ABSTRACT
Schizophrenia, an important brain neurodevelopmental disorder, is observed in 1% of the global population. New-generation antipsychotics have been developed as alternatives to typical antipsychotics for more effective and safe therapy. Chronic administration of asenapine and paliperidone compared to haloperidol on depression, anxiety and analgesy in the forced swimming test (FST), elevated plus maze (EPM) and hot plate tests were examined in mice. Moreover effects of drugs, on expression levels of brain neurotrophic factors [brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB),nerve growth factor (NGF), synapsin and fibroblast growth factor 2 (FGF2)] in the hippocampus of mice, neurogenesis and neurodegeneration, and blood enzyme levels were also investigated. In FST, haloperidol (0.25 mg/kg) significantly increased immobility time while both asenapine (0.075 mg/kg) and paliperidone (0.25 and 0.50 mg/kg) significantly diminished this parameter. In EPM test, haloperidol significantly increased both % time spent in open arms and % open arm entries. Asenapine (0.075 mg/kg) and paliperidone (0.50 mg/kg) significantly increased % time spent in the open arms. They also increased % open arm entries, but this parameter failed to reach a statistically significant value. In hot plate test, haloperidol (0.125 and 0.25 mg/kg) and paliperidone (0.25 and 0.50 mg/kg) significantly increased the latency to lick the hind paws but asenapine had no effect. Asenapine and paliperidone upregulated more neurotrophic factors in the brain and caused less neurodegeneration compared to haloperidol. Investigated drugs had no effect on liver enzymes and plasma glucose levels. Asenapine and paliperidone may be preferred over classical antipsychotics since they have antidepressant-like effect, upregulate more neurotrophic factors and cause less neurodegeneration in naive mice without having diabetogenic and liver damaging effects. Paliperidone seems to possess superior effects compared to asenapine since it also exerts analgesic-like effect.
Subject(s)
Anxiety , Depression , Animals , Brain , Brain-Derived Neurotrophic Factor , Dibenzocycloheptenes , Heterocyclic Compounds, 4 or More Rings , Hippocampus , Mice , Neurogenesis , Paliperidone PalmitateABSTRACT
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has modulating effects on insulin release. GLP-1 and receptors for GLP-1 are widely expressed throughout the body including the brain. The expression of GLP-1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP-1 receptor stimulation enhances glucose-dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose-derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP-1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP-1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 µg/kg, s.c., twice daily for 2 weeks) on GLP-1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice were assessed by quantitative real-time polymerase chain reaction (RT-PCR). The results of this study revealed that hippocampal gene expression of GLP-1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP-1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP-1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA-induced diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide-1 Receptor/agonists , Hippocampus/drug effects , Hypoglycemic Agents/pharmacology , Incretins/pharmacology , Nerve Growth Factor/metabolism , Niacinamide , Peptides/pharmacology , Streptozocin , Venoms/pharmacology , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/genetics , Exenatide , Glucagon-Like Peptide-1 Receptor/genetics , Glucagon-Like Peptide-1 Receptor/metabolism , Hippocampus/metabolism , Male , Mice, Inbred BALB C , Nerve Growth Factor/genetics , Time Factors , Up-RegulationABSTRACT
PURPOSE: Sexual dysfunction is a common condition in patients taking antipsychotics and is the most bothersome symptom and adverse drug effect, resulting in a negative effect on treatment compliance. Pharmacology research into human ejeculatory disorders is limited to clinical studies with registered drugs affecting the ejaculation process; therefore, animal research has become the need. We aimed to investigate the effects of haloperidol, clozapine and aripiprazole on serotonin, noradrenaline, adenosine triphosphate (ATP) and potassium chloride (KCl)-induced contractions of the vas deferens in order to evaluate the effect of haloperidol, clozapine and aripiprazole on the contraction of the vas deferens. METHODS: Male inbred BALB/c ByJ mice aged 7 weeks upon arrival to the laboratory were used in this study. Haloperidol, clozapine, aripiprazole, serotonin, noradrenaline, ATP and KCl were dissolved in 0.9% physiological saline. The mice were randomly divided into experimental groups as follows: saline; haloperidol 0.125 mg/kg; haloperidol 0.25 mg/kg; clozapine 1.25 mg/kg; clozapine 2.5 mg/kg; aripiprazole 3 mg/kg; aripiprazole 6 mg/kg. Mice were treated by ip injection of drugs during 21 days. Mice receiving only the vehicle ip (0.9% saline) during 21 days served as control group (n = 7). Each experimental group consisted of 7 mice. After 21 days of treatment, epididymal and prostatic portions of vas deferens were surgically dissected free and immersed in 20-mL organ baths containing Krebs' solution. The effects of chronic treatment with haloperidol (0.125 and 0.25 mg/kg), clozapine(1.25 and 2.5 mg/kg) and aripiprazole (3 and 6 mg/kg) were investigated on serotonin [10 (-8) to 10 (-4) M], noradrenaline [10 (-8) to 10 (-4) M], ATP [10 (-8) to 10 (-4) M] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of mice isolated vas deferens strips. Statistical comparison between the groups was performed using ANOVA supported by Dunnett's post hoc test. RESULTS: Serotonin-induced contractile responses were significantly increased in the epididymal and prostatic portions of the vas deferens obtained from the haloperidol-treated group and clozapine-treated group. However, aripiprazole treatment had no effect on serotonin responses in both epididymal and prostatic portions of mice vas deferens. On the other hand, haloperidol and clozapine treatments significantly inhibited both noradrenaline and ATP-induced contractions of the prostatic and epididymal portions of the mice vas deferens, but had no effect on KCl-induced contractions of the vas deferens in both portions. There were no significant differences in KCl-induced contractile responses among the groups. CONCLUSIONS: These results revealed that induced contractions of vas deferens were affected after chronic treatment with haloperidol and clozapine but not aripiprazole. Serotonergic, noradrenergic and purinergic receptors may, at least in part, contribute to changes in vas deferens contractions in mice with chronic treatment of haloperidol and clozapine but not aripiprazole.
