RESUMO
A novel pyridine derivative, 8-{4-[(6-methoxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-ylmethyl)-amino]-butyl}-8-aza-spiro[4.5]decane-7,9-dione hydrochloride, termed JB-788, was designed to selectively target 5-HT(1A) receptors. In the present study, the pharmacological profile of JB-788 was characterized in vitro using radioligands binding tests and in vivo using neurochemical and behavioural experiments. JB-788 bound tightly to human 5-HT(1A) receptor expressed in human embryonic kidney 293 (HEK-293) cells with a K(i) value of 0.8 nM. Its binding affinity is in the same range as that observed for the (+/-)8-OH-DPAT, a reference 5HT(1A) agonist compound. Notably, JB-788 only bound weakly to 5-HT(1B) or 5-HT(2A) receptors and moreover the drug displayed only weak or indetectable binding to muscarinic, alpha(2), beta(1) and beta(2) adrenergic receptors, or dopaminergic D(1) receptors. JB-788 was found to display substantial binding affinity for dopaminergic D(2) receptors and, to a lesser extend to alpha(1) adrenoreceptors. JB-788 dose-dependently decreased forskolin-induced cAMP accumulation in HEK cells expressing human 5-HT(1A), thus acting as a potent 5-HT(1A) receptor agonist (E(max.) 75%, EC(50) 3.5 nM). JB-788 did not exhibit any D(2) receptor agonism but progressively inhibited the effects of quinpirole, a D(2) receptor agonist, in the cAMP accumulation test with a K(i) value of 250 nM. JB-788 induced a weak change in cAMP levels in mouse brain but, like some antipsychotics, transiently increased glycogen contents in various brain regions. Behavioral effects were investigated in mice using the elevated plus-maze. JB-788 was found to increase the time duration spent by animals in anxiogenic situations. Locomotor hyperactivity induced by methamphetamine in mouse, a model of antipsychotic activity, was dose-dependently inhibited by JB-788. Altogether, these results suggest that JB-788 displays pharmacological properties, which could be of interest in the area of anxiolytic and antipsychotic drugs.
Assuntos
Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Compostos de Espiro/farmacologia , Animais , Ansiolíticos/farmacologia , Antipsicóticos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Antagonistas dos Receptores de Dopamina D2 , Glicogênio/metabolismo , Humanos , Masculino , Camundongos , Ensaio Radioligante , Receptores de Dopamina D2/metabolismo , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
The aim of this study was to evaluate the effects of various drugs which present antidepressant properties: selective serotonin-reuptake inhibitors (SSRIs, fluoxetine), serotonin and noradrenaline-reuptake inhibitors (Desipramine) and phosphodiesterase inhibitors (PDE, rolipram and tofisopam) on bone microarchitecture and biomechanical properties. Twelve female mice were studied per group starting at an age of 10 weeks. During 4 weeks, they received subcutaneously either placebo or 20 mg kg(-1) day(-1) of desipramine, fluoxetine or 10 mg kg(-1) day(-1) of rolipram or tofisopam. Serum Osteocalcin and CTx were evaluated by ELISA. Bone microarchitecture of the distal femur was characterized by X-ray microCT (Skyscan1072). Mechanical properties were assessed by three-point bending test (Instron 4501) and antidepressant efficacy by forced swimming and open field tests. Fluoxetine displayed lower TbTh (-6.1%, p<0.01) and tofisopam higher TbTh (+5.0%, p<0.05) versus placebo. Rolipram and tofisopam treatments induced higher BV/TV than placebo (+23.8% and +18.3% respectively). Desipramine group had significantly higher cortical area (+4.8%, p<0.01) and fluoxetine lower cortical area (-6.1%, p<0.01) compared to placebo. The stiffness and Young's modulus were lower in the fluoxetine group (77+/-13 N mm(-1), 6431+/-1182 MPa) than in placebo (101+/-9 N mm(-1), 8441+/-1180 MPa). Bone markers indicated a significantly higher bone formation in tofisopam (+8.6%) and a lower in fluoxetine (-56.1%) compared to placebo. These data suggest deleterious effects for SSRIs, both on trabecular and cortical bone and a positive effect of PDE inhibitors on trabecular bone. Furthermore tofisopam anabolic effect in terms of bone markers, suggests a potential therapeutic effect of the PDE inhibitors on bone.
