistin influences tissue blood perfusion in rats. Methods:, Resistin was administered as an intravenous infusion of 7.5 ,g h,1 (1.5 mL h,1) for 30 min to rats anaesthetized with thiobutabarbital. A microsphere technique was used to estimate the blood flow to six different depots of white adipose tissue (WAT), brown adipose tissue (BAT), as well as to the pancreas, islets, duodenum, colon, kidneys, adrenal glands and liver. Results:, Resistin administration led to an increased blood flow to the pancreas and islets and a decrease in subcutaneous WAT and BAT. Intra-abdominal white adipose tissue blood flow and that to other organs were not affected. Conclusion:, Acute administration of resistin markedly affects the blood perfusion of both the pancreas and subcutaneous white adipose tissue depots. At present it is unknown whether resistin exerts a direct effect on the vasculature, or works through local or systemic activation of endothelial cells and/or macrophages. The extent to which this might contribute to the insulin resistance caused by resistin is yet unknown. [source] Effects of lorazepam on visual perceptual abilitiesHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 3 2008S. Pompéia Abstract Objective To evaluate the effects of an acute dose of the benzodiazepine (BZ) lorazepam in young healthy volunteers on five distinguishable visual perception abilities determined by previous factor-analytic studies. Methods This was a double-blind, cross-over design study of acute oral doses of lorazepam (2,mg) and placebo in young healthy volunteers. We focused on a set of paper-and-pencil tests of visual perceptual abilities that load on five correlated but distinguishable factors (Spatial Visualization, Spatial Relations, Perceptual Speed, Closure Speed, and Closure Flexibility). Some other tests (DSST, immediate and delayed recall of prose; measures of subjective mood alterations) were used to control for the classic BZ-induced effects. Results Lorazepam impaired performance in the DSST and delayed recall of prose, increased subjective sedation and impaired tasks of all abilities except Spatial Visualization and Closure Speed. Only impairment in Perceptual Speed (Identical Pictures task) and delayed recall of prose were not explained by sedation. Conclusion Acute administration of lorazepam, in a dose that impaired episodic memory, selectively affected different visual perceptual abilities before and after controlling for sedation. Central executive demands and sedation did not account for results, so impairment in the Identical Pictures task may be attributed to lorazepam's visual processing alterations. Copyright © 2008 John Wiley & Sons, Ltd. [source] Carisbamate, a Novel Antiepileptic Candidate Compound, Attenuates Alcohol Intake in Alcohol-Preferring RatsALCOHOLISM, Issue 8 2009Amir H. Rezvani Background:, Since 1994, when naltrexone (Revia®) was approved by the FDA for the treatment of alcoholism, only 2 other drugs (Campral® and Topamax®) have been approved for alcoholism treatment. However, various experimental drugs, including antiepileptic medications, have been tested in both animal models and in humans with some promising results. The purpose of this project was to study the effect of the novel neuromodulator carisbamate, which is in development for epilepsy treatment, on alcohol intake in selectively bred alcohol-preferring rats. Methods:, Male alcohol-preferring inbred P rats were allowed to freely drink water or alcohol (10%, v/v) using a 2-bottle choice procedure. After stable baselines for alcohol and water intakes were established, the acute effects of oral carisbamate (0, 10, 30, 45, 60, and 90 mg/kg) were assessed. Then, the chronic effect of the compound (60 mg/kg/day for 14 consecutive days) on alcohol intake was assessed in a separate group of male P rats. In another set of experiments, the effects of carisbamate and naltrexone on alcohol withdrawal-induced elevated drinking of alcohol, an index of craving, were compared. Rats were withdrawn from alcohol for 24 hours and were given vehicle, 20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes before re-exposure to alcohol. Alcohol and water intake was measured 6 hours after alcohol re-exposure. To determine the effects of carisbamate on saccharin preference, rats were put on a 2-bottle choice of water versus a solution of 2% saccharin. Then, the effect of the highest dose of carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the vehicle on saccharin preference was determined. Results:, Our results showed that there was a selective dose-dependent reduction in alcohol intake and preference in the alcohol-preferring P rat after an acute oral administration of carisbamate. There were no significant effects on food or water intake. Chronic administration of carisbamate significantly reduced alcohol intake and preference initially, but partial tolerance developed after the 10th treatment. The degree of tolerance development was less than that observed for naltrexone. Acute administration of carisbamate was more effective than naltrexone in reducing enhanced alcohol intake after a period of alcohol deprivation. Compared with control vehicle neither carisbamate nor naltrexone had a significant effect on saccharin intake and preference. Conclusion:, The novel neuromodulator compound carisbamate has a favorable profile of effects on alcohol intake and related measures and should be considered for testing on human alcoholics. [source] Ethanol Consumption Increases Nitric Oxide Production in Rats, and Its Peroxynitrite-Mediated Toxicity Is Attenuated by PolyenylphosphatidylcholineALCOHOLISM, Issue 6 2002Enrique Baraona Background: Nitric oxide generally mediates beneficial responses but becomes deleterious when coexistence with enhanced superoxide formation leads to the synthesis of peroxynitrite, a potent oxidant and nitrating agent. Methods: To study the effects of ethanol and polyenylphosphatidylcholine on nitric oxide metabolism and toxicity, 36 rats were