Subject(s)
Antipsychotic Agents/pharmacology , Aripiprazole/pharmacology , Clozapine/pharmacology , Haloperidol/pharmacology , Vas Deferens/drug effects , Adenosine Triphosphate/pharmacology , Animals , Male , Mice , Mice, Inbred BALB C , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Norepinephrine/pharmacology , Potassium Chloride/pharmacology , Random Allocation , Serotonin/pharmacologyABSTRACT
The neurosecretory cells in the corpus cardiacum of insects synthesize a set of hormones that are called adipokinetic, hypertrehalosemic or hyperprolinemic depending on the insect in question. They are the Adipokinetic Hormone/Red Pigment-Concentrating Hormone (AKH/RPCH) family of peptides. The present study investigated the effects of acute administration of Locusta Migratoria (Locmi-AKHII) and Anax Imperator (Anaim-AKH) on depression, anxiety, pain (analgesy), locomotion and memory in mice in forced swimming (FST), elevated plus maze (EPM), hot plate, locomotor activity and passive avoidance tests. Both Locmi-AKH-II (4 mg/kg) and Anaim-AKH (0.25 and 0.50 mg/kg) decreased immobility time (in sec, s) in the FST test. Anaim-AKH (0.5 and 1 mg/kg) increased the percentage of time spent in open arms/total time spent and the percentage of the number of open arm/total arm entries in the EPM test. Anaim-AKH (1 and 2 mg/kg) significantly increased latency (s) (initial time passed) for mice to lick their hind paws or jumping in the hot plate test. Anaim-AKH (4 mg/kg) significantly decreased the total distance (cm) moved, or the speed (cm/s) of movement of the animals in the locomotor activity test. Neither Locmi-AKH-II nor Anaim-AKH altered the retention latency (s) in the passive avoidance test. Both Locmi-AKH-II and Anaim-AKH exerted antidepressant effects, while only Anaim-AKH had anxiolytic and analgesic effects when administered acutely. Anaim-AKH diminished locomotion at higher doses while Locmi-AKH-II had no such effects. Neither Locmi-AKH-II nor Anaim-AKH disturbed learning and memory when acutely administered. Data of our studies suggest clinical potentials of AKH to be used in depression, anxiety and pain without disturbing memory.
