RESUMO
Exposure of rats to an environment with low O2 levels evokes a panic-like escape behavior and recruits the dorsal periaqueductal gray (dPAG), which is considered to be a key region in the pathophysiology of panic disorder. The neurochemical basis of this response is, however, currently unknown. We here investigated the role played by nitric oxide (NO) within the dPAG in mediation of the escape reaction induced by hypoxia exposure. The results showed that exposure of male Wistar rats to 7% O2 increased nitrite levels, a NO metabolite, in the dPAG but not in the amygdala or hypothalamus. Nitrite levels in the dPAG were correlated with the number of escape attempts during the hypoxia challenge. Injections of the NO synthesis inhibitor NPA, the NO-scavenger c- PTIO, or the NMDA receptor antagonist AP-7 into the dorsolateral column of the periaqueductal gray (dlPAG) inhibited escape expression during hypoxia, without affecting the rats' locomotion. Intra-dlPAG administration of c-PTIO had no effect on the escape response evoked by the elevated-T maze, a defensive behavior that has also been associated with panic attacks. Altogether, our results suggest that NO plays a critical role in mediation of the panic-like defensive response evoked by exposure to low O2 concentrations.
Assuntos
Reação de Fuga/fisiologia , Hipóxia/fisiopatologia , Óxido Nítrico/fisiologia , Pânico/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Tonsila do Cerebelo/metabolismo , Animais , Arginina/administração & dosagem , Arginina/análogos & derivados , Arginina/farmacologia , Reação de Fuga/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microinjeções , Atividade Motora/efeitos dos fármacos , Nitritos/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , RatosRESUMO
BACKGROUND: An excitatory imbalance in the hypothalamus of rodents caused by local chemical stimulation elicits fear-related defensive reactions such as escape and freezing. In addition, these panic attack-like defensive reactions induced by hypothalamic neurons may cause antinociception. However, there is a shortage of studies showing the participation of the anterior hypothalamic nucleus in these adaptive defensive mechanisms. Nitric oxide (NO) donors have been shown to evoke fear-related defensive responses when microinjected into paralimbic and limbic structures, and this excitatory neuromodulation can recruit the glutamatergic system. AIMS: The aim of this work was to investigate the influence of the glutamatergic system in the nitrergic effects on fear-related defensive responses organised by anterior hypothalamic neurons. METHODS: The present study evaluates the effects of the molsidomine active metabolite SIN-1 NO donor administered into the anterior hypothalamus (AH) of mice at different concentrations (75, 150 and 300 nmol/0.1 µL). Then, we investigated the effects of pre-treatment of the AH with AP-7 (an N-methyl-d-aspartate (NMDA) receptor-selective antagonist; 0.02, 0.2 and 2 nmol/0.1 µL) on the behavioural and antinociceptive effects provoked by AH chemical stimulation with SIN-1 microinjections. RESULTS: The 300 nmol dose of SIN-1 was the most effective at causing panic-like defensive behaviours followed by a significant antinociceptive response. In addition, both of these effects were attenuated or inhibited by AH pre-treatment with AP-7. CONCLUSIONS: These findings suggest that the panicogenic and antinociceptive effects evoked by intra-AH microinjections of SIN-1 depend on NMDA receptor activation.