pair-fed liquid diets with 36% of energy either as ethanol or as additional carbohydrate for 24 days and were killed 90 min after intragastric feeding. Half received polyenylphosphatidylcholine in the diet (3 g/liter), and the other half equivalent amounts of essential fatty acids and choline. Nitric oxide was measured by chemiluminescence in arterial blood and liver cytosol and as a product of the inducible nitric oxide synthase activity. Peroxynitrite formation was assessed by the increase in nitrotyrosine protein residues, measured immunochemically. Results: In blood, administration of ethanol with or without polyenylphosphatidylcholine doubled nitric oxide levels. In the liver, ethanol increased nitric oxide by 52% (p < 0.01), and polyenylphosphatidylcholine attenuated this effect. Ethanol consumption increased the cytosolic activity of the inducible nitric oxide synthase and induced microsomal cytochromes P-450 capable of producing both nitric oxide and superoxide. This was associated with an 18% (p < 0.01) increase in nitrotyrosine protein residues, products of peroxynitrite toxicity, which occurred predominantly in steatotic hepatocytes. Polyenylphosphatidylcholine attenuated these changes by decreasing the ethanol effect on both the cytosolic and the microsomal activities, in addition to acting as a powerful antioxidant. Acute administration of the same ethanol dose increased nitric oxide levels, but did not affect nitrotyrosine protein residues. Conclusions: Chronic, but not acute, ethanol administration increases peroxynitrite hepatotoxicity by enhancing concomitant production of nitric oxide and superoxide, both of which are prevented by polyenylphosphatidylcholine. [source] Effect of long-term treatment with octreotide on rectal sensitivity in patients with non-constipated irritable bowel syndromeALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007T. K. KLOOKER Summary Background, Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown. Aim, To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients. Methods, Forty-six non-constipated irritable bowel syndrome patients (52% female, 19,63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly. Results, Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, P < 0.05). In contrast, abdominal pain and defecation frequency were not affected. Conclusions, Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms. [source] Acute neuropsychological effects of methylphenidate in stimulant drug-naïve boys with ADHD II , broader executive and non-executive domainsTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 11 2006Sinéad M. Rhodes Background:, Accumulating evidence supports methylphenidate-induced enhancement of neuropsychological functioning in attention deficit hyperactivity disorder (ADHD). The present study was designed to investigate the acute effects of the psychostimulant drug, methylphenidate (MPH), on neuropsychological performance in stimulant naïve boys with ADHD. Methods:, Seventy-three drug-naïve boys (age 7,15) with ADHD (combined type) completed neuropsychological tasks from the CANTAB battery under randomised, placebo controlled, double-blind conditions following an acute challenge with either placebo (n = 24), .3 (n = 25) or .6 (n = 24) mg/kg oral MPH. Results:, MPH did not impair performance on any task. MPH (.6 mg/kg) lengthened response latencies on a task of Spatial Recognition, shortened response times on a Reaction Time task and restored performance on a Delayed Matching to Sample visual, non-working memory task. Contrary to predictions, MPH did not enhance performance on tasks with a prominent executive component, including Go/NoGo, Spatial Working Memory, Stockings of Cambridge and Attentional Set shifting tasks. Conclusions:, Acute administration of MPH to drug-naïve boys with ADHD did not impair neuropsychological performance. Acute MPH enhanced performance on some aspects of non-executive functioning. MPH-induced slowing of responding on a relatively complex Spatial Recognition memory task and quickened responding on a reaction time task requiring less cognitive resources suggests that MPH may act by improving self-regulatory ability. MPH may not exert its effects on neuropsychological functioning by enhancing executive processes. [source] Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathyANNALS OF NEUROLOGY, Issue 1 2007Christine Brefel-Courbon MD We conducted a randomized, double-blind, placebo-controlled, single-patient (N = 1) trial to evaluate the efficacy of zolpidem in a 48-year-old woman with an akinetic mutism. Motor and cognitive examinations and functional imaging were performed. Acute administration of zolpidem markedly improved motor performance and neuropsychological status. Cerebral metabolism (18F-fluorodeoxyglucose positron emission tomography) increased in postrolandic territories and in frontal cortex. Using the H215O positron emission tomography, we found a drug-induced activation in the anterior cingulate and orbitofrontal cortices. Zolpidem induced a transient improvement in motor and cognitive performances. This paradoxical effect could result from an activation of limbic loops modulating motivational processes. Ann Neurol 2007 [source] Attenuation of acute and chronic effects of morphine by the imidazoline receptor ligand 2-(2-benzofuranyl)-2-imidazoline in rat locus coeruleus neuronsBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2003Eduardo Ruiz-Durántez The aim of this study was to determine if 2-(2-benzofuranyl)-2-imidazoline (2-BFI) interacts with the opioid system in the rat locus coeruleus, using single-unit extracellular recordings. In morphine-dependent rats, acute administration of the selective imidazoline receptor ligands 2-BFI (10 and 40 mg kg,1, i.p. and 100 ,g, i.c.v.) or valldemossine (10 mg kg,1, i.p.) did not modify the naloxone-induced hyperactivity of locus coeruleus neurons compared with that observed in the morphine-dependent control group. After chronic administration of 2-BFI (10 mg