Subject(s)
Anxiety/drug therapy , Anxiety/physiopathology , Depression/drug therapy , Depression/physiopathology , Insect Hormones/administration & dosage , Memory/drug effects , Oligopeptides/administration & dosage , Pain/drug therapy , Pyrrolidonecarboxylic Acid/analogs & derivatives , Animals , Anxiety/diagnosis , Behavior, Animal/drug effects , Depression/diagnosis , Dose-Response Relationship, Drug , Locomotion/drug effects , Locusta migratoria/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred Strains , Pain/diagnosis , Pain/physiopathology , Pyrrolidonecarboxylic Acid/administration & dosage , Treatment OutcomeABSTRACT
Cognitive dysfunction is commonly observed in schizophrenic patients and the administration of antipsychotic treatments results in different outcomes. Although the typical antipsychotic treatments, such as haloperidol, appear to be unable to improve cognition dysfunction, the atypical antipsychotic drugs (quetiapine, aripiprazole and iloperidone) exert a beneficial effect. The purpose of the current study was to investigate the effects of atypical antipsychotics on olfactory memory in mice, utilizing the social transmission of food preference (STFP) tests to evaluate the effects of drugs on MK-801-induced cognitive dysfunction. Female BALB/c mice were treated with quetiapine (5 and 10 mg/kg), aripiprazole (3 and 6 mg/kg), iloperidone (0.5 and 1 mg/kg) or MK-801 (0.1 mg/kg) alone or concurrently prior to retention sessions of STFP tests. In the STFP tests, quetiapine (10 mg/kg; P<0.05), aripiprazole (3 and 6 mg/kg; P<0.01 and P<0.001, respectively), iloperidone (0.5 and 1 mg/kg; P<0.01 and P<0.001, respectively) and MK-801 (P<0.001) significantly decreased cued/total food eaten (%). Quetiapine (5 mg/kg; P<0.05) significantly increased MK-801-induced decreases in cued/total food eaten (%), while aripiprazole and iloperidone demonstrated no significant effects. The results revealed that all of the drugs disturbed olfactory memory in the naive mice; however, only quetiapine reversed MK-801-induced memory impairment in the STFP test.
ABSTRACT
BACKGROUND Glucagon-like peptide-1 (GLP-1), a potent and selective agonist for the GLP-1 receptor, ameliorates the symptoms of diabetes through stimulation of insulin secretion. Exenatide is a potent and selective agonist for the GLP-1 receptor. Cell adhesion molecules are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. MATERIAL AND METHODS The present study demonstrated the effects of exenatide treatment (0.1 µg/kg, subcutaneously, twice daily for 2 weeks) on the gene expression levels of cell adhesion molecules, neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the brain tissue of diabetic BALB/c male mice by real-time quantitative polymerase chain reaction (PCR). Diabetes was induced by streptozotocin/nicotinamide (STZ-NA) injection to male mice. RESULTS The results of this study revealed that hippocampal gene expression of NCAM, ICAM, and VCAM were found to be up-regulated in STZ-NA-induced diabetic mice compared to those of controls. A significant decrease in the gene expression levels of NCAM, ICAM, and VCAM were determined after 2 weeks of exenatide administration. CONCLUSIONS Cell adhesion molecules may be involved in the molecular mechanism of diabetes. Exenatide has a strong beneficial action in managing diabetes induced by STZ/NA by altering gene expression of NCAM, ICAM, and VCAM.
ABSTRACT
Chronic stress which can cause a variety of disorders and illness ranging from metabolic and cardiovascular to mental leads to alterations in content, structure and dynamics of biomolecules in brain. The determination of stress-induced changes along with the effects of antidepressant treatment on these parameters might bring about more effective therapeutic strategies. In the present study, we investigated unpredictable chronic mild stress (UCMS)-induced changes in biomolecules in mouse brain and the restoring effects of tianeptine (TIA), olanzapine (OLZ) and fluoxetine (FLX) on these variations, by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that chronic stress causes different membrane packing and an increase in lipid peroxidation, membrane fluidity. A significant increment for lipid/protein, C=O/lipid, CH3/lipid, CH2/lipid, PO(-)2/lipid, COO(-)/lipid and RNA/protein ratios but a significant decrease for lipid/protein ratios were also obtained. Additionally, altered protein secondary structure components were estimated, such as increment in random coils and beta structures. The administration of TIA, OLZ and FLX drugs restored these stress-induced variations except for alterations in protein structure and RNA/protein ratio. This may suggest that these drugs have similar restoring effects on the consequences of stress activity in brain, in spite of the differences in their action mechanisms. All findings might have importance in understanding molecular mechanisms underlying chronic stress and contribute to studies aimed for drug development.
Subject(s)
Antidepressive Agents/therapeutic use , Benzodiazepines/pharmacology , Brain Chemistry/drug effects , Brain/drug effects , Fluoxetine/pharmacology , Stress, Psychological/drug therapy , Thiazepines/pharmacology , Animals , Benzodiazepines/therapeutic use , Brain/metabolism , Fluoxetine/therapeutic use , Lipid Peroxidation/drug effects , Male , Membrane Fluidity/drug effects , Mice , Mice, Inbred BALB C , Olanzapine , Stress, Psychological/metabolism , Thiazepines/therapeutic useABSTRACT
Exenatide is a potent and selective agonist for the GLP-1 (glucagon-like peptide-1) receptor. Recent studies are focused on the effects of GLP-1 analogues on hippocampal neurogenesis, cognition, learning and memory functions. The aim of this study was to assess the effects of chronic exenatide treatment (0.1 µg/kg, s.c, twice daily for 2 weeks) on spatial memory functions by using the modified elevated plus maze (mEPM) test and emotional memory functions by using the passive avoidance (PA) test in streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice. As the genes involved in neurite remodelling are among the primary targets of regulation, the effects of diabetes and chronic administration of exenatide on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus of mice were also determined using quantitative real-time polymerase chain reaction (RT-PCR). This study revealed that in the mEPM and PA tests, type-2 diabetes-induced mice exhibited significant impairment of learning and memory which were ameliorated by GLP-1 receptor agonist exenatide. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in diabetic mice, and these alterations were increased by exenatide treatment. Since, exenatide improves cognitive ability in STZ/NA-induced diabetic mice and activates molecular mechanisms of memory storage in response to a learning experience, it may be a candidate for alleviation of mood and cognitive disorder.
