RESUMEN
Previous studies showed that the mineralocorticoid receptor (MR) is needed for behavioral flexibility in a fear conditioning paradigm. Female mice with forebrain-specific deletion of the MR gene (MR(CaMKCre) ) were unable to show extinction of contextual fear, and could not discriminate between cue and context fear unlike control mice. In the present study, male and female (MR(CaMKCre) ) mice and control littermates were used to study sex-specific fear conditioning, memory performance and extinction. The fear conditioning paradigm assessed both context- and cue-related fear within one experimental procedure. We observed that at the end of the conditioning all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MR(CaMKCre) mice remembered and feared the context more than the control mice. Furthermore, female MR(CaMKCre) mice were not able to extinguish this memory even on the second day of memory testing. The female mutants also could not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MR(CaMKCre) mice and the controls showed extinction and were capable to discriminate, although the MR(CaMKCre) mice needed more time before they started extinction. These findings further support the relevance of MR for behavioral flexibility and extinction of fear-motivated behavior. In conclusion, the loss of MR in the forebrain results in large differences in emotional and cognitive behaviors between female and male mice, which suggests a role of this receptor in the female prevalence of stress- and anxiety-regulated disorders.
Asunto(s)
Miedo/fisiología , Memoria/fisiología , Prosencéfalo/fisiología , Receptores de Mineralocorticoides/fisiología , Caracteres Sexuales , Animales , Señales (Psicología) , Extinción Psicológica , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Prosencéfalo/metabolismo , Receptores de Mineralocorticoides/genéticaRESUMEN
The prelimbic (PL) subregion of medial prefrontal cortex has been implicated in anxiety regulation. It is unknown, however, whether PL cortex also serves to fine-tuning the level of anxiety-related behavior exhibited on the next exposure to the same potentially threatening situation. To address this, we infused cobalt (1.0 mM) to temporarily inactivate the PL cortex during testing, post-testing or retesting in the elevated plus-maze (EPM). This protocol was chosen because it allowed us to concurrently investigate anxiety and the process of aversive learning and memory. PL cortex inactivation during the EPM testing increased the exploration of open-arms, substantiating its role in anxiety. PL cortex inactivation during the EPM retesting counteracted the further avoidance to open-arms exhibited by rats. Interestingly, as evidenced by min-by-min analysis, the cobalt-treated group behaved on EPM retesting as did the vehicle-treated group on EPM testing. This result may imply that activity in PL cortex is necessary for retrieving previously learned information that adjusts the anxiety response level on EPM retesting. Alternatively, a simple reduction in anxiety could explain the cobalt-induced increase in retest open-arms exploration. Neither test nor post-test PL cortex inactivation affected the further avoidance to open-arms observed on EPM retesting. To extend the investigation of PL cortex role in the regulation of open-arms avoidance, we infused other drugs prior to testing or retesting in the EPM. Antagonism of PL cortex adrenergic beta-1 receptors with atenolol (10 nmol), cholinergic muscarinic receptors with scopolamine (20 nmol) or glutamatergic N-methyl-d-aspartic acid (NMDA) receptors with AP5 (6.0 nmol) interfered with the level of open-arms exploration on testing, but not on retesting.
Asunto(s)
Ansiedad/metabolismo , Sistema Límbico , Aprendizaje por Laberinto/fisiología , Corteza Prefrontal/metabolismo , Animales , Ansiedad/psicología , Reacción de Prevención/fisiología , Conducta Exploratoria/fisiología , Sistema Límbico/metabolismo , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Aprendizaje/fisiología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Midazolam/farmacología , Propranolol/farmacología , Ratas , Ratas WistarRESUMEN
Electrical or glutamate stimulation of the dorsal periaqueductal gray matter (DPAG) of rats induces overt defensive behavior, such as freezing or flight, and hyponociception, while glycine and D-serine, a specific NMDA/GLY(B)-site ligand, produced only subtle defensive behavior related to risk assessment and avoidance from the open arms in the elevated plus-maze test. In order to verify whether the GLY(B) site in the DPAG could also be involved in hyponociception, glycine (GLY; 10, 20, 50, and 80 nmol/0.3 microl) and (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA966; 10 nmol/0.3 microl), a GLY(B)-site antagonist, were microinjected in rats submitted to the radiant heat-induced tail-flick test. GLY increased tail-flick latencies in a dose-dependent way. This hyponociceptive effect was completely reversed by co-administration with HA966. GLY given in the deep layer of superior colliculus did not produce changes in tail-flick latencies. Therefore, the results suggest that the activation of GLY(B) receptors in the DPAG is also involved in the hyponociception elicited by this brain area.