Assuntos
Antidepressivos/farmacologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Animais , Antidepressivos/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacologia , Fenômenos Biomecânicos , Osso e Ossos/fisiologia , Relação Dose-Resposta a Droga , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Osteocalcina/sangue , Pró-Colágeno/sangue , Rolipram/administração & dosagem , Rolipram/farmacologia , Base do Crânio/diagnóstico por imagem , Base do Crânio/efeitos dos fármacos , Base do Crânio/fisiologia , Natação , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: A radionuclide that accumulates in the central nervous system is likely to exert both a chemical and a radiological effect. The present study aimed at assessing the behavioral effect of two radionuclides previously shown to accumulate in the central nervous system after chronic exposure--uranium and cesium. MATERIALS AND METHODS: Rats were exposed for 9 months to drinking water contaminated with either enriched uranium at a dosage of 40 mg U x l(-1) or 137-cesium at a dosage of 6500 Bq x l(-1), which correspond to the highest concentrations measured in some wells in the south of Finland (uranium) or in the milk in Belarus in the year following the Chernobyl accident (137-cesium). RESULTS: At this level of exposure, 137-cesium had no effect on the locomotor activity measured in an open-field, on immobility time in a forced swimming test, on spontaneous alternation in a Y-maze and on novel object exploration in an object recognition test. Enriched uranium exposure specifically reduced the spontaneous alternation measured in the Y-maze after 3 and 9 months exposure although it did not affect the other parameters. CONCLUSION: Enriched uranium exposure altered the spatial working memory capacities and this effect was correlated with previously described accumulation of uranium in the hippocampus which is one of the cerebral areas involved in this memory system.
Assuntos
Sistema Nervoso Central/efeitos da radiação , Radioisótopos de Césio/toxicidade , Ingestão de Líquidos , Aprendizagem em Labirinto/efeitos da radiação , Atividade Motora/efeitos da radiação , Urânio/toxicidade , Animais , Sistema Nervoso Central/metabolismo , Contaminação Radioativa de Alimentos , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The effect of apamin on learning was examined using two behavioral tasks where the animals were subjected to two trials separated by a 24h interval. In the Y maze task, apamin administered before the acquisition session did not enhance performance on both the acquisition session and the restitution session. In the second behavioral task, animals were trained to press a lever to obtain a food pellet (fixed ratio 1). Then, to study the effect of apamin on extinction, animals were submitted to two sessions where a press on the lever was not reinforced. Apamin administered before the acquisition session reduced the number of lever presses during the first 3-min period of the restitution session. These results suggest that the blockade of SK channels could improve the acquisition but not when the task requires the processing of spatial information.
Assuntos
Apamina/farmacologia , Encéfalo/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Nootrópicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Encéfalo/fisiologia , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Aprendizagem/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Canais de Potássio Cálcio-Ativados/metabolismo , Ratos , Ratos Wistar , Canais de Potássio Ativados por Cálcio de Condutância Baixa , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologiaRESUMO
Effects of low to mild doses of soman on central and blood cholinesterase (ChE) activities and anxiety behavior were studied in mice 30 min, 24 h and 7 days after poisoning. At these two latter time points, histopathological consequences of soman intoxication were also studied. The 30-microg/kg dose of soman produced 30 min after intoxication, about 35% of central ChE inhibition, and an anxiolytic effect without toxic signs or histopathological changes. The 50-microg/kg dose of soman produced at the same time, about 56% of central ChE inhibition, slight clinical signs of poisoning without convulsions, an anxiogenic effect with a slight hypolocomotion but no brain damage. A mild dose of soman (90 microg/kg) produced at this same time point about 80% of central ChE inhibition, and led to ataxia and tremors in every mouse and to convulsions in some of them. Thirty minutes and 24 h after poisoning, the behavioral tests revealed neither anxiolytic nor anxiogenic responses despite a clear hypolocomotion. Only mice that experienced long-lasting convulsions developed neuropathological changes. The functional implication of our results, as well as the biological relevance of blood vs. brain ChE levels, as an index of intoxication severity are discussed.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Colinesterases/metabolismo , Soman/administração & dosagem , Tonsila do Cerebelo/patologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores da Colinesterase/efeitos adversos , Masculino , Camundongos , Soman/efeitos adversosRESUMO