Subject(s)
Brain-Derived Neurotrophic Factor/biosynthesis , Cognition/drug effects , Diabetes Mellitus, Experimental/metabolism , Hypoglycemic Agents/pharmacology , Peptides/pharmacology , Venoms/pharmacology , Animals , Brain-Derived Neurotrophic Factor/genetics , Cognition/physiology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Exenatide , Gene Expression Regulation , Hypoglycemic Agents/therapeutic use , Male , Maze Learning/drug effects , Maze Learning/physiology , Mice , Mice, Inbred BALB C , Peptides/therapeutic use , Up-Regulation/drug effects , Up-Regulation/physiology , Venoms/therapeutic useABSTRACT
BACKGROUND: Homeopathy is a form of alternative medicine in which uses highly diluted preparations that are believed to cause healthy people to exhibit symptoms similar to those exhibited by patients. The aim of this study was to investigate the effects of dragonfly (Anax imperator, Anax i.) on learning and memory in naive mice using the Morris water maze (MWM) test; moreover, the effects of dragonfly on MK-801-induced cognitive dysfunction were evaluated. METHODS: Male balb-c mice were treated with dragonfly (30C and 200C) or MK-801 (0.2 mg/kg) alone or concurrently (n = 10). Dragonfly (D) and MK-801 were administered subchronically for 6 days intraperitoneally 60 min and 30 min, respectively, before the daily performance of the MWM test. RESULTS: This study revealed that in the familiarization session and first session of the MWM test, Anax i. D30 significantly decreased escape latency compared to the control group, although MK-801, D30 and D200 significantly increased escape latency at the end of five acquisition sessions. Anax i. combined with dizocilpine maleate (MK-801) also significantly decreased escape latency in the familiarization session and first session of the MWM test, although this combination increased escape latency compared to the MK-801 alone group at the end of the test. Time spent in escape platform's quadrant in the probe trial significantly decreased while mean distance to platform significantly increased in MK-801, D30 and D200 groups. In the MWM test, Anax i. combined with MK-801 significantly decreased speed of the animals compared to the MK-801 alone group. General cell morphology was disturbed in the MK-801 group while D30 and D200 seemed to improve cell damage in the MK-801 group. CONCLUSIONS: These results suggest that the homeopathic Anax i. can impair learning acquisition and reference memory, and it has beneficial effects on disturbed cell morphology.
Subject(s)
Homeopathy/methods , Materia Medica/therapeutic use , Odonata/chemistry , Animals , Dose-Response Relationship, Drug , Insect Hormones/adverse effects , Insect Hormones/therapeutic use , Male , Maze Learning/drug effects , Memory/drug effects , Mice , Mice, Inbred BALB C , Oligopeptides/adverse effects , Oligopeptides/therapeutic use , Pyrrolidonecarboxylic Acid/adverse effects , Pyrrolidonecarboxylic Acid/analogs & derivatives , Pyrrolidonecarboxylic Acid/therapeutic useABSTRACT
Neurosecretory cells in corpus cardiacum of insects synthesize a set of hormones that are called adipokinetic, hypertrehalosaemic or hyperprolinaemic, depending on insect in question. This study investigated effects of chronic administration of Anax imperator adipokinetic hormone (Ani-AKH), Libellula auripennis adipokinetic hormone (Lia-AKH), and Phormia-Terra hypertrehalosaemic hormone (Pht-HrTH) on depression, anxiety, analgesy, locomotion in forced swimming (FST), elevated plus-maze (EPM), hot plate, and locomotor activity tests. Ani-AKH (1 and 2 mg/kg), Lia-AKH (1 and 2 mg/kg), and Pht-HrTH (1 and 2 mg/kg) had antidepressant effects in forced swimming test. Lia-AKH (2 mg/kg) and Pht-HrTH (1 and 2 mg/kg) had anxiolytic effects when given chronically in elevated plus-maze test. Ani-AKH (1 and 2 mg/kg) and Pht-HrTH (2 mg/kg) had antinociceptive effects in hot plate test in male balb-c mice. Ani-AKH (2 mg/kg), Lia-AKH (1 and 2 mg/kg), and Pht-HrTH had locomotion-enhancing effects in locomotor activity test in male balb-c mice. Drug treatment significantly increased brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) gene expression levels compared to control levels. Pht-HrTH and Ani-AKH groups had significantly increased numbers of BrdU-labeled cells, while neurodegeneration was lower in the Pht-HrTH group. Our study showed that AKH/RPCH family peptides may be used in treatment of psychiatric illness such as depression and anxiety, in treatment of pain and in diseases related to locomotion system. AKH/RPCH family peptides increase neurotrophic factors in brain and have potential proliferative and neuroprotective effects in hippocampal neurogenesis and neurodegeneration.