Asunto(s)
Conducta Animal/efectos de los fármacos , Glicina/farmacología , Umbral del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal , Animales , Relación Dosis-Respuesta a Droga , Ligandos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microinyecciones , Dimensión del Dolor , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
As well as being considered a reliable measurement instrument of animal anxiety-like behavior, the elevated plus-maze (EPM) is also used as a post-hoc test to evaluate emotionality in genetically modified rodents. The present review considers factors which may further improve the validity (predictive/face/construct) of the EPM model: (1) the importance of measuring defensive patterns of response such as risk assessment in addition to traditional measures such as open arm time; (2) other methodological refinements such as min-by-min scoring and use of a test/retest protocol; and (3) the identification and control of major sources of variability in this test. To estimate whether current use of the EPM by researchers takes the above factor into account, a survey of the recent literature was conducted. Results showed that the majority of studies have not yet assimilated these important considerations into their use of the EPM. For example, although risk assessment measures may be more sensitive to anxiety modulating drugs than traditional measures, only a quarter of studies have adopted them. It is hoped that this review can provide insights into the optimal use of the EPM, a simple task that can be very complex in terms of behavioral analysis.
Asunto(s)
Ansiedad , Etología , Aprendizaje por Laberinto/fisiología , Modelos Biológicos , Agresión , Animales , Ansiolíticos/farmacología , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Etología/historia , Etología/tendencias , Historia del Siglo XX , Historia del Siglo XXI , Aprendizaje por Laberinto/efectos de los fármacosRESUMEN
A learned avoidance response has been one of the hypotheses proposed to explain the 'one-trial tolerance' (OTT) phenomenon, which represents a drug's loss of anxiolytic-like effect in the elevated plus-maze (EPM) test in experienced rodents. Based on these facts, if some kind of learning occurs throughout Trial 1, then an impairment of its acquisition would maintain the drug's anxiolytic-like effect on Trial 2. Using male Wistar rats, the present study examined whether scopolamine (SCO; 0.5-1.5 mg/kg), a drug that impairs learning acquisition, given 30 min prior to Trial 1, actually prevents the OTT phenomenon to either the midazolam (MDZ; 0.5 mg/kg) or the memantine (MEM; 8.0 mg/kg) anxiolytic-like effect on the EPM Trial 2 (48 h later). According to the results, both MDZ and MEM increased open-arm exploration (indicating anxiolysis) on Trial 2 only in rats that had been treated previously with 1.5 mg/kg SCO. These results were observed in the absence of change in general exploratory activity. The present findings suggest that SCO impaired the acquisition of the behavioral strategy to cope with the subsequent EPM exposure that supposedly underlies the OTT phenomenon, thereby revealing the anxiolytic-like effects of MDZ and MEM on Trial 2.