RATIONALE: Tolerance to delay of gratification, taken to reflect impulsiveness, has been proposed to be under the preferential control of central serotonin (5-HT) processes. OBJECTIVE: The present study further examined the effects of drugs which directly or indirectly alter 5-HT transmission, on behaviour controlled by a delayed positive reinforcer. METHODS: Rats were given the choice in a T-maze between two magnitudes of reward: small (two food pellets) and immediate versus large (ten pellets) but delayed. When a 15-s waiting period was imposed in the arm leading to the large reward, rats selected this arm on 65-70% of the trials. This frequency was reduced to less than 40% when the large reward was delayed by 25 s. RESULTS: In rats whose ascending 5-HT pathways had been lesioned by infusion of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal raphe, the introduction of the 15-s delay contingency resulted in a transient larger reduction of the frequency of choice of the now-delayed reward, compared to sham operated controls. In contrast, choice behaviour of rats given 5,7-DHT into the substantia nigra did not differ from controls. para-Chlorophenylalanine (pCPA, 150 mg/kg IP, daily for 3 days), a 5-HT synthesis inhibitor, bretazenil (0.5-8 mg/kg IP), a benzodiazepine (BZD) receptor partial agonist, and muscimol (0.25-1 mg/kg IP), a GABA(A) receptor agonist, induced a shift toward immediate reward. In contrast to the other BZDs, alprazolam (1-2 mg/kg IP) enhanced the frequency of choice of the large-but-25 s-delayed reward. Similar increased preference for the large-but-delayed reward was induced by the selective 5-HT reuptake inhibitors, fluoxetine (4-8 mg/kg IP) and fluvoxamine (4 mg/kg IP). The full 5-HT(1A) receptor agonist, 8-OH-DPAT (0.015-0.5 mg/kg IP) enhanced the frequency of choice of the large reward delayed by 25 s, whereas the partial agonists, buspirone (1-4 mg/kg IP), ipsapirone (0.5-1 mg/kg IP) and MDL 73005EF (1-2 mg/kg SC), and the antagonist, WAY 100635 (4 mg/kg SC), reduced the number of choices of the large reward delayed by 15 s. Unexpectedly, WAY 100635 (2 mg/kg), which had no effect on choice whatever the delay, did not counteract the increased tolerance to delay induced by 8-OH-DPAT (0.06 mg/kg) and further reduced the frequency of choice of the large-but- 15 s-delayed reward induced by ipsapirone (0.5 mg/kg). CONCLUSIONS: These effects on tolerance to delay may be accounted for by a subtle balance between the opposing functional consequences of pre- versus post-synaptic 5-HT(1A) receptor activation or blockade. Overall, the present results provide further support to the idea that 5-HT processes participate in the control of impulsive-related behaviour, as assessed from tolerance to delay of reward in this particular T-maze procedure.
Assuntos
Fenclonina/farmacologia , Comportamento Impulsivo/tratamento farmacológico , Núcleos da Rafe/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Substância Negra/efeitos dos fármacos , 5,7-Di-Hidroxitriptamina , Animais , Ansiolíticos/farmacologia , Benzodiazepinas/farmacologia , Comportamento Impulsivo/fisiopatologia , Comportamento Impulsivo/psicologia , Masculino , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Recompensa , Inibidores Seletivos de Recaptação de Serotonina , Substância Negra/metabolismoRESUMO
The present study describes the effects of intraseptal infusions of 1 nmol AMPA and 12 nmol NBQX on both frequency and amplitude of physostigmine-induced theta rhythm in urethane-anesthetized rats. Infusion of AMPA increased the theta frequency. This effect was blocked by a prior infusion of NBQX. Infusion of NBQX decreased the theta amplitude, and this effect was not altered by AMPA. These results suggest that the septal AMPA/glutamate receptors exert subtle modulatory influences on septohippocampal cells involved in theta rhythm generation.