Subject(s)
Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Hippocampus/drug effects , Insect Hormones/pharmacology , Neurogenesis/drug effects , Neuropeptides/pharmacology , Oligopeptides/pharmacology , Pyrrolidonecarboxylic Acid/analogs & derivatives , Analgesics/isolation & purification , Analgesics/pharmacology , Animals , Anti-Anxiety Agents/isolation & purification , Anti-Anxiety Agents/pharmacology , Hippocampus/metabolism , Insect Hormones/isolation & purification , Maze Learning/drug effects , Mice, Inbred Strains , Motor Activity/drug effects , Neuropeptides/isolation & purification , Neuroprotective Agents/isolation & purification , Neuroprotective Agents/pharmacology , Oligopeptides/isolation & purification , Pyrrolidonecarboxylic Acid/isolation & purification , Pyrrolidonecarboxylic Acid/pharmacology , SwimmingABSTRACT
Introduction: Patients with schizophrenia have cognitive dysfunctions; positive psychotic symptoms are the primary purposes for schizophrenia treatment. Improvements in cognitive function should be a characteristic of all newly developed drugs for the treatment of schizophreniawith dementia. Thus,we investigated the effects of the second-generation antipsychotic ziprasidone, dopamine D1 antagonist SCH-23390 and dopamine D3 antagonist SB-277011 on spatial learning and memory. Materials and methods: Male inbred mice were used. The effects of ziprasidone, SCH-23390 and SB-277011 were investigated using the Morris water maze test. Results: Ziprasidone (0.5 and 1mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on the time spent in the target quadrant in naive mice.MK-801 (0.1mg/kg) significantly decreased the time spent in the target quadrant. The time spent in the target quadrant was significantly prolonged by Ziprasidone (0.5 and 1 mg/kg) and SCH-23390 (0.1 mg/kg), but not with SB-277011 (20 mg/kg) in MK-801-treated mice. Ziprasidone (0.5 and 1mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on themean distance to the platformin naivemice.MK-801 significantly increased themean distance to the platform. Ziprasidone (1 mg/kg) and SCH-23390 (0.1 mg/kg) significantly decreased the mean distance to the platform in MK-801-treated mice, but SB-277011 (20 mg/kg) didn't. MK-801 significantly increased the total distance moved. Ziprasidone (0.5 and 1 mg/kg), SCH-23390 (0.05 and 0.1 mg/kg) and SB-277011 (10 and 20 mg/kg) had no effect on the total distance moved in naive mice. Ziprasidone (1 mg/kg) and SCH-23390 (0.1 mg/kg) significantly decreased the total distance moved in MK-801-treated mice, but SB-277011 (20 mg/kg) didn't. Conclusions: The second-generation antipsychotic drug ziprasidone and D1 antagonist SCH23390, but not the D3 antagonist SB277011, might be clinically useful for the treatment of cognitive impairments in patients with schizophrenia.
Subject(s)
Antipsychotic Agents/pharmacology , Benzazepines/pharmacology , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Maze Learning/drug effects , Nitriles/pharmacology , Piperazines/pharmacology , Spatial Memory/drug effects , Tetrahydroisoquinolines/pharmacology , Thiazoles/pharmacology , Animals , Male , Mice , Mice, Inbred BALB C , Motor Activity/drug effects , Psychomotor Performance/drug effectsABSTRACT
Nitric oxide (NO) is an atypical neurotransmitter that causes changes in cognition. Nitric oxide synthase (NOS) and guanylate cyclase (GC) inhibitors have been shown to exert some effects on cognition in previous studies; however, the findings have been controversial. This study was aimed at understanding the effects of an NOS inhibitor, 7-nitroindazole (7-NI), and a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on spatial memory in modified elevated plus maze (mEPM), Morris water maze (MWM), and radial arm maze (RAM) tests. Male Balb-c mice were treated via intraperitoneal injections with 7-NI (15 mg/kg), ODQ (3, 10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline. ODQ (3 mg/kg) and 7-NI (15 mg/kg) significantly increased the second-day latency in the mEPM test. 7-NI (15 mg/kg) and ODQ (10 mg/kg) significantly increased the escape latency in second, third, and fourth sessions, decreased the time spent in the escape platform's quadrant, and increased the mean distance to the platform in the probe trial of the MWM test. ODQ (3, 10 mg/kg) and 7-NI (15 mg/kg) significantly increased the number of errors, whereas only 7-NI increased the latency in the RAM test. The administration of L-arginine (100 mg/kg) prior to 7-NI inverted the effects of 7-NI, which supports the role of NO on cognition. Our study shows that the NO/cGMP/GS pathway can regulate spatial memory in mice.