Asunto(s)
Ansiolíticos/farmacología , Nivel de Alerta/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Memantina/farmacología , Midazolam/farmacología , Escopolamina/farmacología , Adaptación Psicológica/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Tolerancia a Medicamentos , Conducta Exploratoria/efectos de los fármacos , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Premedicación , Ratas , Ratas WistarRESUMEN
The periaqueductal gray matter (PAG) is functionally organized in longitudinal columns arranged along the aqueduct. Stimulation of lateral and dorsal columns produces a complex set of unconditioned behaviors named the 'defense reaction.' Overt responses in rats comprise a tense immobile display, fully opened eyes (herein named exophthalmus), trotting, galloping, jumping, micturition and defecation. Besides, the PAG is rich in glutamate and respective receptors, including the N-methyl-d-aspartic acid (NMDA) type. Therefore, the present study employed regression analysis to map out electrically and NMDA-induced single components of defensive behaviors produced by stepwise increasing stimulation of PAG. Data confirmed the defensive nature of PAG-evoked responses. Neither the appetitive, nor offensive, mouse-killing or male reproductive behaviors were produced by stimulation of PAG in presence of appropriate targets. Threshold and dose-response logistic analyses largely corroborated the columnar organization of PAG-evoked responses. Thus, whereas the defecation was restricted to PAG lateral column, exophthalmus, micturition and somatic defensive responses were similarly organized in dorsolateral and lateral, but not in the ventrolateral column. Moreover, thresholds of dorsolateral and lateral repertoires were strictly hierarchical, with exophthalmus, immobility, trotting, galloping and jumping appearing in this very order. However, the defensive responses of PAG dorsolateral column required NMDA doses significantly lower than those of lateral PAG. Accordingly, NMDA receptors within the dorsolateral PAG are likely to play a major role in the initiation of PAG-evoked defensive responses. In contrast, the present data do not support the organization of unconditioned defensive behaviors in ventrolateral PAG. The neuroanatomical substrate of each response and the role of PAG and NMDA receptors are discussed in relation to the present data. Further, this is the first report on PAG columnar organization of single components of defensive behaviors.
Asunto(s)
Conducta Animal/fisiología , Mapeo Encefálico , Sustancia Gris Periacueductal/fisiología , Animales , Estimulación Eléctrica , Electrofisiología , Potenciales Evocados/fisiología , Masculino , Ratas , Ratas Wistar , Receptores de N-Metil-D-AspartatoRESUMEN
The influence of the first exposure length upon the effect of midazolam (MDZ) administration prior to the second exposure in the elevated plus-maze (EPM) was investigated. Drug-free rats were assigned to freely explore the EPM for 1, 2 or 5 min (Trial 1). Twenty-four hours later, each group was subdivided in two further groups, which were retested in the EPM for 5 min, 30 min after either saline or MDZ (1.5 mg kg(-1)) administration (Trial 2). The data showed that during Trial 2, the percentage of entries (%Open arm entries) and time spent in the open arms (%Open arm time) were decreased if rats were pre-exposed to the EPM for 2- or 5-min Trial 1, while the group submitted to 1-min Trial 1 length displayed decreased %Open arm time only. The anxiolytic effect of MDZ prior to Trial 2 was present in the group submitted to 1-min, impaired in the group submitted to 2-min and absent in the group submitted to 5-min Trial 1 length. Data are analyzed taking into account the emotional learning which underlies the exploratory behavior during the EPM Trial 2.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/psicología , Midazolam/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Prior test experience compromises the anxiolytic efficacy of benzodiazepines (BZs) either in rats or mice, a phenomenon not exclusive to the elevated plus-maze (EPM) animal model of anxiety, which is referred to as "one-trial tolerance." However, it remains to be determined whether a similar event occurs when testing other drugs that also possess binding-sites on the GABA(A) receptor, such as ethanol and barbiturates. In the present study, we have addressed this issue using maze-naive and maze-experienced (free exploration of the EPM 48 h earlier for 5 min) rats pretreated with ethanol (1.0-1.4 g/kg) or phenobarbital (20-60 mg/kg) and submitted to the EPM. The results confirmed the anxiolytic profile of both drugs, represented by increased open arm exploration and decreased risk assessment behavior, in maze-naive rats. However, in maze-experienced rats, neither ethanol nor phenobarbital anxiolytic effects were observed, suggesting that prior maze experience compromised the drugs' anxiolytic activity. Thus, the "one-trial tolerance" phenomenon might also be extended to other drugs that bind to the GABA(A) receptor complex.