Assuntos
Medo/efeitos dos fármacos , Molsidomina/análogos & derivados , Doadores de Óxido Nítrico/administração & dosagem , Pânico/efeitos dos fármacos , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipotálamo Anterior/efeitos dos fármacos , Hipotálamo Anterior/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções , Molsidomina/administração & dosagem , Molsidomina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
To better understand information transfer along the hippocampal pathways and its plasticity, here we studied the antidromic responses of the dentate gyrus (DG) and CA3 to activation of the mossy fibers and Schaffer collaterals, respectively, in hippocampal slices from naïve and epileptic rats. We applied trains of 600 electrical stimuli at functionally meaningful frequencies (θ, ß/γ and γ). The responses of the DG to θ frequency trains underwent rapid potentiation that lasted about 400 stimuli, after which they progressively returned to control value. At ß/γ and γ frequencies, however, the initial potentiation was followed by a strong frequency-dependent depression within the first 50 stimuli. In kindled animals, the initial potentiation was stronger than in control preparations and the resonant phase at θ frequency lasted longer. In contrast, CA3 responses were exponentially depressed at all frequencies, but depression was significantly less intense at θ frequency in epileptic preparations. Failure of fibers to fire action potentials could account for some of the aforementioned characteristics, but waveforms of the intracellular action potentials also changed as the field responses did, i.e., half-duration and time-to-peak increased in both structures along the stimulation trains. Noteworthy, block of glutamate and GABA ionotropic receptors prevented resonance and reduced the depression of antidromic responses to ß/γ and γ stimulation recorded in the DG, but not in CA3. We show that the different behavior in the information transfer along these pathways depends on the frequency at which action potentials are generated, excitability history and anatomical features, including myelination and tortuosity. In addition, the mossy fibers are endowed with ionotropic receptors and terminal active properties conferring them their sui generis non-passive antidromic responses.
Assuntos
Região CA3 Hipocampal/fisiologia , Hipocampo/fisiologia , Fibras Musgosas Hipocampais/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Animais , Região CA3 Hipocampal/efeitos dos fármacos , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Hipocampo/efeitos dos fármacos , Fibras Musgosas Hipocampais/efeitos dos fármacos , Picrotoxina/administração & dosagem , Quinoxalinas/administração & dosagem , Ratos , Ratos WistarRESUMO
The inferior colliculus (IC), a midbrain structure that processes acoustic information of aversive nature, is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Recent evidence relating the IC to motor behavior shows that glutamate-mediated mechanisms in the neural circuits at the IC level modulate haloperidol-induced catalepsy. It has been shown that N(G)-nitro-L-arginine (L-NOARG), inhibitor of enzyme nitric oxide synthase (NOS), can induce catalepsy after intraperitoneal (ip), intracerebroventricular or intrastriatal administration. The present study examined whether the catalepsy induced by L-NOARG (ip) can be influenced by collicular glutamatergic mechanisms and if a NO-dependent neural substrate into the IC plays a role in this immobility state. L-NOARG-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, AP7 (20 or 40 nmol/0.5 µl), or of the NMDA receptor agonist N-methyl-D-aspartate (NMDA, 30 nmol/0.5 µl). Catalepsy was evaluated by positioning both forepaws of the rats on an elevated horizontal wooden bar and recording the time for which the animal maintained this position. The results showed that intracollicular microinjection of AP7 previous to systemic injections of L-NOARG (90 mg/kg) significantly attenuated the catalepsy. Conversely, intracollicular microinjection of NMDA increased the time of catalepsy when administered 10 min before systemic L-NOARG (10 or 45 mg/kg). The microinjection of L-NOARG (50 or 100 nmol) directly into the IC was not able to induce catalepsy. These findings suggest that glutamate-mediated mechanisms in the neural circuits of the IC modulate L-NOARG-induced catalepsy and participate in the regulation of motor activity.
