RESUMO
Experimental evidence indicates that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists ketamine and MK-801 induce schizophrenia-like symptoms in rodents, including cognitive deficits. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders comprising schizophrenia. The present study was designed to evaluate the efficacy of the joint administration of sub-effective doses of crocins with those of the atypical antipsychotics clozapine and risperidone in alleviating nonspatial recognition and emotional memory deficits induced either by ketamine (3 mg/kg) or MK-801 (0.1 mg/kg) in the rat. To this end, the object recognition and the step-through passive avoidance tests were used. Co-administration of sub-effective doses of crocins (5 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted nonspatial recognition and emotional memory deficits induced by NMDA receptor antagonists. The current findings suggest that this combinatorial treatment was efficacious in attenuating cognitive impairments related to the blockade of the NMDA receptor. In addition, the present results support the potential of crocins as an adjunctive drug for the therapy of schizophrenia.
Assuntos
Antipsicóticos , Carotenoides , Clozapina , Crocus , Maleato de Dizocilpina , Transtornos da Memória , Ratos Wistar , Receptores de N-Metil-D-Aspartato , Risperidona , Animais , Crocus/química , Carotenoides/farmacologia , Antipsicóticos/farmacologia , Risperidona/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Ratos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Masculino , Clozapina/farmacologia , Maleato de Dizocilpina/farmacologia , Ketamina/farmacologia , Esquizofrenia/tratamento farmacológico , Extratos Vegetais/farmacologiaRESUMO
Close to 19% of the world population suffers from anxiety. Current medications for this chronic mental disorder have improved treatment over the last half century or more, but the newer anxiolytics have proved disappointing, and enormous challenges remain. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of anxiety. In particular, excessive NO production might contribute to its pathology. This implies that it might be useful to reduce nitrergic activity; therefore, molecules aiming to downregulate NO production such as NO synthase inhibitors (NOSIs) might be candidates. Here, it was intended to critically review advances in research on these emerging molecules for the treatment of anxiety disorders. Current assessment indicates that, although NOSIs are implicated in anxiety, their potential anti-anxiety action remains to be established.
Assuntos
Ansiolíticos , Óxido Nítrico , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêuticoRESUMO
RATIONALE: Several lines of evidence indicate that the neurosteroid dehydroepiandrosterone (DHEA) is involved in anxiety. BNN27 is a new DHEA derivative lacking steroidogenic effects. The beneficial effects exerted by BNN27 in preclinical models of schizophrenia and memory disorders have been recently reported. OBJECTIVES: The present study was designed to investigate the effects of this DHEA novel analog on anxiety-like behavior in rats. METHODS: To this end, the light/dark box, the open field, the contextual fear conditioning, and the excessive self-grooming induced by the serotonin 5-HT2c receptor agonist mCPP tests were utilized. RESULTS: Animals treated acutely with BNN27 (1, 3, and 6 mg/kg) dose dependently spent more time in the bright compartment of the light/dark box and in the central zone of the open field with respect to their vehicle-treated cohorts. Further, BNN27 reduced freezing behavior and weakened the mCPP-induced excessive self-grooming. CONCLUSIONS: Our data indicate that BNN27 is a highly potent anxiolytic agent, as in all studied paradigms it showed anxiolytic-like effects in male rats.
Assuntos
Ansiolíticos , Ansiedade , Ratos , Masculino , Animais , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológico , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Desidroepiandrosterona/farmacologiaRESUMO
Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D1/D2 receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia.
Assuntos
Apomorfina , Clozapina , Ratos , Animais , Apomorfina/farmacologia , Molsidomina/efeitos adversos , Doadores de Óxido Nítrico/farmacologia , Agonistas de Dopamina/farmacologia , Óxido Nítrico , Dopamina , Risperidona , Ratos Wistar , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/induzido quimicamenteRESUMO
Obsessive-compulsive disorder (OCD) is as serious devastating anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs) are largely used for the treatment of this mental disease. This pharmacological approach presents consistent limitations including modest efficacy and important side effects. There is pressing need, therefore, to develop new molecules with higher efficacy and safety. Nitric oxide (NO) is an intra-and inter-cellular messenger in the brain. Its involvement in the pathogenesis of OCD has been proposed. In a series of preclinical studies, the anxiolytic profile of NO modulators has been emerged. In the present review I intended to critically evaluate advances in research of these molecules as potential novel agents for the treatment of OCD, comment their advantages over currently used pharmacological therapy as well remaining challenges. Up to now, few preclinical studies have been carried out to this end. Nonetheless, experimental evidence proposes a role for NO and its modulators in OCD. Additional research is mandatory aiming to definitively determine a role for NO modulators for the treatment of OCD. A note of caution, however, is needed on account of potential neurotoxicity and narrow therapeutic window of NO compounds.