Assuntos
Hipocampo/fisiologia , Receptores de AMPA/fisiologia , Ritmo Teta , Animais , Ansiolíticos/farmacologia , Eletroencefalografia , Masculino , Fisostigmina/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Septo Pelúcido/fisiologia , Ritmo Teta/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/antagonistas & inibidores , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaRESUMO
Nicotine was investigated for its mnemonic effect in a two trials object recognition task. In the first trial, two copies of the same object were presented. In the second trial (24 h after), one of the familiar object and a new object were presented. The time spent exploring the new object by control rats was not significantly different from the exploration time of the familiar object, indicating that they did not remember the familiar object. Rats injected with nicotine before the first trial, after the first trial or before the second trial spent more time in exploring the new object than the familiar one at the second trial. These results suggest that, in normal rats, acute nicotine enhances acquisition, consolidation and restitution of the information in an object recognition task.
Assuntos
Memória/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Animais , Masculino , Ratos , Ratos WistarRESUMO
The present study describes the effects of intraseptal microinjections of 2 nmol of AP5 upon memory of rats subjected to a two trial object recognition task. This task allows us to detect either a disruption or an improvement of memory according to the duration of the interval between the sample trial (T1) and the choice trial (T2). AP5 injected before T1 did not disrupt memory in a schedule able to detect an amnesia. In a schedule able to detect an improvement of memory, AP5 injected either 10 min before or just after T1, or 10 min before T2, improved retention. These results suggest that microinjection of a low dose of AP5 in the septum improves the acquisition, the consolidation and the restitution of the information in a working memory task.
Assuntos
2-Amino-5-fosfonovalerato/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Memória/efeitos dos fármacos , N-Metilaspartato/antagonistas & inibidores , Desempenho Psicomotor/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Injeções Intraventriculares , Locomoção/efeitos dos fármacos , Masculino , Memória/fisiologia , Microinjeções , Ratos , Ratos Wistar , Núcleos Septais/fisiologiaRESUMO
This study consists of two parts, first to compare the pharmacological profile of atropine and CEB-1957 substance toward muscarinic receptor subtypes. In various rat brain structures, binding properties were determined by competition experiments of [3H]pirenzepine, [3H]AF-DX 384, and [3H]4-DAMP in quantitative autoradiography of M1, M2, and M3 muscarinic receptor subtypes, respectively. Competition curves have shown that atropine presents similar nanomolar inhibition constants toward each subtype, while CEB-1957 has distinct affinities (Ki from 0.26 to 73 nM) with the following range order: M3 > or = M2 > M1. The second part is to compare atropine and CEB-1957 (in combination with pralidoxime) for their ability to protect against the lethality induced by 2 x LD50 of the acetylcholinesterase inhibitor sarin. CEB-1957 reduced the mortality at doses 10 times lower than atropine. Finally, from these results, it is proposed that a selective blockade of M2 and M3 receptor subtypes could play a pivotal role in the protective effect against sarin poisoning.
Assuntos
Atropina/farmacologia , Encéfalo/efeitos dos fármacos , Inibidores da Colinesterase/intoxicação , Antagonistas Muscarínicos/farmacologia , Sarina/intoxicação , Tiofenos/uso terapêutico , Animais , Atropina/metabolismo , Autorradiografia , Ligação Competitiva , Encéfalo/metabolismo , Masculino , Antagonistas Muscarínicos/metabolismo , Parassimpatolíticos/metabolismo , Parassimpatolíticos/farmacologia , Piperidinas/metabolismo , Piperidinas/farmacologia , Pirenzepina/análogos & derivados , Pirenzepina/metabolismo , Pirenzepina/farmacologia , Intoxicação/tratamento farmacológico , Ratos , Ratos Wistar , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Receptor Muscarínico M3 , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Tiofenos/farmacologiaRESUMO
The neurotoxicity of Penitrem A (PA) in rats was assessed against neurophysiological, behavioral and histopathological parameters. Animals were acutely given intracerebroventricular (22-45 mg) or intraperitoneal injections (0.5-1.5 mg/kg) of PA. A typical trembling syndrome associated with PA was always noted. Depending on the dose administered, animals may convulse and eventually die (1-1.5 mg/kg). PA-induced transient alterations of the EEG involving an increase in the frequency and voltage of electrical activity recorded from the cerebral cortex. Hippocampal activity was not modified and some pathologic activities may be recorded at the thalamus. Generally these EEG alterations disappeared at d 3 after the injection and the animals progressively recovered. However in the most severe cases, neuromotor disturbances were maintained at d 7 (rotarod test). Coronal sections of the brain at the striatal, thalamic, hippocampal and pons levels mainly revealed that PA was able to induce dose related injuries in the cerebellum with massive degeneration of Purkinje cells and a significant vacuolization within the molecular layer. The neurotoxic mechanism remains unclear. Action of the mycotoxin on the cerebello-thalamo-cortical tract is discussed.