ABSTRACT
BACKGOUND: Homeopathy is a medical theory and practice that asserts that disease can be cured by remedies that produce symptoms in a healthy person similar to those suffered by a patient with a malady. METHODS: The aim of this study was to investigate effects of homeopathic Anax imperator (dragonfly) (Anax-i 30c and Anax-i 200c) in the forced swim test (FST), elevated plus-maze (EPM) test, hot plate (HP) test and open field test and examined NPY1 receptor expression, in naive mice. RESULTS: In the FST, treatment with Anax-i 30c or Anax-i 200c significantly diminished immobility time while in EPM test, Anax-i 200c increased the percentage of time spent in open arms as well as the percentage of open arm/total arms. In the HP test, Anax-i 30c or Anax-i 200c decreased the total time mice spent licking their hind paws while in open field test, treatment with Anax-i 200c increased the total distance and speed mice traveled compared to the control group. Three weeks of daily injections with Anax-i 30c or Anax-i 200c caused significant weight loss in mice. Anax-i 30c or Anax-i 200c treatment significantly decreased NPY1 receptor expression, and Anax-i 30c also decreased NPY2 receptor expression. CONCLUSION: These results suggest that the homeopathic Anax-i exerts antidepressant, anxiolytic and analgesic-like effects and causes hyperlocomotion and weight loss.
Subject(s)
Analgesics/pharmacology , Anti-Anxiety Agents/pharmacology , Behavior, Animal , Homeopathy , Insecta , Maze Learning , Swimming , Animals , Male , Mice , Mice, Inbred BALB C , Receptors, N-Methyl-D-Aspartate/analysis , Receptors, Neuropeptide Y/analysisABSTRACT
BACKGROUND: Comorbid neurobehavioral disturbances and type-2 diabetes mellitus (T2DM) warrant immediate research attention. Exenatide, which is a potent and selective agonist for the glucagon-like peptide-1 (GLP-1), is used in the treatment of T2DM. Exenatide displays a multitude of effects in the central nervous system. The aim of this study was to investigate the anxiolytic- and antidepressant-like effects and analgesic effects of exenatide in a type-2 diabetic mouse model. MATERIAL/METHODS: Modified elevated plus-maze test for anxiolytic-like, forced swimming test for depression-like behavior and hotplate test for neuropathy were used as behavioral tasks. Behavioral parameters were investigated in a streptozocin--(100 mg/kg, i.p.) and nicotinamide--(240 mg/kg, i.p.) induced type-2 diabetic mouse model. Exenatide (0.1 µg/kg, s.c., twice daily) was administered for 2 weeks. Vehicle (control), diabetic, and exenatide-treated diabetic mice were tested. RESULTS: Our results confirm that exenatide exerts anxiolytic- and antidepressant-like effects and might be effective in diabetic neuropathy in a diabetic mouse model. CONCLUSIONS: Exenatide may be a good candidate as a treatment option for depression, anxiety, and neuropathy in patients with type-2 diabetes.
Subject(s)
Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetic Neuropathies/drug therapy , Peptides/therapeutic use , Venoms/therapeutic use , Animals , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Diabetic Neuropathies/physiopathology , Disease Models, Animal , Exenatide , Immobilization , Male , Maze Learning/drug effects , Mice, Inbred BALB C , Motor Activity/drug effects , Peptides/pharmacology , Reaction Time/drug effects , Time Factors , Venoms/pharmacologyABSTRACT
BACKGROUND: Phosphodiesterase (PDE) inhibitors in the central nervous system have been shown to stimulate neuronal functions and increase neurogenesis in Alzheimer disease (AD) patients. MATERIAL/METHODS: The aim of this study was to investigate the effects of zaprinast, a PDE5 inhibitor, and rolipram, a PDE4 inhibitor, on learning and memory in elevated plus maze (EPM) and passive avoidance (PA) tests in naive mice. Male Balb-c mice received short-term treatment with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) before the acquisition trial of the EPM and PA tests. The exploratory activity of the animals was also investigated in the Hughes box test. RESULTS: Both zaprinast (10 mg/kg) and rolipram (0.1 mg/kg) significantly decreased second-day latency compared to the control group in the EPM test, while only rolipram (0.1 mg/kg) significantly increased second-day latency in the PA test. Both zaprinast (10 mg/kg) and rolipram (0.1 mg/kg) significantly decreased the number of entries to new areas and time spent in new areas in the Hughes box test. CONCLUSIONS: Our study revealed that both zaprinast and rolipram enhanced spatial memory in EPM, while rolipram seemed to have more emotional memory-enhancing effects in the PA test compared to zaprinast. Both zaprinast and rolipram diminished exploratory activity in the Hughes box test, which can be attributed to the drugs' anxiogenic effects.