Assuntos
Transtorno Obsessivo-Compulsivo , Transtorno Obsessivo-Compulsivo/metabolismo , Humanos , Animais , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Encéfalo/metabolismoRESUMO
The deficiency of the gaseous molecule nitric oxide (NO) seems to be critically involved in the pathogenesis of schizophrenia. Thus, molecules that can normalize NO levels, as are NO donors, might be of utility for the medication of this psychiatric disease. The aim of the present study was to detect the ability of the NO donor molsidomine to reduce schizophrenia-like impairments produced by the blockade of the N-methyl-D-aspartate (NMDA) receptor in rats. Molsidomine's ability to attenuate social withdrawal and spatial recognition memory deficits induced by the NMDA receptor antagonist ketamine were assessed using the social interaction and the object location test, respectively. Further, the efficacy of the combination of sub-effective doses of molsidomine with sub-effective doses of the atypical antipsychotic clozapine in alleviating non-spatial recognition memory deficits was evaluated utilizing the object recognition task. Molsidomine (2 and 4 mg/kg) attenuated social withdrawal and spatial recognition memory deficits induced by ketamine. Co-administration of inactive doses of molsidomine (1 mg/kg) and clozapine (0.1 mg/kg) counteracted delay-dependent and ketamine-induced non-spatial recognition memory deficits. The current findings suggest that molsidomine is sensitive to glutamate hypofunction since it attenuated behavioral impairments in animal models mimicking the negative symptoms and cognitive deficits of schizophrenia. Additionally, the present results support the potential of molsidomine as an adjunctive drug for the therapy of schizophrenia.
Assuntos
Clozapina , Disfunção Cognitiva , Ketamina , Ratos , Animais , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/uso terapêutico , Molsidomina/efeitos adversos , Ketamina/efeitos adversos , Receptores de N-Metil-D-Aspartato , Óxido Nítrico/uso terapêutico , Ratos Wistar , Clozapina/efeitos adversos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Transtornos da Memória/tratamento farmacológico , Isolamento Social , CogniçãoRESUMO
Several lines of evidence suggest that the intra- and inter-cellular messenger nitric oxide (NO) is critically involved in anxiety. Contrasting findings are reported, however, regarding the effects of NO donors in preclinical models of anxiety. Previous research has shown that challenge with a low dose range of the NO donors sodium nitroprusside (SNP) and molsidomine induce anti-anxiety-like effects in rodents. There is poor information concerning the effects of these NO donors on preclinical models mimicking the obsessive-compulsive disorder (OCD) and the post-traumatic stress disorder (PTSD). The present research was designed to investigate this issue in the rat. To this end, the mCPP-induced excessive self-grooming and the contextual fear conditioning (CFC) test which are behavioural paradigms resembling OCD and PTSD respectively in rodents were used. Acute administration of SNP (1 mg/kg) and molsidomine (4 mg/kg) attenuated excessive self-grooming induced by the 5-HT2C receptor agonist mCPP (0.6 mg/kg). Further, at the same dosage, both these NO donors reduced freezing behaviour evidenced in the CFC test. The present results suggest that NO donors are efficacious in attenuating abnormal behaviours revealed in animal models of OCD and PTSD which are among the most severe pathologies of anxiety.