Assuntos
Encéfalo/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Micotoxinas/toxicidade , Animais , Encéfalo/patologia , Encéfalo/fisiologia , Cerebelo/patologia , Eletroencefalografia/efeitos dos fármacos , Masculino , Destreza Motora/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The effects of various drugs were assessed in rats responding under a Differential-Reinforcement-of-Low-Rate 30-s (DRL 30-s) schedule. Atropine, scopolamine, and CEB-1957 (a new muscarinic blocker) increased response rate and decreased reinforcement rate, while methylatropine only decreased reinforcement rate. Physostigmine decreased response and reinforcement rates, when pyridostigmine had few effect on DRL responding. The irreversible acetylcholinesterase (AChE) inhibitors organophosphorus compounds (OPC) soman and sarin, injected at one-third of the LD50 did not consistently alter DRL performance, suggesting that they produce few behavioral effects in the rat when administered at subtoxic doses. Three oximes--pralidoxime, pyrimidoxime, and HI-6--decreased both response and reinforcement rates. Mecamylamine had few consistent effects on performance, and nicotine, d-amphetamine, diazepam, and the wakening drug modafinil increased response rate and decreased reinforcement rate. These two latter drugs also increased the number of very premature responses. These results, taken together, indicate that a DRL schedule is a useful tool to bring to light the existence of psychotropic effects of a drug. The explanation of drug-induced alterations of DRL performance, in terms of effects on cognition or on mood, is also discussed.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Compostos Organofosforados/antagonistas & inibidores , Compostos Organofosforados/farmacologia , Animais , Ansiolíticos/farmacologia , Benzodiazepinas , Estimulantes do Sistema Nervoso Central/farmacologia , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , Compostos Organofosforados/toxicidade , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar , Esquema de ReforçoRESUMO
The present study describes the effects of intraseptal microinjections of N-methyl-D-aspartate (NMDA) or AP5, an agonist and an antagonist of the NMDA receptors, respectively, upon memory of rats. Animals were injected with the drug or vehicle immediately after the first exposure to two identical objects, and the duration of exploration of the familiar and a new object were evaluated 45 min or 24 h later. Vehicle-treated rats explored the new object longer than the familiar object when the intertrial time was 45 min, indicating that they remembered the familiar object, but not when the intertrial time was 24 h. The difference of exploration time between the objects was increased by NMDA, but not by AP5, when the intertrial time was 24 h, and decreased by AP5 when the intertrial interval was 45 min. These results suggest that NMDA and AP5 improves and disrupts, respectively, the consolidation in a working memory task.
Assuntos
2-Amino-5-fosfonovalerato/farmacologia , Memória/fisiologia , N-Metilaspartato/farmacologia , Reconhecimento Visual de Modelos , Receptores de N-Metil-D-Aspartato/fisiologia , Núcleos Septais/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , Animais , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Infusões Parenterais , Ligantes , Masculino , Memória/efeitos dos fármacos , N-Metilaspartato/administração & dosagem , Ratos , Ratos Wistar , Tempo de Reação , Núcleos Septais/efeitos dos fármacosRESUMO
Results of direct-current cardioversion of 48 patients with atrial arrhythmia taking oral flecainide were compared with those of 96 control-matched patients. After completion of 3 shocks, 98% of flecainide patients were converted versus 78% of control patients (p <0.01). Thus, despite an experimental increase in defibrillation threshold, flecainide given before cardioversion seems to have a beneficial effect.