kg,1, i.p., three times daily, for 5 days) and morphine, naloxone-induced hyperactivity and tolerance to morphine were attenuated. This effect was not observed when a lower dose of 2-BFI (1 mg kg,1, i.p.) or valldemossine (10 mg kg,1, i.p.) were used. Acute administration of 2-BFI (10 and 40 mg kg,1, i.p. and 100 ,g, i.c.v.) but not valldemossine (40 mg kg,1, i.p.) diminished the potency of morphine to inhibit locus coeruleus neuron activity in vivo (ED50 values increased by 2.3, 2.9; and 3.1 fold respectively). Similarly, the potency of Met5 -enkephalin to inhibit locus coeruleus neurons was decreased when 2-BFI (100 ,M) was applied to rat brain slices (EC50 increased by 5.6; P<0.05). The present data demonstrate that there is an interaction between 2-BFI and the opioid system in the locus coeruleus. This interaction leads to an attenuation of both the hyperactivity of locus coeruleus neurons during opiate withdrawal and the development of tolerance to morphine when 2-BFI is chronically administered. These results suggest that imidazoline drugs may prove to be useful agents for the management of opioid dependence and tolerance. British Journal of Pharmacology (2003) 138, 494,500. doi:10.1038/sj.bjp.0705052 [source] Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brainCELL BIOCHEMISTRY AND FUNCTION, Issue 3 2003M. Kemal Irmak Abstract Oxygen-derived free radicals have been implicated in the pathogenesis of cerebral injury after ischaemia,reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant properties. The purpose of the present study was to investigate the effects of ischaemia and subsequent reperfusion on rat brain and to investigate the effects of two free radical scavengers, CAPE and alpha-tocopherol, on this in vivo model of cerebral injury. Ischaemia was induced by bilateral occlusion of the carotid arteries for 20,min and reperfusion was achieved by releasing the occlusion to restore the circulation for 20,min. Control rats underwent a sham operation. CAPE at 10,,;mol,kg,1 or alpha-tocopherol at 25,,mol,kg,1 was administered intraperitoneally before reperfusion. Reperfusion led to significant increase in the activity of xanthine oxidase and higher malondialdehyde levels in the brain. Acute administration of both CAPE and alpha-tocopherol suppressed ischaemia,reperfusion-induced cerebral lipid peroxidation and injury, but CAPE seems to offer a better therapeutic advantage over alpha-tocopherol. Copyright © 2003 John Wiley & Sons, Ltd. [source] Caffeic acid phenethyl ester changes the indices of oxidative stress in serum of rats with renal ischaemia,reperfusion injuryCELL BIOCHEMISTRY AND FUNCTION, Issue 4 2001Hüseyin Özyurt Abstract Oxygen-derived free radicals have been implicated in the pathogenesis of renal injury after ischaemia,reperfusion. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, exhibits antioxidant properties. To investigate whether treatment with either CAPE or alpha-tocopherol modifies the levels of the endogenous indices of oxidant stress, we examined their effects on an in vivo model of renal ischaemia,reperfusion injury in rats. CAPE at 10,,mol,kg,1 or alpha-tocopherol at 10,mg,kg,1 was administered intraperitoneally before reperfusion. Acute administration of both CAPE and alpha-tocopherol altered the indices of oxidative stress differently in renal ischaemia,reperfusion injury. Copyright © 2001 John Wiley & Sons, Ltd. [source] Resistin increases islet blood flow and decreases subcutaneous adipose tissue blood flow in anaesthetized ratsACTA PHYSIOLOGICA, Issue 2 2009T. Danielsson Abstract Aim:, Resistin is an adipokine which has been suggested to participate in the induction of insulin resistance associated with type 2 diabetes. The aim of the present study was to investigate whether acute administration of resistin influences tissue blood perfusion in rats. Methods:, Resistin was administered as an intravenous infusion of 7.5 ,g h,1 (1.5 mL h,1) for 30 min to rats anaesthetized with thiobutabarbital. A microsphere technique was used to estimate the blood flow to six different depots of white adipose tissue (WAT), brown adipose tissue (BAT), as well as to the pancreas, islets, duodenum, colon, kidneys, adrenal glands and liver. Results:, Resistin administration led to an increased blood flow to the pancreas and islets and a decrease in subcutaneous WAT and BAT. Intra-abdominal white adipose tissue blood flow and that to other organs were not affected. Conclusion:, Acute administration of resistin markedly affects the blood perfusion of both the pancreas and subcutaneous white adipose tissue depots. At present it is unknown whether resistin exerts a direct effect on the vasculature, or works through local or systemic activation of endothelial cells and/or macrophages. The extent to which this might contribute to the insulin resistance caused by resistin is yet unknown. [source] PRECLINICAL STUDY: Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in ratsADDICTION BIOLOGY, Issue 1 2008Firas H. Kobeissy ABSTRACT Club drug abuse is a growing problem in the United States. Beyond addiction and toxicity are endocrine effects which are not well characterized. Specifically, the changes in appetite following exposure to drugs of abuse are an interesting but poorly understood phenomenon. Serum hormones such as leptin, ghrelin, growth hormone (GH), and neuropeptide-Y (NP-Y) are known to affect appetite, but have not been studied extensively with drugs of abuse. In this work, we examine the effects of club drugs 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) and methamphetamine (METH) (doses of 5, 20 and 40 mg/kg) on serum concentrations of these hormones in adult male Sprague-Dawley rats 6, 12, 24 and 48 hours after drug administration. In a dose-dependent manner, MDMA was shown to cause transient significant decreases in serum leptin and GH followed by a base line recovery after 24 hours. Conversely, serum ghrelin increased and normalized after 24 hours. Interestingly, serum NP-Y showed a steady