Assuntos
Catalepsia/induzido quimicamente , Catalepsia/patologia , Inibidores Enzimáticos/toxicidade , Colículos Inferiores/metabolismo , Nitroarginina/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , Animais , Catalepsia/prevenção & controle , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Colículos Inferiores/efeitos dos fármacos , Masculino , Microinjeções , N-Metilaspartato/administração & dosagem , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Fatores de TempoRESUMO
The hippocampus, basolateral amygdala and ventromedial prefrontal cortex participate in the extinction of inhibitory avoidance and contextual fear conditioning. We studied the effect of drugs acting on receptors involved in synaptic modulation on extinction of both tasks. The drugs were given bilaterally right after the first of two sessions of extinction in each task through cannulae implanted into the mentioned areas. The doses used are known to influence memory consolidation of the original tasks. Their effects were evaluated on a second extinction session 24h later, and assumed to result from influences on the consolidation of extinction. The glutamate NMDA receptor stimulant d-serine (50 µg/side) and the histamine methyl-transferase inhibitor SKF9188 (12.5 µg/side) enhanced, and the NMDA antagonist amino-phosphonopentanoate (5 µg/side) and the H2 histamine receptor antagonist ranitidine (17.5 µg/side) inhibited, extinction of both tasks regardless of the region into which they were administered. Thus, glutamate NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Norepinephrine (1 µg/side), the ß-adrenoceptor antagonist timolol (1 µg/side), the D1 dopamine receptor agonist SKF38393 (12.5 µg/side) and the D1 antagonist SCH23390 (1.5 µg/side) also affected extinction of both tasks, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by ß- and D1 receptors is more complex. In conclusion, extinction of two different aversive tasks is modulatable by various systems, which bears upon the behavioral and pharmacological treatment of fear-motivated brain disorders.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/psicologia , Hipocampo/efeitos dos fármacos , Motivação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzazepinas/administração & dosagem , Benzazepinas/farmacologia , Região CA1 Hipocampal/fisiologia , Cateterismo , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Microinjeções , Ranitidina/efeitos adversos , Ranitidina/farmacologia , Ratos , Ratos Wistar , Timolol/farmacologiaRESUMO
NMDA receptor antagonist D-AP5 was injected into the dorsal hippocampus of Wistar rats before or immediately after the training session in fear conditioning. Training was conducted both with signaled (background context) or unsignaled (foreground context) footshocks. Contextual fear conditioning was assessed 24 h later and tone fear conditioning 48 h after training (only in the signaled footshock condition). Pretraining injections impaired conditioned fear to contextual features, both in background and foreground configurations, whereas tone fear conditioning was left intact. Posttraining injections were ineffective in all cases. We conclude that dorsal hippocampal NMDA receptors are required for contextual fear acquisition independently of context saliency and that they are not required to early consolidation processes.
Assuntos
2-Amino-5-fosfonovalerato/administração & dosagem , Condicionamento Clássico/fisiologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Medo/psicologia , Hipocampo/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Condicionamento Clássico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/efeitos dos fármacosRESUMO
The involvement of the dorsolateral periaqueductal gray in the regulation of fear-related behaviors such as escape and freezing is well established. It is still a matter of investigation, however, whether this midbrain area may have a relevant role in the modulation of more subtle defensive responses associated with anxiety such as risk assessment and inhibitory avoidance. By stimulating N-methyl-D-aspartic acid glutamate receptors located in the dorsolateral periaqueductal gray with its prototypical agonist N-methyl-D-aspartic acid (50 pmol), we report here an increase in both risk assessment and inhibitory avoidance behaviors of male Wistar rats tested in the elevated T-maze. These results are indicative of an anxiogenic-like effect. The selective N-methyl-D-aspartic acid receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (2.0 and 4.0 nmol) had the opposite effect on both defensive tasks. Pretreatment with an ineffective dose of DL-2-amino-7-phosphonoheptanoic acid (1.0 nmol) prevented the N-methyl-D-aspartic acid anxiogenic-like effect. At the dose range of DL-2-amino-7-phosphonoheptanoic acid and/or N-methyl-D-aspartic acid tested, neither the escape response from one of the elevated T-maze open arms nor the general exploratory activity as assessed in the open-field test was affected. The present results suggest that the dorsolateral periaqueductal gray column is also involved in the regulation of defensive behaviors related to anxiety, and N-methyl-D-aspartic acid glutamate receptors are recruited for this action.
Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Medo/efeitos dos fármacos , Medo/psicologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Assunção de Riscos , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Anticonvulsivantes/farmacologia , Etossuximida/farmacologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Microinjeções , N-Metilaspartato/administração & dosagem , N-Metilaspartato/farmacologia , Ratos , Ratos WistarRESUMO
Exposure to uncontrollable stressors causes behavioral changes that have been related to depressive states in humans. Poststress intrahippocampal administration of amino-7-phosphonoheptanoic acid (AP-7), a glutamate NMDA-receptor antagonist, attenuated the restraint-induced decreased exploration of an elevated plus maze 24 h later. The objective of the study was to test if this treatment would also attenuate the increased immobility seem in the forced swim test (FST) due to preexposition to this stressful situation. Male Wistar rats with cannulae aimed at the dorsal hippocampus were submitted to 15 min of forced swimming and tested 24 h later. They received bilateral intrahippocampal injections of AP-7 (10 nmol) either before or after the pretest swimming session or before the test. Poststress treatment increased latency to display the first episode of immobility and tended to reduce total immobility time. The drug was ineffective when given before stress or before test and in nonstressed animals. This suggests that glutamate NMDA receptors located in the dorsal hippocampus are involved in the behavioral changes observed in the FST.
Assuntos
2-Amino-5-fosfonovalerato/análogos & derivados , Antidepressivos/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , 2-Amino-5-fosfonovalerato/administração & dosagem , Animais , Hipocampo/fisiologia , Imobilização/fisiologia , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Estresse Fisiológico/tratamento farmacológicoRESUMO
Previous studies have shown that the activation of 5-HT3 receptors in the nucleus tractus solitarii (NTS) increases the baseline mean arterial pressure (MAP). In the present study, we evaluated the possible involvement of NMDA receptors in this pressor response. Four days before the experiments, under tribromoethanol anesthesia, rats received two guide cannulas in the direction of the NTS, and 1 day before the experiments, under tribromoethanol anesthesia, the femoral artery was cannulated for pulsatile arterial pressure (PAP), MAP, and heart rate (HR) measurements. On the day of the experiments, 2-methyl-serotonin, a 5-HT3 agonist, was microinjected into the NTS after microinjection of saline or AP-5, a selective NMDA receptor antagonist. Microinjection of 2-methyl-serotonin (5 nmol/50 nl) into the NTS after the vehicle (saline) produced a significant increase in MAP (+ 20 +/- 5 mm Hg, n = 8) while microinjection of 2-methyl-serotonin after microinjection of AP-5 (10 nmol/50 nl) produced no change in baseline MAP (-1 +/- 3 mm Hg, n = 11). Microinjection of AP-5 into the NTS produced no significant changes in the baseline MAP and HR. The data show that the increase in MAP in response to microinjection of a 5-HT3 agonist into the NTS is dependent on NMDA receptors.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/análogos & derivados , Serotonina/farmacologia , Núcleo Solitário/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/administração & dosagem , Ácido Glutâmico/farmacologia , Masculino , Microinjeções , Ratos , Ratos Wistar , Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Cloreto de Sódio/administração & dosagem , Cloreto de Sódio/farmacologia , Núcleo Solitário/efeitos dos fármacosRESUMO
The effect of the blockade of N-methyl-D-aspartic acid (NMDA)-type glutamatergic receptors in the nucleus accumbens septi (Acc) during different phases of a passive avoidance task (step-through paradigm, two chambers) of learning was studied in male rats which had been bilaterally cannulated into the Acc. Animals were trained with a punishment procedure (3 s shock of 1 mA) to avoid one of the chambers. The rats received either saline or (+/-)2-amino-7-phosphonoheptanoic acid (AP-7) solution (1 microg/1 microl) 10 min before training (pretraining schedule) or immediately after the shock (posttraining schedule). In the test phase, the animals were placed back into the white chamber after 1 and 8 days later. In this moment, rats stayed there for 1 min, after which the time elapsed between the removal of the door to the introduction into the dark chamber of the head (Latency 1) and body (Latency 2) and fecal boli expelled were recorded. In the pretraining injection schedule, the drug treatment significantly reduced Latency 2 (P<.05) and fecal boli (P<0.01) on Day 1, and all parameters on Day 8 (P<.05). The posttraining injection schedule did not modify behavior. We conclude that a preshock NMDA-glutamatergic blockade of the Acc leads to cognitive disturbances during acquisition and a decrease in anxiety levels, but that the consolidation of a learned task is not affected by postshock administration.