Subject(s)
Emotions/drug effects , Exploratory Behavior/drug effects , Maze Learning/drug effects , Purinones/pharmacology , Rolipram/pharmacology , Spatial Memory/drug effects , Animals , Avoidance Learning/drug effects , Male , Mice, Inbred BALB C , Purinones/administration & dosage , Rolipram/administration & dosageABSTRACT
The role of phosphodiesterase (PDE) inhibitors in central nervous system has been investigated and shown to stimulate neuronal functions and increase neurogenesis in Alzheimer patients. The aim of this study is to investigate effect of PDE5 inhibitor zaprinast and PDE4 inhibitor rolipram on visual memory in novel object recognition (NOR) test, on olfactory memory in social transmission of food preference (STFP) test, and also on locomotion and anxiety in open field test in naive mice. Male Balb-c mice were treated intraperitoneally (i.p.) with zaprinast (3 and 10 mg/kg), rolipram (0.05 and 0.1 mg/kg), or physiological saline. Zaprinast (10 mg/kg) significantly increased cued/non-cued food eaten compared to control group, while rolipram had a partial effect on retention trial of STFP test. Zaprinast (10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) significantly increased ratio index (RI) compared to control group in retention trial of NOR test. There was no significant effect of zaprinast and rolipram on total distance moved, speed, and center zone duration in open field test. Results of this study revealed that both zaprinast and rolipram enhanced visual memory in NOR test, however zaprinast exerted a significant memory-enhancing effect compared to rolipram in STFP test in mice.
ABSTRACT
BACKGROUND: Nitric oxide (NO) is an intercellular messenger that plays a critical role in learning and memory processes. Effects of nitric oxide synthase (NOS) inhibitors and guanylate cyclase (GC) inhibitors on cognitive function remain controversial. MATERIAL AND METHODS: The aim of this study was to investigate effects of an NOS inhibitor, 7-nitroindazole (7-NI), and a GC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), on different aspects of memory in passive avoidance (PA), novel object recognition (NOR), and social transmission of food preference (STFP) tests. Male Balb-c mice were treated intraperitoneally with 7-NI (15 mg/kg), ODQ (3,10 mg/kg), L-arginine (100 mg/kg) + 7-NI (15 mg/kg), or physiological saline. RESULTS: ODQ (10 mg/kg) and 7-NI (15 mg/kg) significantly decreased second-day latency in PA test. 7-NI (15 mg/kg) and ODQ (10 mg/kg) significantly decreased the ratio index in the NOR test. 7-NI and ODQ (10 mg/kg) decreased cued/non-cued food eaten in STFP test. Amount of time spent in center zone significantly increased in ODQ (10 mg/kg) and 7-NI (15 mg/kg) groups in open field test, but there was no effect on total distance moved and speed of animals. ODQ (10 mg/kg) significantly increased number of entries into new compartments in exploratory activity apparatus, while 7-NI had no effect. Administration of L-arginine (100 mg/kg) before 7-NI reversed 7-NI-induced effects, supporting the role of NO in cognition. CONCLUSIONS: Our results confirm that inhibition of NO/cGMP/GS pathway might disturb emotional, visual, and olfactory memory in mice. Also, 7-NI and ODQ had anxiolytic effects in open field test, and ODQ also enhanced exploratory activity.