Asunto(s)
Ansiolíticos/farmacología , Etanol/farmacología , Conducta Exploratoria/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Fenobarbital/farmacología , Animales , Conducta Exploratoria/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Ratas WistarRESUMEN
The elevated T-maze (ETM) is a putative model for the assessment of anxiety and memory in rodents. This study was designed to further evaluate the utility of the ETM in the study of memory processes. We compared the performance of rats in the ETM, the water maze (WM) and the two-way avoidance task (TWA), after pretreatment with scopolamine (SCO; 0.3 or 1.2 mg/kg i.p.). In the ETM, rats were first trained to meet the criterion of remaining inside the enclosed arm for 300 seconds. Seventy-two hours after training, a retrieval test session was performed. At the lower dose, SCO impaired performance in the retrieval session on all three tasks, whereas in the training session an effect was noted only on the WM task. At the higher dose, SCO impaired the performance of rats in the training sessions for ETM and WM, but not TWA. In a fourth experiment using the elevated plus-maze, SCO showed anxiolytic-like effects at the higher dose only. In conclusion, the effects of SCO in rats submitted to the ETM were dose dependent, with the lower dose exerting a selective effect detected only on retrieval, whereas the higher dose induced motor effects that disrupted inhibitory avoidance acquisition, resulting in impaired retrieval. The results are discussed in terms of the utility of the ETM in the study of drug effects and the neurobiological mechanisms underlying anxiety, learning and memory.
Asunto(s)
Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Escopolamina/farmacología , Animales , Ansiolíticos/farmacología , Ansiedad/psicología , Reacción de Prevención/efectos de los fármacos , Masculino , Ratas , Ratas WistarRESUMEN
In rodents, prior maze experience increases open arm avoidance (OAA) and compromises the anxiolytic effects of benzodiazepines in a subsequent exposure to the elevated plus-maze (EPM), a phenomenon referred to as "one trial tolerance" (OTT). Nevertheless, a possible correlation between these intriguing events remains unclear. Using maze-naive and maze-experienced (free exploration of the EPM for 5 min) rats, Experiment 1 confirmed the anxiolytic effects of midazolam (MDZ; 0.125-1.0 mg/kg) in maze-naive rats, while both increased OAA and OTT to the MDZ anxiolytic effects were observed in maze-experienced rats. However, our results from Experiment 2, designed to assess whether open, enclosed or both arms experience is involved in increased OAA and OTT, showed that MDZ retained its efficacy in rats confined either to an open or enclosed arm, where no significant changes in open arm exploration were observed when compared to the maze-naive group, therefore suggesting that prior experience in the whole apparatus may be involved in the loss of the anxiolytic MDZ effects. Results are discussed in terms of a possible correlation between increased OAA and the OTT phenomenon elicited in a subsequent exposure to the EPM.
Asunto(s)
Conducta Exploratoria/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Midazolam/farmacología , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Midazolam/uso terapéutico , Ratas , Ratas WistarRESUMEN
This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification.
Asunto(s)
Ansiedad , Modelos Animales de Enfermedad , Pánico , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Benzodiazepinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Miedo/efectos de los fármacos , Humanos , Pánico/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/fisiopatología , Serotonina/farmacologíaRESUMEN
This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification
Asunto(s)
Humanos , Ansiedad , Modelos Animales de Enfermedad , Pánico , Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/fisiopatología , Benzodiazepinas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Redes de Comunicación de Computadores , Miedo/efectos de los fármacos , Pánico/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/fisiopatología , Serotonina/farmacologíaRESUMEN
Glutamate (GLU) associated with glycine, act as co-transmitter at the N-methyl-D-aspartate/glycine-B (NMDA/GLY(B)) receptor. Dorsal periaqueductal gray (dPAG) neurons express NMDA/GLY(B) receptors suggesting a GLU physiological role in mediating the responses elicited by stimulation of this area. Immunohistochemical data provided evidence of a possible correlation among elevated plus-maze (EPM), fear-like defensive behavior, and dPAG activity. The present data show that whereas the NMDA/GLY(B) receptor agonists increased the open-arm avoidance responses in the EPM, the antagonists had the opposite effects. Microinjection of NMDA/GLY(B) receptor agonists within the dPAG during test sessions in the EPM resulted in an enduring learned fear response detected in the retest. Therefore, in addition to the proposed role for the dPAG in panic attacks (escape), these findings suggest that the dPAG can also participate in more subtle anxiety-like behaviors.