decrease in both treatment of MDMA and METH at different time points and dosages. In humans, abuse of these drugs reduces eating. As evident from these data, acute administration of METH and MDMA had significant effects on different serum hormone levels involved in appetite regulation. Future studies should be performed to see how chronic, low dose drug administration would affect hormone levels and try to answer questions about the physiological mechanisms involved in the anorexic paradigm observed in drug use. [source] GDNF hyperalgesia is mediated by PLC,, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versicanEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2008Oliver Bogen Abstract The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4,saporin, a selective toxin for IB4+/Ret+ -nociceptors, attenuates GDNF but not NGF hyperalgesia. Conversely, intrathecal antisense to Trk A attenuated NGF but not GDNF hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFR,1/Ret: PLC,, CDK5, PI3K, MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype. [source] A test of the opponent-process theory of motivation using lesions that selectively block morphine rewardEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Hector Vargas-Perez Abstract The opponent-process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine-naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place-conditioning paradigm. The conditioned place aversion induced by 16-h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP-lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors. [source] Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol inPKC,-deficient miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000M. Foster Olive Abstract There is increasing evidence that individual protein kinase C (PKC) isozymes mediate specific effects of ethanol on the nervous system. In addition, multiple lines of evidence suggest that the mesoaccumbens dopamine reward system is critically involved in the rewarding and reinforcing effects of ethanol. Yet little is known about the role of individual PKC isozymes in ethanol reinforcement processes or in regulation of mesolimbic systems. In this study, we report that mice lacking the epsilon isoform of PKC (PKC,) show reduced operant ethanol self-administration and an absence of ethanol-induced increase in extracellular dopamine levels in the nucleus accumbens. PKC, null mice exhibited a 53% decrease in alcohol-reinforced operant responses under basal conditions, as well as following ethanol deprivation. Behavioural analysis revealed that while both genotypes had the same number of drinking bouts following deprivation, PKC, null mice demonstrated a 61% reduction in number of ethanol reinforcers per bout and a 57% reduction in ethanol-reinforced response rate. In vivo microdialysis experiments showed that, in contrast to wild-type mice, PKC, null mice exhibited no change in extracellular levels of dopamine in the nucleus accumbens following acute administration of ethanol (1 and 2 g/kg i.p.), while mesolimbic dopamine responses to cocaine (20 mg/kg i.p.) or high potassium (100 m m) in these mice were comparable with that of wild-types. These data provide further evidence that increases in extracellular mesolimbic dopamine levels contribute to the reinforcing effects of ethanol, and indicate that pharmacological agents inhibiting PKC, may be useful in the treatment of alcohol dependence. [source] Nitric oxide and thyroid gland: modulation of cardiovascular function in autonomic-blocked anaesthetized ratsEXPERIMENTAL PHYSIOLOGY, Issue 3 2004Andrea Lorena Fellet We have previously reported that acute administration of NG -nitro- l -arginine methyl ester (l -NAME) increases the mean arterial pressure (MAP) and heart rate (HR) in autonomic-blocked (CAB) anaesthetized rats. In the present study we examined whether thyroid and adrenal glands are involved in these pressor and chronotropic responses. Sprague-Dawley rats were studied after bilateral vagotomy and ganglionic blockade with hexamethonium (10 mg kg,1), and stabilization of MAP with infusion of phenylephrine (PE) (6 ,g kg,1 min,1). The rats were divided into groups: L, CAB; PE, CAB + PE bolus (6 ,g kg,1); L-TX, thyroidectomy + CAB; L-AX, adrenalectomy + CAB; TX, only thyroidectomy; C, CAB. L, L-AX and L-TX groups received a bolus of l -NAME (7.5 mg kg,1). Triiodothyronine (T3), thyroxin (T4) and thyrotropin (TSH) levels were measured in L and L-TX rats before and after l -NAME administration. Reduced nicotamide adenine dinucleotide (NADPH) diaphorase activity was determined in heart and aorta of the TX group. The pressor response induced by l -NAME was similar in all groups. l -NAME-induced-tachycardia was associated with this rise in MAP. Adrenalectomy did not modify this chronotropic response, but it was attenuated by thyroidectomy. Thyroidectomy by itself decreased the circulating levels of T3 but it had no effect on the plasma levels of T4 and TSH. L and L-TX groups showed similar levels of circulating T4 and TSH, meanwhile the plasma level of T3 decreased in the L group. Nitric oxide synthase (NOS) activity in atria as well as in aorta was greater in the TX group compared with C. When autonomic influences are removed, the thyroid gland modulates intrinsic heart rate via a mechanism that involves, at least in part, the nitric oxide pathway. [source] Effect of Losartan on Sodium Appetite of Hypothyroid Rats Subjected to Water and Sodium Depletion and Water, Sodium and Food DeprivationEXPERIMENTAL PHYSIOLOGY, Issue 5 2001D. Badauê-Passos Jr The involvement of angiotensin AT1 receptors in sodium appetite was studied in hypothyroid rats treated with the angiotensin II antagonist losartan. Losartan was administered chronically by the oral route or acutely by the subcutaneous route after water and sodium depletion or water, sodium and food deprivation. Three days after addition of losartan to the food at the dose of 1.0 mg g,1, the rats significantly reduced (P < 