Assuntos
Antiarrítmicos/uso terapêutico , Cardioversão Elétrica , Flecainida/uso terapêutico , Taquicardia/terapia , Administração Oral , Idoso , Antiarrítmicos/administração & dosagem , Doença Crônica , Eletrocardiografia , Feminino , Flecainida/administração & dosagem , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Male Wistar rats were trained, in two-lever operant chambers, to press one lever (L5) after the presentation of a conditioned stimulus (a light) for 5 s (CS5) or the other lever (L20) after a conditioned stimulus for 20 s (CS20). Various drugs were administered before experimental sessions, during which CS5, CS20 and a stimulus of the intermediate duration of 12 s (CS12) were randomly presented. Rats pretreated with vehicle made approximately 50% of presses on L5 after the presentation of CS12. Atropine, diazepam, desipramine, clomipramine and moderate doses of haloperidol or of scopolamine increased the percentage of responses made on L5 after the presentation of CS20 and/or CS12. These effects could be due to a reduction of the speed of an internal clock. High doses of either haloperidol or scopolamine decreased the percentage of correct responses, an effect that was interpreted as a disruption of temporal discrimination. Nicotine and d-amphetamine decreased the percentage of responses made on L5 after the presentation of CS5 and/or CS12, an effect that could reflect an acceleration in the speed of the internal clock. Physostigmine, buspirone, mianserin and piracetam did not consistently alter performance, suggesting that these drugs do not affect timing processes.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Psicotrópicos/farmacologia , Animais , Atropina/farmacologia , Clomipramina/farmacologia , Desipramina/farmacologia , Diazepam/farmacologia , Aprendizagem por Discriminação , Haloperidol/farmacologia , Masculino , Nicotina/farmacologia , Ratos , Ratos Wistar , Escopolamina/farmacologiaRESUMO
The effects of apamin, a selective blocker of the small conductance K(Ca) channels were examined in both passive avoidance and habituation of exploratory activity in rats. In the two experiments, animals were subjected to two trials separated by a 24 h interval. Apamin was administered either before or after the first session (acquisition) or before the second session (restitution). In the passive avoidance test, apamin did not alter performance whenever the time of administration. In the habituation task, apamin (0.4 mg/kg) decreased activity (distance travelled, rearing) on the two sessions only when it was injected before acquisition but not when injection took place just after the acquisition session or before the restitution session. Taken together, these findings support the view that the blockade of apamin sensitive K(Ca) channels improved the acquisition in non-stressful task, but not in a stressful situation.
Assuntos
Apamina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Cálcio/fisiologia , Habituação Psicofisiológica/efeitos dos fármacos , Bloqueadores dos Canais de Potássio , Análise de Variância , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacosRESUMO
Object recognition was investigated in rats in a two trial unrewarded task. In the first trial, two copies of the same object were presented. In the second trial, one of the familiar object and a new object were presented. Rats explored the new object longer than the familiar object when the intertrial time was 1 h, indicating that they remembered the familiar object, but not when the intertrial time was 24 h. Rats injected with apamin (a toxin which blocks specifically Ca(2+)-activated K(+)-channels) before the first trial spent more time in exploring the new object than the familiar object at the second trial, when it took place 24 h after the first trial. Injection of apamin just after the first trial or before the second trial did not modify the difference in exploration time between the new and the familiar object. These results suggest that the blockade of Ca(2+)-activated K(+)-channels could improve learning, but not consolidation nor restitution of the information, in an object recognition task.