Asunto(s)
Agresión/fisiología , Sustancia Gris Periacueductal/fisiología , Receptores de Glicina/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Ratas , Transmisión Sináptica/fisiologíaRESUMEN
Studies have shown an increased open arm avoidance in rats re-exposed to the elevated plus-maze (EPM), which suggests a qualitative shift in emotional states from an unconditioned (Trial 1) to a learned (Trial 2) form of fear response, but a precise source of aversion has not been determined. Using rats submitted to the EPM or various EPM-derived configurations, this study was designed to investigate what previous maze experiences in Trial 1 are required to increase avoidance of open arms in EPM Trial 2. Results obtained from rats submitted to the EPM or EPM-derived configurations confirmed the increased open arms avoidance in Trial 2. Rats confined to either open or enclosed arms failed to show the increased avoidance of open arms in Trial 2. The results are discussed in terms of the minimum prerequisite in Trial 1 to elicit an avoidance learning response to open arms in Trial 2, and also the implications of an acquired fear response in rats for the study of the biological basis of anxiety.
Asunto(s)
Ansiedad/psicología , Reacción de Prevención , Modelos Animales de Enfermedad , Miedo , Aprendizaje por Laberinto , Práctica Psicológica , Animales , Emociones , Masculino , Ratas , Ratas Wistar , Medición de RiesgoRESUMEN
The present study was outlined in order to provide additional behavioral validation to the elevated T-maze as a model of anxiety and memory. In this model, rats acquire an inhibitory avoidance response after successive exposures, and memory can be estimated by retesting later. Two experiments were carried out with rats initially tested at the ages of 30, 60, 90 and 120 days. Experiment 1 showed that, while 100% of subjects studied learned inhibitory avoidance, regardless of their ages, 60-day-old rats needed a higher number of trials in order to reach the criterion to stay 300 s inside the enclosed arm. Experiment 2 explored the relevancy of the aversive stimulus in maintaining the learned experience by retesting the subjects monthly. The results showed that after acquisition of inhibitory avoidance there is remarkable long-lasting memory retrieval. Risk assessment behavior, increasing in the first trial of the retest day, revealed also the approach-avoidance conflict while on the enclosed arm. The results are discussed in terms of age effects and the implications of an enduring learned emotional response in animal models of anxiety and memory.
Asunto(s)
Ansiedad/psicología , Reacción de Prevención/fisiología , Envejecimiento/psicología , Animales , Masculino , Memoria/fisiología , Ratas , Ratas Wistar , Asunción de RiesgosRESUMEN
The effects of glycine (GLY) or (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA966), a GLY receptor antagonist, microinjections into sites along the rostrocaudal axis of the dorsal periaqueductal gray matter (dPAG) were studied in rats placed on the elevated plus maze (EPM). Selective alterations in the open-arm entries (OAEs) or open-arm time (OAT) of the EPM were the indexes of anxiety. HA966 (30 or 100 nmol, 0.3 microl) increased OAEs and OAT in all 3 dPAG sites, suggesting an anxiolytic effect. GLY (80 and 120 nmol, 0.3 microl) selectively reduced OAEs and OAT, suggesting an anxiogenic effect only when injections were given within the caudal dPAG. When administered together, HA966 reversed the anxiogenic effect of 120 nmol GLY, indicating pharmacological selectivity for the effects of GLY on GLY receptors. Results reinforce an involvement of N-Methyl-D-aspartate-coupled GLY receptors in anxiety and suggest that saturation of this receptor may vary along the dPAG.