0.02) their spontaneous intake of 1.8% NaCl. Increasing the dose of losartan to 2.0 and 4.0 mg g,1 did not reduce NaCl intake; in contrast, the intensity of the sodium appetite gradually returned to previous levels. The simultaneous administration of captopril, an angiotensin converting enzyme inhibitor, and losartan significantly increased (P < 0.05) NaCl intake and after captopril removal NaCl intake returned to the levels observed with losartan treatment alone. The administration of losartan 4 days after the beginning of captopril treatment significantly reduced (P < 0.0001) NaCl intake. Following acute administration of losartan, water- and sodium-depleted rats significantly reduced their NaCl and water intake (P < 0.001). The administration of losartan also induced a significant reduction in NaCl and water intake in water, NaCl and food-deprived rats (P < 0.0001 and P < 0.001, respectively). The present results show that chronic treatment with oral losartan inhibited spontaneous sodium appetite in hypothyroid rats. Continuation of treatment rendered rats resistant to the blockade of AT1 receptors. Water and sodium depletion and water, NaCl and food deprivation induced sodium appetite, which in the short term depends on cerebral angiotensinergic activity mediated by the activation of AT1 receptors. [source] Lamotrigine pharmacokinetic/pharmacodynamic modelling in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2005M.M. Castel-Branco Abstract The aim of this study was to perform a pharmacokinetic/pharmacodynamic (PK/PD) modelling of lamotrigine following its acute administration to rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. Plasma and brain samples were obtained at predetermined times over 120 h post-dose and analysed by liquid chromatography. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. As a linear relationship between lamotrigine plasma and brain profiles was observed, only the plasma data set was used to establish the PK/PD relationship. To fit the effect,time course of lamotrigine, the PK/PD simultaneous fitting link model was used: the pharmacokinetic parameters and dosing information were used in the one-compartment first-order model to predict concentrations, which were then used to model the pharmacodynamic data with the sigmoid Emax model, in order to estimate all the parameters simultaneously. The following parameters were obtained: Vd = 2.00 L/kg, kabs = 8.50 h,1, kel = 0.025 h,1, ke0 = 3.75 h,1, Emax = 100.0% (fixed), EC50 = 3.44 mg/L and , = 8.64. From these results, it can be stated that lamotrigine is extensively distributed through the body, its plasma elimination half-life is around 28 h and a lamotrigine plasma concentration of 3.44 mg/L is enough to protect 50% of the animals. When compared with humans, the plasma concentrations achieved with this dose were within the therapeutic concentration range that had been proposed for epileptic patients. With the present PK/PD modelling it was possible to fit simultaneously the time-courses of the plasma levels and the anticonvulsant effect of lamotrigine, providing information not only about the pharmacokinetics of lamotrigine in the rat but also about its anticonvulsant response over time. As this approach can be easily applied to other drugs, it becomes a useful tool for an explanatory comparison between lamotrigine and other antiepileptic drugs. [source] Verbal memory improved by D -amphetamine: influence of the testing effectHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2010Inge Zeeuws Abstract Objective The improvement of long-term retention of verbal memory after an acute administration of D -amphetamine in recall and recognition tasks has been ascribed to an influence of the drug on memory consolidation. Because recent research has demonstrated that intermediate testing is of overriding importance for retention, we investigated whether D -amphetamine modulates the repeated testing effect in verbal long-term recognition. Method Forty men participated in two double blind placebo controlled studies. In Experiment 1, we manipulated the number of recognition tests and in Experiment 2, we compared repeated with nonrepeated testing of the same items. Results Drug effects were observed on delayed tests only, leaving immediate recognition unaffected. Number of intermediate recognition tests and repeated testing of the same items were not affected by D -amphetamine. Conclusions We conclude that the D -amphetamine memory enhancement is not related to the testing effect. This result supports that D -amphetamine modulates other aspects of the consolidation process, probably related to context effects. Copyright © 2010 John Wiley & Sons, Ltd. [source] Verbal memory performance improved via an acute administration of D -amphetamineHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2007Inge Zeeuws Abstract Background An improved long-term retention of verbal memory was observed after an acute D -amphetamine administration. It was proposed that D -amphetamine modulates consolidation, but a possible drug effect on retrieval could not be rejected. Objectives We want to provide additional support for the consolidation hypothesis, and investigate whether an influence on intervening retrieval can be refuted. Methods Thirty-six male paid volunteers participated in a double blind, counterbalanced, placebo-controlled design in which the number of intermediate free recall tests was manipulated. Results A significant D -amphetamine facilitation effect on recall performance emerged 1 h and 1 day after list learning. In line with the consolidation hypothesis, no effect was found on immediate tests. Importantly, the number of intermediate retrievals did not affect the magnitude of the drug effect, suggesting that the D -amphetamine facilitation effect is independent of retrieval. Conclusion The D -amphetamine facilitation effect on verbal memory does not involve a modulation of the initial encoding or short-term memory (STM) processes. Moreover, the drug