Subject(s)
Avoidance Learning/drug effects , Exploratory Behavior/drug effects , Food Preferences/drug effects , Indazoles/pharmacology , Memory/drug effects , Oxadiazoles/pharmacology , Quinoxalines/pharmacology , Social Behavior , Animals , Anxiety/physiopathology , Arginine/pharmacology , Indazoles/administration & dosage , Male , Mice , Mice, Inbred BALB C , Motor Activity/drug effects , Oxadiazoles/administration & dosage , Quinoxalines/administration & dosage , Smell/drug effectsABSTRACT
Agomelatine, a novel antidepressant with established clinical efficacy, acts as an agonist of melatonergic MT1 and MT2 receptors and as an antagonist of 5-HT2C receptors. The present study was undertaken to investigate whether chronic treatment with agomelatine would block unpredictable chronic mild stress (UCMS)-induced cognitive deterioration in mice in passive avoidance (PA), modified elevated plus maze (mEPM), novel object recognition (NOR), and Morris water maze (MWM) tests. Moreover, the effects of stress and agomelatine on brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) messenger ribonucleic acid (mRNA) levels in the hippocampus was also determined using quantitative real-time polymerase chain reaction (RT-PCR). Male inbred BALB/c mice were treated with agomelatine (10 mg/kg, i.p.), melatonin (10 mg/kg), or vehicle daily for five weeks. The results of this study revealed that UCMS-exposed animals exhibited memory deterioration in the PA, mEPM, NOR, and MWM tests. The chronic administration of melatonin had a positive effect in the PA and +mEPM tests, whereas agomelatine had a partial effect. Both agomelatine and melatonin blocked stress-induced impairment in visual memory in the NOR test and reversed spatial learning and memory impairment in the stressed group in the MWM test. Quantitative RT-PCR revealed that CREB and BDNF gene expression levels were downregulated in UCMS-exposed mice, and these alterations were reversed by chronic agomelatine or melatonin treatment. Thus, agomelatine plays an important role in blocking stress-induced hippocampal memory deterioration and activates molecular mechanisms of memory storage in response to a learning experience.
ABSTRACT
BACKGROUND: Sildenafil is a selective PDE5 inhibitor that increases cGMP levels in the target tissues and is an effective treatment agent for erectile dysfunction. The nitric oxide-cGMP pathway might be implicated in regulation of certain CNS functions, including locomotor activity and anxiety. MATERIAL AND METHODS: The aim of the current study was to investigate effects of sildenafil (3 and 10 mg/kg) on anxiety and locomotor activity in open field and elevated plus maze (EPM) tests in young and aged mice. RESULTS: Sildenafil (3 and 10 mg/kg) significantly decreased the percent of time spent in the open arms compared to the control group in young animals in the EPM test, but only the 10 mg/kg dose significantly decreased the percentage of total number of entries to the open arms in young animals. Sildenafil (3 and 10 mg/kg) significantly decreased the percentage of total number of entries to the open arms in aged animals in the EPM test, but it significantly increased total distance moved and speed of the animals in the locomotor activity test in young animals. The total distance moved and the speed of the animals significantly decreased in aged animals compared to the young control group, although sildenafil (3 and 10 mg/kg) did not alter these parameters in aged mice. CONCLUSIONS: Our results show that sildenafil had anxiogenic effects in young as well as aged mice, but it enhanced locomotor activity only in the young mice in the EPM test. Thus, sildenafil seems to exert different effects on anxiety and locomotion in young and aged animals.
Subject(s)
Aging/pathology , Anti-Anxiety Agents/therapeutic use , Anxiety/drug therapy , Anxiety/physiopathology , Motor Activity/drug effects , Piperazines/pharmacology , Piperazines/therapeutic use , Sulfones/pharmacology , Sulfones/therapeutic use , Animals , Anti-Anxiety Agents/pharmacology , Locomotion/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Inbred BALB C , Purines/pharmacology , Purines/therapeutic use , Sildenafil CitrateABSTRACT
Anxiety disorders are the most common behavioral disorders, and they exhibit high comorbidity rates. The aim of the present study was to confirm the effects of Amibegron, the first selective beta 3 adrenergic agent, on anxiety and to demonstrate that different serotoninergic receptor subtypes are involved in this effect. We administered the serotonin 5-HT1A receptor antagonist WAY-100635, the serotonin 5-HT2A receptor antagonist Ketanserin and the serotonin 5-HT3 receptor antagonist Ondansetron in mice and evaluated their performance in the elevated plus-maze test. Mice administered with Amibegron (5 and 10 mg/kg) showed a dose-dependent prolonged time spent in the open arms and an increase in the number of entries into the open arms during the elevated plus-maze (EPM) test. However, in the control mice, administration of WAY, Ketanserin and Ondansetron demonstrated no effect on the time spent in the open arms and the number of entries into the open arms. In addition, these treatments all significantly reversed the effect of the Amibegron-induced (10 mg/kg) increase in the time spent in the open arms. However, only WAY and Ketanserin treatments reversed the Amibegron-induced increase in the number of entries into the open arms. In conclusion, Amibegron exerted a significant anxiolytic effect, which was as effective as Diazepam, in mice during the EPM test. This effect of Amibegron may be mediated by interactions with the serotonin 5-HT1A, 5-HT2A and 5-HT3 receptors.