Assuntos
2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , 2-Amino-5-fosfonovalerato/administração & dosagem , Animais , Eletrochoque , Injeções , Masculino , Ratos , Esquema de Reforço , Técnicas EstereotáxicasRESUMO
RATIONALE: Glutamate antagonists microinjected into the dorsolateral PAG (DLPAG) show an anxiolytic-like profile in the elevated plus maze. Other columns of the PAG are also involved in defensive reactions. Few studies, however, have investigated the effects of pharmacological manipulation of the ventrolateral PAG (VLPAG) on procedures that predict anxiolytic activity. OBJECTIVES: To investigate the effects of the NMDA receptor (NMDAr) antagonist 2-amino-7-phosphonoheptanoic acid (AP7) microinjected into the DL or VLPAG in two procedures that predict anxiolytic activity using distinct aversive contingencies, the elevated plus maze and the Vogel punished licking test. METHODS: Male Wistar rats (7-14/group) with cannulas aimed at the DLPAG or VLPAG received AP7 (2 nmol/0.5 microl) or saline and 10 min later were submitted to the behavioural tests. In the punished licking experiment, water deprived (48 h) animals were allowed to drink for 3 min, receiving a 0.5 mA shock every 20 licks. The elevated plus maze test was performed as described elsewhere. Using this test, a dose response-curve for AP7 (0.2-20 nmol) injected in a smaller volume (0.25 microl) into the VLPAG was also performed. RESULTS: AP7 increased exploration of open arms of the EPM when microinjected into either the DLPAG or VLPAG ( P<0.05, ANOVA). The drug also increased the number of punished licks when administered into those columns (ANOVA, P<0.05). CONCLUSIONS: The results suggest that antagonism of endogenous excitatory amino acid neurotransmission in the DLPAG or VLPAG is able to reverse behavioral suppression induced by distinct aversive contingencies.
Assuntos
2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Ansiolíticos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , 2-Amino-5-fosfonovalerato/administração & dosagem , Animais , Ansiedade/psicologia , Comportamento Consumatório/efeitos dos fármacos , Injeções , Masculino , Medição da Dor/efeitos dos fármacos , Punição , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacosRESUMO
Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus, the entorhinal cortex, anterior cingulate cortex, posterior parietal cortex, or the basolateral complex of the amygdala. The animals were trained in one-trial step-down inhibitory avoidance and tested 24 h later. Prior (10 min) to the retention test, through the cannulae, they received 0.5 microl infusions of a vehicle (2% dimethylsulfoxide in saline), or of the following drugs dissolved in the vehicle: the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5, 2.0 or 5.0 microg), the AMPA receptor blocker, 6,7-dinitroquinoxaline-2,3 (1H,4H)dione (DNQX, 0.4 or 1.0 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG, 0.5 or 2.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the PKA stimulant, Sp-cAMPs (0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK), PD098059 (10 or 50 microM). All these drugs, at the same doses, had been previously found to alter long-term memory formation of this task. Here, retrieval test performance was blocked by DNQX, MCPG, Rp-cAMPs and PD098059 and enhanced by Sp-cAMPs infused into CA1 or the entorhinal cortex. The drugs had similar effects when infused into the parietal or anterior cingulate cortex, except that in these two areas AP5 also blocked retrieval, and in the cingulate cortex DNQX had no effect. Infusions into the basolateral amygdala were ineffective except for DNQX, which hindered retrieval. None of the treatments that affected retrieval had any influence on performance in an open field or in a plus maze; therefore, their effect on retention testing can not be attributed to an influence on locomotion, exploration or anxiety. The results indicate that the four cortical regions studied participate actively in, and are necessary for, retrieval of the one-trial avoidance task. They require metabotropic and/or NMDA glutamate receptors and PKA and MAPK activity. In contrast, the basolateral amygdala appears to participate only through a maintenance of its regular excitatory transmission mediated by glutamate AMPA receptors.