does not enhance long-term retention by acting on intervening retrieval processes. The current findings are in line with the conjecture of an involvement of the consolidation process in the D -amphetamine facilitation effect on verbal memory in healthy humans. Copyright © 2007 John Wiley & Sons, Ltd. [source] Self-report of memory and affective dysfunction in association with medication use in a sample of individuals with chronic sleep disturbanceHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 8 2000Mary Pat McAndrews Abstract Benzodiazepines produce memory disturbance after acute administration. It is not clear whether chronic use of benzodiazepines is hazardous to memory processes. Epidemiological data indicate that a large proportion (10,30 per cent) of individuals with sleep dysfunction take hypnotic aids for a year or longer. The purpose of the present study was to evaluate self-reported memory dysfunction in a sample of individuals who considered their sleep disturbance sufficiently severe to seek investigation in sleep clinics. It was hypothesized that individuals taking benzodiazepines for sleep would report greater perceived everyday memory failures than individuals taking other sleep aids or no medication. Questionnaires were given to 368 individuals referred into the study by investigators in six sleep disorders clinics. All respondents completed a lengthy (700-item) questionnaire, which included scales assessing memory difficulties, affective status and sleep disturbance. Respondents also reported any medication use for sleep problems and duration of use of the current drug. Information on medication use was reported by 289 participants. Fifty-six per cent of respondents reported using some form of psychoactive medication (antidepressants, benzodiazepines, Zopiclone). Twenty-two per cent reported using no medication. Analysis of covariance showed that these medications had no detectable effect on subjective memory difficulties during chronic use, F(4,226)=1·34, p=0·25. Copyright © 2000 John Wiley & Sons, Ltd. [source] Reversal of aging-associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor functionAGING CELL, Issue 5 2010Yuan-Jian Yang Summary Deficits in learning and memory accompanied by age-related neurodegenerative diseases are closely related to the impairment of synaptic plasticity. In this study, we investigated the role of thiol redox status in the modulation of the N -methyl- d -aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in CA1 areas of hippocampal slices. Our results demonstrated that the impaired LTP induced by aging could be reversed by acute administration of reductants that can regulate thiol redox status directly, such as dithiothreitol or ,-mercaptoethanol, but not by classical anti-oxidants such as vitamin C or trolox. This repair was mediated by the recruitment of aging-related deficits in NMDAR function induced by these reductants and was mimicked by glutathione, which can restore the age-associated alterations in endogenous thiol redox status. Moreover, antioxidant prevented but failed to reverse H2O2 -induced impairment of NMDAR-mediated synaptic plasticity. These results indicate that the restoring of thiol redox status may be a more effective strategy than the scavenging of oxidants in the treatment of pre-existing oxidative injury in learning and memory. [source] Vitamins E and C prevent the impairment of retention of an inhibitory avoidance task caused by arginine administrationJOURNAL OF NEUROCHEMISTRY, Issue 2002E. A. Reis Hyperargininemia is an inherited metabolic disease of urea cycle caused by the deficiency of arginase I activity, resulting in tissue accumulation of arginine (Arg). Patients affected by this disease usually develop spasticity, epilepsy and mental retardation as principal symptoms. Previous studies from our laboratory have showed that acute administration of Arg impairs retention of the inhibitory avoidance task and that l -NAME (NOS inhibitor) prevents this effect. In the present study, we investigated the effect of chronic treatment with antioxidants (vitamins E and C) on the retrieval of the inhibitory avoidance task in adults rats subjected to experimental model of acute hyperargininemia in order to investigate the participation of oxidative stress on this phenomenon. Sixty-day-old-rats were treated for one week with i.p. injection of saline (0.9%) or vitamins E and C (vit E 40 mg/kg and vit C 100 mg/kg). Twelve hours after the last injection Arg (0.8 g/kg) or an equivalent volume of saline were administered 1 h before training, 1 h before testing or immediately after training sessions. Memory was significantly impaired in Arg-treated group, whereas the rats chronically treated with vitamins E and C had this effect prevented. Present data strongly indicate that Arg administration impairs memory, an effect probably mediated by oxidative stress since treatment with vitamins E and C prevented amnesia. Assuming the possibility that this might occur in the human condition, reported results may be relevant to explain, at least in part, neurologic dysfunction associated with hyperargininemia. [source] GPR30 Differentially Regulates Short Latency Responses of Luteinising Hormone and Prolactin Secretion to OestradiolJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2009D. Lebesgue Rapid, nongenomic actions of 17,-oestradiol (E2) on hypothalamic neurones that may be relevant to reproductive function were described decades ago. The orphan G protein-coupled receptor, GPR30, was recently shown to bind oestrogens and to trigger rapid signalling in vitro, and is expressed in several rat and human brain regions, including the hypothalamus. We used two complementary approaches to investigate the role of GPR30 in hypothalamic responses to E2 that are relevant to reproductive physiology. Serial blood sampling after the acute administration of the selective GPR30 agonist G1 was used to assess the role of GPR30 in short latency negative-feedback inhibition of