Assuntos
Transtorno Obsessivo-Compulsivo , Transtornos de Estresse Pós-Traumáticos , Ratos , Animais , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Óxido Nítrico , Doadores de Óxido Nítrico/farmacologia , Molsidomina , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Nitroprussiato/farmacologiaRESUMO
Conspicuous experimental evidence indicates that anesthetic doses of the non-competitive NMDA receptor antagonist ketamine disrupt memory abilities in rodents. BNN27 is a synthetic analogue of dehydroepiandrosterone (DHEA) with potent antioxidant properties and its involvement in cognition has recently been shown. It is not yet clarified whether BNN27 can attenuate the cognition deficits induced by anesthetic ketamine. The present study was designed to elucidate this issue in the rat. For this purpose, the object recognition and the object location tests which are behavioral procedures evaluating non-spatial and spatial recognition memory respectively in rodents were used. The effects of compounds on motility were also tested utilizing a motor activity cage. Post-training administration of BNN27 (3 and 6 mg/kg, intraperitoneally) counteracted anesthetic ketamine (100 mg/kg, intraperitoneally)-induced non-spatial and spatial recognition memory deficits. Further, these effects cannot be attributed to changes to locomotor activity. Our findings clearly show the protective role of BNN27, on recognition memory impairment induced by anesthetic ketamine, indicating a functional interaction following co-administration of synthetic microneurotrophins and ketamine.
Assuntos
Anestésicos , Ketamina , Animais , Desidroepiandrosterona/farmacologia , Ketamina/efeitos adversos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Ratos , Ratos Wistar , Reconhecimento Psicológico/fisiologiaRESUMO
Natural products or organic compounds isolated from natural sources as primary or secondary metabolites have inspired numerous drugs [...].
Assuntos
Crocus/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologiaRESUMO
Schizophrenia is a severe psychiatric disorder affecting up to 1% of the worldwide population. Available therapy presents different limits comprising lack of efficiency in attenuating negative symptoms and cognitive deficits, typical features of schizophrenia and severe side effects. There is pressing requirement, therefore, to develop novel neuroleptics with higher efficacy and safety. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, appears to be implicated in the pathogenesis of schizophrenia. In particular, underproduction of this gaseous molecule is associated to this mental disease. The latter suggests that increment of nitrergic activity might be of utility for the medication of schizophrenia. Based on the above, molecules able to enhance NO production, as are NO donors, might represent a class of compounds candidates. Sodium nitroprusside (SNP) is a NO donor and is proposed as a promising novel compound for the treatment of schizophrenia. In the present review, we intended to critically assess advances in research of SNP for the therapy of schizophrenia and discuss its potential superiority over currently used neuroleptics.
Assuntos
Antipsicóticos/farmacologia , Doadores de Óxido Nítrico/farmacologia , Nitroprussiato/farmacologia , Esquizofrenia/tratamento farmacológico , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Humanos , Camundongos , Atividade Motora/efeitos dos fármacos , Óxido Nítrico/farmacologia , Nitroprussiato/química , Ensaios Clínicos Controlados Aleatórios como Assunto , RatosRESUMO
Schizophrenia is a chronic mental devastating disease. Current therapy suffers from various limitations including low efficacy and serious side effects. Thus, there is an urgent necessity to develop new antipsychotics with higher efficacy and safety. The dried stigma of the plant Crocus sativus L., (CS) commonly known as saffron, are used in traditional medicine for various purposes. It has been demonstrated that saffron and its bioactive components crocins and safranal exert a beneficial action in different pathologies of the central nervous system such as anxiety, depression, epilepsy and memory problems. Recently, their role as potential antipsychotic agents is under investigation. In the present review, I intended to critically assess advances in research of these molecules for the treatment of schizophrenia, comment on their advantages over currently used neuroleptics as well-remaining challenges. Up to our days, few preclinical studies have been conducted to this end. In spite of it, results are encouraging and strongly corroborate that additional research is mandatory aiming to definitively establish a role for saffron and its bioactive components for the treatment of schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Carotenoides/uso terapêutico , Crocus/química , Cicloexenos/uso terapêutico , Extratos Vegetais/uso terapêutico , Esquizofrenia/tratamento farmacológico , Terpenos/uso terapêutico , Animais , Antipsicóticos/química , Antipsicóticos/isolamento & purificação , Carotenoides/química , Carotenoides/isolamento & purificação , Cicloexenos/química , Cicloexenos/isolamento & purificação , Humanos , Medicina Tradicional , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Terpenos/química , Terpenos/isolamento & purificaçãoRESUMO
Consistent experimental evidence suggests that anesthetic doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine cause severe memory impairments in rodents. Crocins are among the various bioactive ingredients of the plant Crocus sativus L., and their implication in memory is well-documented. It has not yet been elucidated if crocins are able to attenuate the memory deficits produced by anesthetic ketamine. The present study was undertaken aiming to clarify this issue in the rat. For this aim, the object recognition, the object location and the habituation tests, reflecting non-spatial recognition memory, spatial recognition memory and associative memory, respectively, were utilized. A post-training challenge with crocins (15-30 mg/kg, intraperitoneally (i.p.), acutely) counteracted anesthetic ketamine (100 mg/kg, i.p.)-induced performance impairments in all the above-mentioned behavioral memory paradigms. The current findings suggest that crocins modulate anesthetic ketamine's amnestic effects.