Assuntos
Aprendizagem da Esquiva/fisiologia , Córtex Cerebral/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Transdução de Sinais/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , Adenilil Ciclases/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Córtex Entorrinal/fisiologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Lateralidade Funcional/fisiologia , Glicina/administração & dosagem , Glicina/análogos & derivados , Glicina/farmacologia , Hipocampo/fisiologia , Injeções , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacosRESUMO
Exposure to a novel environment (an open field) for 2 min, 1 h after one-trial inhibitory avoidance training, hindered memory of the avoidance task measured 24 h later. The effect was seen regardless of the intensity of the avoidance training footshock. The effect was not seen if the exposure to novelty was carried out 5 min before, or 6 h after, the avoidance training, or if the animals did not perceive the open field as new and react accordingly. The amnesic effect of the novelty presented 1 h after avoidance training was blocked by the intrahippocampal infusion of D-2-amino-5-phosphono-pentanoic acid (AP5, 25 nmoles per side) or 1-(N, O-bis-[5-isoquinolinylsulphonyl]-N-methyl-L-tyrosyl)-4- phenylpiperazine (KN62, 100 micromoles per side) but not by that of C32H25N3O6 (KT5720, 90 micromoles per side) given 5 min before the novelty. In the open field there was habituation, measured by the decrease in exploration between the first and second minute. AP5 and KN62 impaired this habituation, but not KT5720. Exploration of the open field was similar in the groups exposed to the avoidance task 5 min later, or 1 h or 6 h before. Therefore, there was no reciprocity between the effect of the two tasks: novelty was amnesic for the one-trial avoidance task, but the opposite was not true. The amnesic effect of novelty appears to rely on N-methyl-D-aspartate (NMDA) receptor- and calcium/calmodulin-dependent protein kinase II (CaMKII)-dependent, but not on PKA-dependent, aspects of its habituation learning.
Assuntos
Amnésia Retrógrada/psicologia , Aprendizagem da Esquiva/fisiologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Carbazóis , Hipocampo/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Meio Ambiente , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hipocampo/enzimologia , Hipocampo/metabolismo , Indóis/administração & dosagem , Indóis/farmacologia , Injeções , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Pirróis/administração & dosagem , Pirróis/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Fatores de TempoAssuntos
2-Amino-5-fosfonovalerato/análogos & derivados , Aprendizagem da Esquiva/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Núcleo Accumbens/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Microinjeções , Núcleo Accumbens/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Vaginocervical stimulation (VS) releases multiple neurotransmitters into superfusates of the spinal cord; these can stimulate both nociceptive (e.g., glutamate, and glycine acting at the NMDA site), and antinociceptive (e.g., GABA, norepinephrine, 5-HT, and glycine acting at the strychnine-sensitive receptor) systems. Although the balance between these two opposing systems can determine the nature, magnitude, and duration of the response to VS, the characteristic prevailing response to VS is analgesia. We hypothesized that by counteracting the nociceptive component of this system, the magnitude and duration of the response to VS would be augmented. In the present study, the NMDA receptor antagonist AP5 [10 microg injected intrathecally (i.t.)] significantly increased the magnitude and duration of the analgesia (measured as tail flick latency to radiant heat) produced by VS (200 g force). At several time points the analgesic effect of AP5 combined with VS was greater than the sum of the effects of AP5 and VS separately, suggesting that they act synergistically. We propose that AP5 potentiates the analgesic effect of VS by two mechanisms: (a) antagonizing the putative pain-producing action of glutamate and glycine acting jointly at the NMDA receptor, and consequently, (b) permitting the unimpeded expression of the analgesic action of inhibitory neurotransmitters released by VS (e.g., glycine at the strychnine-sensitive receptor, and GABA).