luteinising hormone (LH) secretion and facilitation of prolactin secretion in ovariohysterectomised female rats. In vivo RNA interference (RNAi), mediated by adeno-associated virus-expressing small hairpin RNA (shRNA) infused into the mediobasal hypothalamus, was used to study the effects of GPR30 knockdown on these rapid responses to E2. Longer-term actions of E2 on female sexual behaviour (lordosis) were also examined in female rats subjected to in vivo RNAi. Administration of E2 or G1 triggered a short latency surge of prolactin secretion, and animals subjected to GPR30 RNAi showed significantly less E2 -dependent prolactin release than animals receiving control virus. G1 did not mimic E2 negative-feedback inhibition of LH secretion, and GPR30 RNAi did not interfere with E2 suppression of LH or facilitation of lordosis behaviour. These findings suggest that activation of GPR30 promotes short latency prolactin secretion but does not mediate E2 negative-feedback inhibition of LH secretion or E2 facilitation of female reproductive behaviour. [source] Effect of Corticosteroid Treatment In Vitro on Adrenalectomy-Induced Impairment of Synaptic Transmission in the Rat Dentate GyrusJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2000Stienstra Removal of the rat adrenals results after 3 days in the appearance of apoptotic cells in the dentate gyrus. Apoptosis is accompanied by an impaired synaptic transmission in the dentate gyrus. Substitution in vivo with a low dose of corticosterone was found to prevent both the appearance of apoptotic cells and the functional impairment. In the present study we determined whether the functional normalisation after corticosterone treatment critically depends on prevention of apoptosis. To address this question, brain slices from rats showing apoptosis after adrenalectomy were treated in vitro with the mineralocorticoid aldosterone (3 nM) or with 30 nM corticosterone, which is assumed to activate both mineralo- and glucocorticoid receptors. Steroids were briefly applied either during recording (acute effects) or several hours before recording (long-term effects). While the slope of the fEPSP recorded in the outer molecular layer of the dentate gyrus in response to perforant path stimulation was not affected up to 1 h after acute administration of the steroids, fEPSP slopes recorded 2.5,3 h after corticosterone or aldosterone treatment were significantly increased, to the level of the sham-operated controls. The results indicate that delayed corticosteroid effects through in vitro activation of mineralocorticoid receptors (MRs) are sufficient to normalise synaptic transmission in the dentate gyrus of ADX rats, even in the presence of apoptotic cells. We tentatively conclude that the impaired synaptic transmission seen after ADX is probably not primarily caused by the appearance of apoptotic cells. [source] Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbensJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2006José Antonio Fuentealba Abstract Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16,0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K+ -stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K+ compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K+ -stimulated DA levels in control rats, it did not decrease significantly either basal or K+ -stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc. © 2006 Wiley-Liss, Inc. [source] Morphine activates Arc expression in the mouse striatum and in mouse neuroblastoma Neuro2A MOR1A cells expressing ,-opioid receptorsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2005Barbara Zió, kowska Abstract Activity-regulated cytoskeleton-associated protein (Arc) is an effector immediate early gene product implicated in long-term potentiation and other forms of neuroplasticity. Earlier studies demonstrated Arc induction in discrete brain regions by several psychoactive substances, including drugs of abuse. In the present experiments, the influence of morphine on Arc expression was assessed by quantitative reverse transcription real-time PCR and Western blotting in vivo in the mouse striatum/nucleus accumbens and, in vitro, in the mouse Neuro2A MOR1A cell line, expressing ,-opioid receptor. An acute administration of morphine produced a marked increase in Arc mRNA and protein level in the mouse striatum/nucleus accumbens complex. After prolonged opiate treatment, tolerance to the stimulatory effect of morphine on Arc expression developed. No changes in the striatal Arc mRNA levels were observed during spontaneous or opioid antagonist-precipitated morphine withdrawal. In Neuro2A MOR1A cells, acute, but not prolonged, morphine treatment elevated Arc mRNA level by activation of ,-opioid receptor. This was accompanied by a corresponding increase in Arc protein level. Inhibition experiments revealed that morphine induced Arc expression in Neuro2A MOR1A cells via intracellular signaling pathways involving mitogen-activated protein (MAP) kinases and protein kinase C. These results lend further support to the notion that stimulation of opioid receptors may exert an activating influence on some intracellular pathways and leads to induction of immediate early genes. They also demonstrate that Arc is induced in the brain in vivo after morphine administration and thus may play a role in neuroadaptations produced by the drug. © 2005 Wiley-Liss, Inc. [source] ,-Endorphin Mediates Behavioral Despair and the Effect of Ethanol on the Tail Suspension Test in MiceALCOHOLISM, Issue 6 2010Elizabeth T. Barfield Background:, The opioid peptide ,-endorphin (,-E) is synthesized and released in response to stressful stimuli as well as acute alcohol administration. The release of ,-E following exposure to an inescapable aversive situation may mediate behaviors that contribute to allostasis of the stress response. The present study examines the effects of ,-E on immobility in assays involving inescapable stress, both under basal conditions and after acute administration