Assuntos
Carotenoides/farmacologia , Crocus/química , Ketamina/efeitos adversos , Transtornos da Memória/tratamento farmacológico , Anestésicos/efeitos adversos , Anestésicos/química , Anestésicos/farmacologia , Animais , Carotenoides/química , Humanos , Ketamina/química , Ketamina/farmacologia , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/patologia , RatosRESUMO
RATIONALE: Schizophrenia is a devastating mental disease that affects nearly 1% of the population worldwide. It is well documented that the dopaminergic (DAergic) system is compromised in schizophrenia. It is of note that the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induces schizophrenia-like symptoms in rodents, including disruption of memory abilities. Neuroactive steroids, comprising dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), were shown to affect brain DAergic system and to be involved in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. It has recently been reported that BNN27 counteracted schizophrenia-like behavioural deficits produced by glutamate hypofunction in rats. OBJECTIVES: The aim of the present study was to investigate the ability of BNN27 to attenuate non-spatial, spatial recognition and discrete memory deficits induced by apomorphine in rats. METHODS: To this end, the object recognition task (ORT), the object location task (OLT) and the step-through passive avoidance test (STPAT) were used. RESULTS: BNN27 (3 and 6 mg/kg, i.p.) attenuated apomorphine (0.5 mg/kg, i.p.)-induced non-spatial, spatial recognition and discrete memory deficits. Interestingly, the effects of compounds on memory cannot be ascribed to changes in locomotor activity. CONCLUSIONS: Our findings suggest that BNN27 is effective to DA dysfunction caused by apomorphine, attenuating cognitive impairments induced by this D1/D2 receptor agonist in rats. Additionally, our findings illustrate a functional interaction between BNN27 and the DAergic system that may be of relevance for schizophrenia-like behavioural symptoms.
Assuntos
Apomorfina/farmacologia , Disfunção Cognitiva/prevenção & controle , Desidroepiandrosterona/farmacologia , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Animais , Cognição/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Transtornos da Memória/psicologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/metabolismoRESUMO
Anxiety is a chronic severe psychiatric disorder. Crocins are among the various bioactive components of the plant Crocus sativus L. (Iridaceae) and their implication in anxiety is well-documented. However, which is the mechanism of action underlying the anti-anxiety effects of crocins remains unknown. In this context, it has been suggested that these beneficial effects might be ascribed to the agonistic properties of these bioactive ingredients of saffron on the GABA type A receptor. The current experimentation was undertaken to clarify this issue in the rat. For this research project, the light/dark and the open field tests were used. A single injection of crocins (50 mg/kg, i.p., 60 min before testing) induces an anti-anxiety-like effect revealed either in the light-dark or open field tests. Acute administration of the GABAA-benzodiazepine receptor antagonist flumazenil (10 mg/kg, i.p., 30 min before testing) abolished the above mentioned anxiolytic effects of crocins. The current findings suggest a functional interaction between crocins and the GABAA receptor allosteric modulator flumazenil on anxiety.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Benzodiazepinas/metabolismo , Carotenoides/toxicidade , Crocus/química , Flumazenil/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Ansiedade/patologia , Comportamento Animal/efeitos dos fármacos , Masculino , Extratos Vegetais/toxicidade , Ratos , Ratos WistarRESUMO
Ketamine, a non-competitive NMDA receptor antagonist, has been reported to mimic the cognitive symptoms of schizophrenia in animals. It has been reported to produce learning and memory deficits in rodents. However, there have limited number of reports that investigated the specific components of memory process that are affected with ketamine. In the present study, we investigated the effects of ketamine [8 and 20 mg/kg, intraperitoneally, (i.p.)] on storage and retrieval of information in rats using an object recognition test. We examined also whether a low dose range of the D1/D2 dopamine receptor agonist apomorphine (0.05 and 0.1 mg/kg, i.p.) would counteract the effects of ketamine. The results show that ketamine dose-dependently impaired storage of information while it did not affect rats' retrieval abilities. Administration of apomorphine reversed the ketamine-induced performance deficits in the ORT. The current findings show a differential modulation of post-training memory components (storage and retrieval of information) by ketamine and suggest a functional interaction between dopamine and NMDA receptors in the control of memory storage which may be of relevance to cognitive deficits a core feature of schizophrenia.