Assuntos
2-Amino-5-fosfonovalerato/farmacologia , Analgésicos/farmacologia , Colo do Útero/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Vagina/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , Analgésicos/administração & dosagem , Animais , Feminino , Injeções Espinhais , Medição da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The nucleus accumbens septi (Acc) is thought to be involved in the control of cognitive processes and to be implicated in the pathophysiology of schizophrenia. Because perceptual-cognitive distortions are a core symptom in schizophrenia, any evidence that the Acc intervenes in a sensory recognition task in an animal species would be of interest. Pigeons were instrumentally trained to discriminate visual shapes. The acute effects of drug microinjections into the Acc on the discrimination of the training shapes, on the correction responding after errors, and on the generalisation to different shapes were examined. The effects of conduction blockade with lidocaine, glutamatergic blockade with 7-aminophosphonoheptanoic acid, and dopaminergic stimulation with apomorphine on behavioural performance were tested. No effects were observed with lidocaine and apomorphine. A significant and reversible performance disruption to near chance levels was obtained after aminophosphonoheptanoic acid injections into the Acc. It appears that a glutamatergic blockade of the Acc interferes with the visual discrimination processes of pigeons.
Assuntos
Discriminação Psicológica/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Núcleo Accumbens/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Animais , Apomorfina/administração & dosagem , Apomorfina/farmacologia , Columbidae , Discriminação Psicológica/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Generalização do Estímulo/efeitos dos fármacos , Lidocaína/administração & dosagem , Lidocaína/farmacologia , Microinjeções , Condução Nervosa/efeitos dos fármacos , Núcleo Accumbens/anatomia & histologia , Núcleo Accumbens/efeitos dos fármacosRESUMO
The hippocampus and amygdala, the entorhinal cortex and the parietal cortex participate, in that sequence, both in the formation and in the expression of memory for a step-down inhibitory avoidance task in rats. Bilateral infusion of AP5 or muscimol caused retrograde amnesia when given 0 min after training into both hippocampus and amygdala, when given or 180 min after training into the entorhinal cortex, or when given 180 min after training into the parietal cortex. Therefore, memory formation requires the sequential and integrated activity of all these areas mediated by glutamate NMDA receptors in each case. Pre-test administration of CNQX 1 day after training into hippocampus and amygdala, 1 or 31 days after training in entorhinal cortex, or 1, 31 or 60 days after training in the parietal cortex temporarily blocked retention test performance. Therefore, 1 day after training, all these brain structures are necessary for retrieval; 1 month later, the hippocampus and amygdala are no longer necessary for retrieval but the entorhinal and parietal cortex still are; and 60 days after training only the parietal cortex is needed. In all cases the mechanisms of retrieval require intact glutamate AMPA receptors.
Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Mapeamento Encefálico , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Lobo Parietal/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/administração & dosagem , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Amnésia Retrógrada/induzido quimicamente , Amnésia Retrógrada/fisiopatologia , Animais , Comportamento Exploratório , Lateralidade Funcional , Infusões Parenterais , Masculino , Memória/efeitos dos fármacos , Muscimol/administração & dosagem , Muscimol/farmacologia , Ratos , Ratos Wistar , Tempo de Reação , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Fatores de TempoRESUMO
In the present study we evaluated the role of NMDA receptors on the pressor and bradycardic responses to L-glutamate (L-Glu) microinjected into the nucleus tractus solitarius (NTS) of unanesthetized rats. L-Glu (1 nmol/100 nl) was microinjected into the NTS before and 10 min after microinjection of phosponovaleric acid (AP-5), a selective NMDA receptor antagonist, into the NTS of three different groups of rats (0.5, 2.0 and 10.0 nmol/100 nl). Microinjection of AP-5 into the NTS produced a dose-dependent reduction in the bradycardic response to L-Glu. However, no significant change in the pressor response to L-Glu was observed. These results indicate that the activation of the cardiovagal component (bradycardia) by L-Glu involves NMDA receptors and suggest that the activation of the sympatho-excitatory component (pressor response) by L-Glu in the commissural NTS is mediated by non-NMDA receptors.