of EtOH. Methods:, Female and male transgenic mice with varying capacities to translate ,-E were subjected to either the forced swim (FST, Experiment 1) or the tail suspension test (TST, Experiment 2). In Experiment 3, mice were divided into three groups based on hormonal status (male, female-estrous, and female-nonestrous) and injected with either 1 g/kg EtOH or equivolume saline 14 minutes prior to behavioral assessment on the TST. Results:, Experiments 1 and 2 demonstrated a direct relationship between ,-E levels and immobility. There were also sex differences in behavior in these tests, with males displaying more immobility than females. A main effect of genotype in Experiment 3 replicated findings in Experiments 1 and 2. There was also an effect of EtOH (increasing immobility) and a significant interaction reflecting a particularly robust effect of the drug in mice with low ,-E. In addition, there were interactions between ,-E, EtOH effects, and hormonal status. Conclusions:, These findings support the contention that ,-E moderates behavioral responses to stressful stimuli and suggest a role for this peptide in coping behavior. Furthermore, the effects of EtOH on the response to stress may be mediated by ,-E. Sex differences in this influence may contribute to sex differences in disease susceptibility and expression. [source] Ethanol-Induced Increase of Agouti-Related Protein (AgRP) Immunoreactivity in the Arcuate Nucleus of the Hypothalamus of C57BL/6J, but not 129/SvJ, Inbred MiceALCOHOLISM, Issue 4 2010Inmaculada Cubero Background:, The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor, pro-opiomelanocortin (POMC). Previous research has shown that MC receptor (MCR) agonists reduce, and MCR antagonists increase, ethanol consumption in rats and mice. Consistently, genetic deletion of the endogenous MCR antagonist, agouti-related protein (AgRP), causes reductions of ethanol-reinforced lever pressing and binge-like ethanol drinking in C57BL/6J mice. Ethanol also has direct effects on the central MC system, as chronic exposure to an ethanol-containing diet causes significant reductions of ,-melanocyte stimulating hormone (,-MSH) immunoreactivity in specific brain regions of Sprague-Dawley rats. Together, these observations suggest that the central MC system modulates neurobiological responses to ethanol. To further characterize the role of the MC system in responses to ethanol, here we compared AgRP and ,-MSH immunoreactivity in response to an acute injection of saline or ethanol between high ethanol drinking C57BL/6J mice and moderate ethanol drinking 129/SvJ mice. Methods:, Mice received an intraperitoneal (i.p.) injection of ethanol (1.5 g/kg or 3.5 g/kg; mixed in 0.9% saline) or an equivolume of 0.9% saline. Two hours after injection, animals were sacrificed and their brains were processed for AgRP and ,-MSH immunoreactivity. Results:, Results indicated that acute ethanol administration triggered a dose-dependent increase in AgRP immunoreactivity in the arcuate (ARC) of C57BL/6J mice, an effect that was not evident in the 129/SvJ strain. Although acute administration of ethanol did not influence ,-MSH immunoreactivity, C57BL/6J mice had significantly greater overall ,-MSH immunoreactivity in the ARC, dorsomedial, and lateral regions of the hypothalamus relative to the 129/SvJ strain. In contrast, C57BL/6J mice displayed significantly lower ,-MSH immunoreactivity in the medial amygdala. Conclusions:, The results show that acute ethanol exposure has direct effects on endogenous AgRP activity in ethanol preferring C57BL/6J mice. It is suggested that ethanol-induced increases in AgRP may be part of a positive feedback system that stimulates excessive binge-like ethanol drinking in C57BL/6J mice. Inherent differences in ,-MSH immunoreactivity may contribute to differences in neurobiological responses to ethanol that are characteristically observed between the C57BL/6J and 129/SvJ inbred strains of mice. [source] Deletion of the ,7 Nicotinic Receptor Subunit Gene Results in Increased Sensitivity to Several Behavioral Effects Produced by AlcoholALCOHOLISM, Issue 3 2005Barbara J. Bowers Background: The finding that most people with alcoholism are also heavy smokers prompted several research groups to evaluate the effects of ethanol on neuronal nicotinic acetylcholine receptor (nAChR) function. Data collected in vitro indicate that physiologically relevant concentrations of ethanol inhibit the functional activation of homomeric ,7 nAChRs, which are one of the most abundant nAChR subtypes expressed in the mammalian brain. The studies outlined here used ,7 gene knockout (null mutant) mice to evaluate the potential role of ,7 nAChRs in modulating selected behavioral and physiological effects produced by ethanol. Methods: Current evidence indicates that many responses to ethanol are not genetically correlated. Therefore, the authors measured the effects of acute administration of ethanol on several behaviors that are altered by both ethanol and nicotine: two tests of locomotor activity, acoustic startle, prepulse inhibition of acoustic startle, and body temperature. Ethanol-induced durations of loss of righting reflex and ethanol elimination rates were also determined. These studies used null mutant (,7,/,) and wild-type (,7+/+) mice. Results: Relative to ,7+/+ mice, ,7,/, mice were more sensitive to the activating effects of ethanol on open-field activity, ethanol-induced hypothermia, and duration of loss of the righting response. Deletion of the ,7 gene did not influence the effects of ethanol on Y-maze crossing or rearing activities, acoustic startle, or prepulse inhibition of startle. Gene deletion did not alter ethanol metabolism. Conclusions: These results indicate that some but not all of the behavioral effects of ethanol are mediated in part by effects on nAChRs that include the ,7 subunit and may help to explain the robust association between alcohol consumption and the use of tobacco. [source] | |||||||||||||||||||||||||