Assuntos
Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Memória/efeitos dos fármacos , Animais , Masculino , Rememoração Mental/efeitos dos fármacos , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Several lines of evidence indicate that anesthetic doses of the non-competitive N-methyl-D-aspartate receptor antagonist ketamine disrupt memory functions in rodents. The mechanism by which anesthetic ketamine produces its adverse behavioural effects is not yet clarified. The implication of nicotinic acetylcholine receptor as a potential site of action of anesthetic ketamine adverse effects on memory is proposed. We investigated the ability of α4ß2 nicotinic receptor agonist ABT-418 (0.01, 0.03, 0.1 mg/kg, i.p.) and α7 nicotinic receptor agonist GTS-21 (0.3, 1, 3 mg/kg, i.p.) to counteract recognition memory deficits produced by acute post-training administration of anesthetic ketamine (100 mg/kg, i.p.) in rats. For this purpose, the novel object recognition test, a behavioural paradigm assessing recognition memory abilities in rodents was used. Post-training acute administration of GTS-21 (3 mg/kg) counteracted anesthetic ketamine-induced performance deficits in the novel object recognition memory task. By contrast, ABT-418 failed to reverse the recognition memory deficits caused by anesthetic ketamine. The present findings propose that an α7 nicotinic receptor component might modulate anesthetic ketamine's adverse effects on recognition memory.
Assuntos
Anestésicos Dissociativos/administração & dosagem , Ketamina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Nicotínicos/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Masculino , Ratos Wistar , Reconhecimento Psicológico/fisiologiaRESUMO
Sodium nitroprusside (SNP) is a nitric oxide (NO) donor which actually is under assessment as a potential candidate for the treatment of schizophrenia. It is well documented that anxiety symptoms are a prominent future in various psychiatric diseases comprising schizophrenia. Prior research has shown that acute challenge with SNP (1-3 mg/kg) induced anti-anxiety effects in rats but these effects at high doses were confounded by sedation and were disappeared after repeated application of it. It is still unknown if administration of a lower SNP dose range, either acutely or sub-chronically, could induce anxiolytic-like behaviour. The present study was designed to investigate this issue in rats. For this aim, the light/dark and the open field tests were used. Acute challenge with SNP (0.1 and 0.3 mg/kg, 30 min before testing) did not affect rodents' performance in the above mentioned behavioural paradigms. Conversely, rats treated sub-chronically with SNP (0.1 and 0.3 mg/kg, once per day, for 5 consecutive days), displayed longer time spent in the light chamber of the light/dark box and in the central area of the open field with respect to their vehicle-treated counterparts. Interestingly, SNP did not influence the first latency to enter the dark chamber and the number of transitions between the light and dark compartments of the apparatus in the light/dark test and did not modify the number of squares crossed, grooming episodes and rearings in the open field test. Finally, acute administration of SNP (0.1, 0.3 and 1 mg/kg, 10 min before testing) also did not influence rats' performance in the light/dark test. The present results indicate that short-term repeated but not acute application of a range of low doses of the NO donor SNP in a dose-independent manner induced an anti-anxiety behaviour in the rat which was not accompanied by undesired effects.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Doadores de Óxido Nítrico/uso terapêutico , Nitroprussiato/uso terapêutico , Animais , Ansiolíticos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Doadores de Óxido Nítrico/administração & dosagem , Nitroprussiato/administração & dosagem , Ratos WistarRESUMO
Consistent experimental evidence supports an important role of the glutamatergic system in the etiopathogenesis of schizophrenia. Numerous studies propose that blockade of the NMDA receptor by its antagonist ketamine impairs cognition and can mimic certain aspects of positive and negative symptoms of schizophrenia in rodents. Neuroactive steroids, including dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were shown to affect brain glutamatergic system and to be implicated in schizophrenia. BNN27 is a novel DHEA derivative, which is devoid of steroidogenic activity. The neuroprotective effects of BNN27 have been recently evidenced. The aim of the present study was to investigate the ability of BNN27 to counteract schizophrenia-like behavioural deficits produced by ketamine in rats. BNN27's ability to attenuate hypermotility, stereotypies and ataxia induced by ketamine were evaluated using a motor activity cage. To assess the efficacy of BNN27 to reverse non-spatial and spatial recognition memory deficits caused by ketamine, the object recognition task and the object location task were used. Finally, the social interaction test was utilized in order to examine the effects of BNN27 on ketamine-induced social withdrawal. BNN27 (3 and 6â¯mg/kg, i.p.) attenuated ketamine (10â¯mg/kg, i.p.)-induced ataxia and to some extent also hypermotility. BNN27 (3-6â¯mg/kg, i.p.) counteracted ketamine (3â¯mg/kg, i.p.)-induced non-spatial and spatial recognition memory deficits. Further, BNN27 (6â¯mg/kg, i.p.) reduced the ketamine (8â¯mg/kg, i.p.)-induced social isolation. Our findings show that BNN27 is sensitive to glutamate hypofunction produced by ketamine since it reduced schizophrenia-like behavioural deficits induced by this NMDA receptor antagonist in rats.