Assuntos
Apamina/farmacologia , Aprendizagem/efeitos dos fármacos , Nootrópicos/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Análise de Variância , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Intraperitoneal administration of the mycotoxin penitrem A 30 min before a training session in passive avoidance task, impaired performance of rats subjected to a test-session 24 h after. This effect was not antagonised by pretraining administration of physostigmine or bicuculline. Administration of penitrem A 20 min before a training session or 30 min before a test-session did not impair performance. In the Morris water maze, doses of penitrem A that induces slight to moderate tremors, but not a lower dose, disrupted place learning. These results suggest that penitrem A disrupts the processes that take place at the time of acquisition, but not those just after acquisition, and does not alter the restitution of information. This effect would not be related to a decrease of cholinergic neurotransmission nor to a stimulation of GABA A receptors. Nevertheless, it could not be totally excluded that the performance impairments induced by penitrem A would be secondary to a motor disruption.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Micotoxinas/farmacologia , Animais , Bicuculina/farmacologia , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Antagonistas GABAérgicos/farmacologia , Masculino , Fisostigmina/farmacologia , Ratos , Ratos WistarRESUMO
Performance in cognitive tasks which require the subject to wait and/or to process a large amount of information can be disrupted by an increase in impulsive-like behaviour. Accordingly, a decrease in impulsive-like behaviour can improve performance in such tasks. Conversely, impulsive-like behaviour may improve performance in cognitive tasks where simple and fast responses and/or only little information processing is required. Thus, impulsivity constitutes a confounding factor in studies of cognitive function. Impulsive-like behaviour may be modified by serotonergic (5-HT) activity, with underactivity in 5-HT neurotransmission increasing impulsivity and vice versa. Drug- or lesion-induced alteration in 5-HT neurotransmission may, therefore, constitute suitable tools to investigate the role of impulsivity in animal tests of cognitive function. Benzodiazepines also increase impulsive-like behaviour, possibly by decreasing 5-HT neurotransmission. Hence, the effects of modulation of 5-HT systems and of the benzodiazepine-binding site on performance in animals tests of cognitive function will be discussed. It is predicted that the effects of manipulations of serotonergic activity or of benzodiazepine administration depend upon the nature of the response required, and that these effects may be mediated through changes in impulse control.
Assuntos
Cognição/fisiologia , Memória/fisiologia , Vias Neurais/fisiologia , Animais , Benzodiazepinas/farmacologia , Modelos Animais de Doenças , Serotonina/farmacologiaRESUMO
Right sided accessory pathways with slow and decremential anterograde conduction differ from the anatomical substrates of the nodo-ventricular connections described by Mahaim. The connection may also be atrio-ventricular or atrio-fascicular. The authors report a series of 6 patients (2 men, average age 31 +/- 9 years) with antidromic reciprocating tachycardia implicating accessory pathways with decremential conduction (wide QRS complexes with left bundle branch block) the radiofrequency ablation of which was centered on the proximal atrial pole. The increment of pre-excitation was 75 +/- 18 ms. No nodo-ventricular or nodo-fascicular connections were observed. One patient had an atrio-ventricular connection, the mapping and ablation (5 applications) of which were performed on the annulus, as if it were a bundle of Kent. Five patients had a nodo-fascicular connection which was masked during sinus rhythm. The localisation of the proximal atrial insertion on the tricuspid annulus was initially estimated by studying the superior junction of the circuit and by endocavitary stimulation, and then by recording the M potential (activation of the accessory pathway). This was recorded in 4 patients, either at a specific point on the annulus (lateral or postero-lateral) which was the target of ablation (3 patients, 5 +/- 3 applications) or over a wider region (2 cm) at which ablation failed (1 patient: 13 applications). The site of the increment was determined in 2 patients and was proximal to the M potential. The M potential could not be recorded on the annulus in one patient. In 2 patients, the M potential was also recorded along the side of the pathway on the antero-lateral wall of the right ventricle of the tricuspid valve at its distal pole. In 2 patients, ablation was centered on the distal pole in second intention, near to the terminal part of the right bundle where it was localised in one of the two (18 applications). Finally, ablation was obtained in 5 out of 6 patients. They remain asymptomatic after 12 +/- 7 months follow-up. These cases show that accessory pathways with slow decremential conduction usually behave like a complete conduction pathway with an accessory laterally situated atrioventricular node on the tricuspid, an accessory bundle and a distal insertion which are all accessible to ablation.