Assuntos
2-Amino-5-fosfonovalerato/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Núcleo Solitário/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/administração & dosagem , Masculino , Microinjeções , Ratos , Ratos Wistar , Núcleo Solitário/efeitos dos fármacos , Fatores de TempoRESUMO
1. Experiments using localized microinfusions of specific agonists and antagonists of neurotransmitter receptors have shown that the amygdala, hippocampus, medial septum and entorhinal cortex are involved in memory consolidation, storage and expression. The data are consistent with observations derived from lesion studies suggesting a role for these structures in memory processes, but permit many additional conclusions concerning the mechanisms involved and their timing. 2. Memories are initially processed by glutamatergic N-methyl-D-aspartate (NMDA) receptors in amygdala, hippocampus and medial septum, which are sensitive to amino-phosphono valerate (AP5). Memory of inhibitory avoidance is processed by the three structures; memory of habituation to a novel environment is processed only by the hippocampus. At the time of consolidation, immediately after training, gamma-aminobutyrate type A (GABA-A) receptors, modulated by endogenous benzodiazepines, play an inhibitory role, and cholinergic muscarinic and beta-noradrenergic transmission play a modulatory role. 3. From 90 to 180 min after training, memories are blocked by cyano-nitro-quinoxalinedione (CNQX) given into the amygdala, septum and hippocampus. CNQX blocks non-NMDA glutamatergic receptors. Also between 90 and 180 min after training, memory of the habituation and inhibitory avoidance tasks is blocked by the infusion of AP5 or of the GABA-A agonist, muscimol, into the entorhinal cortex. This late post-training intervention of the entorhinal cortex is essential for the integration of successively acquired memories, and occurs in response to the simultaneous activation of CNQX-sensitive synapses in amygdala and hippocampus. 4. The expression of memory is blocked by the infusion of CNQX, at the time of testing, into the amygdala and hippocampus (inhibitory avoidance), into the hippocampus but not the amygdala (habituation), or into the entorhinal cortex (for the two tasks). Since consolidation is blocked by AP5 infused into these structures (see above), the data agree with the hypothesis that memories are mediated by (or actually consist of) long-term potentiation (LTP) in these areas of the brain. LTP induction is blocked by AP5 and LTP expression is blocked by CNQX. It is possible that, at the time of memory expression, the entorhinal cortex is an output of the amygdala and hippocampus.
Assuntos
Tonsila do Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , 2-Amino-5-fosfonovalerato/administração & dosagem , 2-Amino-5-fosfonovalerato/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona , Animais , Memória/efeitos dos fármacos , Muscimol/administração & dosagem , Muscimol/farmacologia , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacologia , Ratos , Receptores de GABA/efeitos dos fármacos , Receptores de GABA/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
The NMDA receptor antagonist, D-2-amino-5-phosphonopentanoic acid (AP5) (5 micrograms) and the GABAA receptor agonist, muscimol (0.03 microgram) were infused bilaterally into the entorhinal cortex of rats 0, 90, 180, or 360 min after training in habituation to a novel environment or in step-down inhibitory avoidance. Animals were tested for retention 22 h after training in each task. AP5 and muscimol were amnestic for both tasks when given 90 or 180 min after training, but had no effect when given 0 or 360 min after training. In contrast, intraamygdala injections or AP5 or muscimol were amnestic when given 0 but not 90 min after inhibitory avoidance training. The results indicate that the entorhinal cortex plays a late but important role in posttraining memory processing; this role involves glutamatergic NMDA receptors and is inhibited by GABAA receptors. The intervention of the entorhinal cortex in posttraining memory processing is subsequent, and could be secondary, to that of the amygdala and other limbic structures.