Assuntos
Comportamento Animal/efeitos dos fármacos , Desidroepiandrosterona/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Atividade Motora/efeitos dos fármacos , Comportamento Social , Memória Espacial/efeitos dos fármacos , Animais , Masculino , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Isolamento SocialRESUMO
There is scarce information regarding the effects of anesthetic doses of the non-competitive N-methyl-D-aspartate receptor antagonist ketamine on anxiety. The current study evaluated the acute effects of intraperitoneally (i.p.) administered anesthetic ketamine (100 mg/kg) i.p. on anxiety in rats. For this purpose, the light/dark and the open field tests were utilized. The effects of anesthetic ketamine on motility were also examined using a motility cage. In the light/dark test, anesthetic ketamine, administered 24 h before testing reduced the number of transitions between the light and dark compartments and the time spent in the light compartment in the rats compared with their control cohorts. In addition, ketamine was found to exert a depressive effect on rats' motility. In the open field test, animals treated with anesthetic ketamine 24 h before testing spent essentially no time in the central area of the apparatus, decreased horizontal ambulatory activity, and preserved to a certain extent their exploratory behaviour compared to their control counterparts. The results suggest that, in spite of its hypokinetic effect, a single anesthetic ketamine administration apparently induces an anxiety-like state, while largely preserving exploratory behaviour in the rat. These effects were time-dependent they since they were extinguished when testing was carried out 48 h after anesthetic ketamine administration.
Assuntos
Anestésicos Dissociativos/uso terapêutico , Ansiedade/tratamento farmacológico , Ketamina/uso terapêutico , Locomoção/efeitos dos fármacos , Anestésicos Dissociativos/farmacologia , Animais , Ansiedade/psicologia , Ketamina/farmacologia , Locomoção/fisiologia , Masculino , Fotoperíodo , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Experimental evidence indicates that anesthetic doses of the non-competitive NMDA receptor antagonist ketamine impair memory abilities in rodents. The mechanism by which anesthetic ketamine produces its adverse behavioural effects is not yet clarified. In this context, it has been proposed that the effects of anesthetic ketamine on memory might be attributed to its agonistic properties on the GABA type A receptor. The present study was designed to address this issue. Thus, we investigated the ability of the benzodiazepine receptor antagonist flumazenil (1, 3, 6â¯mg/kg, i.p.) and the GABAA receptor antagonist bicuculline (0.5, 1.5, 3â¯mg/kg, i.p.) to counteract recognition memory deficits produced by anesthetic ketamine (100â¯mg/kg, i.p.) in rats. For this purpose, the novel object recognition task, a behavioural paradigm assessing recognition memory abilities in rodents was used. Compounds were coadministered 24â¯h before testing or retention. Pre (24â¯h before testing) or post-training (24â¯h before retention) administration of flumazenil (6â¯mg/kg, i.p.) counteracted anesthetic ketamine-induced performance deficits in the novel object recognition memory task. Conversely, bicuculline failed to attenuate the recognition memory deficits caused by anesthetic ketamine. Our findings propose a functional interaction between anesthetic ketamine and the GABAA receptor allosteric modulator flumazenil on recognition memory.