Asunto(s)
Ansiolíticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Pirrolidinonas/farmacología , Animales , Mapeo Encefálico , Relación Dosis-Respuesta a Droga , Masculino , Microinyecciones , Ratas , Ratas WistarRESUMEN
The glutamatergic system of the dorsal periaqueductal gray matter (DPAG) has been implicated in anxiety. This study shows that microinjections of glycine (GLY) or D-serine (D-SER), into the DPAG of rats, dose-dependently reduced the number of entries and the time spent on open arms of an elevated plus-maze (EPM), an established animal model for measuring anxiety-related behavior. This anxiogenic-like effect was greatest following DPAG application of either 80 nmol GLY or 160 and 320 nmol D-SER. Microinjections of these same amino acid doses outside the DPAG, or of L-serine (320 nmol) inside the DPAG, produced neither of these pro-anxiety effects. The current results suggest that, in vivo, the GLY modulatory site of N-methyl-D-aspartate receptors is not fully saturated, and further substantiate a role for the DPAG excitatory amino acid system in anxiety.
Asunto(s)
Ansiedad/inducido químicamente , Glicina/farmacología , Sustancia Gris Periacueductal/fisiología , Serina/farmacología , Animales , Ansiedad/psicología , Relación Dosis-Respuesta a Droga , Glicina/administración & dosificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microinyecciones , Sustancia Gris Periacueductal/anatomía & histología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/administración & dosificación , EstereoisomerismoRESUMEN
To investigate if blockade of the modulatory glycine site of NMDA receptors in the dorsal periaqueductal grey (DPAG) would produce anxiolytic effects, groups of 9-14 rats received microinjections into this structure of 7-chloro-kynurenic acid (7-Cl-KY, 4 and 8 nmol) or 3-amino-1-hydroxypyrrolid-2-one (HA-966, 30 or 100 nmol), two selective antagonists at the strychnine-insensitive glycine modulatory site, and were submitted to the elevated plus-maze, an ethologically based animal model of anxiety. Both drugs increased the percentage of entries and of time spent in open arms as compared to rats receiving isotonic saline. Injections of the active compounds outside the DPAG were not effective. In another experiment microinjections of 7-Cl-KY (8 nmol) and HA-966 (100 nmol) into the DPAG raised the threshold of aversive electrical stimulation of the rat DPAG. These results indicate that microinjections of 7-Cl-KY and HA-966 into the DPAG cause anxiolytic effects in two different models of anxiety and support the proposal that NMDA-mediated neurotransmission in the DPAG may be related to anxiety and panic.
Asunto(s)
Ansiolíticos/farmacología , Glicina/antagonistas & inhibidores , Sustancia Gris Periacueductal/fisiología , Animales , Ansiolíticos/administración & dosificación , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Estimulación Eléctrica , Ácido Quinurénico/administración & dosificación , Ácido Quinurénico/análogos & derivados , Ácido Quinurénico/farmacología , Masculino , Microinyecciones , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacología , Ratas , Ratas Wistar , Receptores de Glicina/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
We have compared the performance of male and female Wistar rats at different ages (45, 60, 90, 120 and 150 days) in the elevated plus-maze test, a reliable animal model of anxiety. Up to 60 days of age, rats of both sexes exhibited a high number of entries and of time spent on open arms (50% or above). At 120 days of age or more, rats of both sexes characteristically exhibited a reduction in the number of entries and of the time spent on open arms (below 50%). Within the range of 60 and 120 days there are statistically significant sex differences. At 90 days of age male rats showed a marked switch in their performance in the apparatus, reaching levels of the latter stage, whereas in females it happened around 120 days. These results suggest an ontogenetic difference in rats that accounts for at least two distinct performances for rats placed in an elevated plus-maze. Gender effects were found in a certain range, suggesting caution on interpreting data obtained in rats within 60 and 120 days old. Also, the results obtained highlight the importance of carefully controlling animal age in studies using the elevated plus-maze.