RESUMO
Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.
Assuntos
Complexo Nuclear Corticomedial/fisiologia , Agonistas de Receptores de GABA-A/fisiologia , Agonistas dos Receptores de GABA-B/fisiologia , Resposta de Imobilidade Tônica/fisiologia , Animais , Baclofeno/administração & dosagem , Baclofeno/análogos & derivados , Baclofeno/antagonistas & inibidores , Baclofeno/farmacologia , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Complexo Nuclear Corticomedial/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/administração & dosagem , Antagonistas de Receptores de GABA-A/farmacologia , Agonistas dos Receptores de GABA-B/administração & dosagem , Agonistas dos Receptores de GABA-B/farmacologia , Antagonistas de Receptores de GABA-B/administração & dosagem , Antagonistas de Receptores de GABA-B/farmacologia , Cobaias , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Muscimol/administração & dosagem , Muscimol/antagonistas & inibidores , Muscimol/farmacologiaRESUMO
Previous studies have indicated that central GABAergic mechanisms are involved in the heart rate (HR) responses at the onset of exercise. On the basis of previous research that showed similar increases in HR during passive and active cycling, we reasoned that the GABAergic mechanisms involved in the HR responses at the exercise onset are primarily mediated by muscle mechanoreceptor afferents. Therefore, in this study, we sought to determine whether central GABA mechanisms are involved in the muscle mechanoreflex-mediated HR responses at the onset of exercise in humans. Twenty-eight healthy subjects (14 men and 14 women) aged between 18 and 35 yr randomly performed three bouts of 5-s passive and active cycling under placebo and after oral administration of diazepam (10 mg), a benzodiazepine that produces an enhancement in GABAA activity. Beat-to-beat HR (electrocardiography) and arterial blood pressure (finger photopletysmography) were continuously measured. Electromyography of the vastus lateralis was obtained to confirm no electrical activity during passive trials. HR increased from rest under placebo and further increased after administration of diazepam in both passive (change: 12 ± 1 vs. 17 ± 1 beats/min, P < 0.01) and active (change: 14 ± 1 vs. 18 ± 1 beats/min, P < 0.01) cycling. Arterial blood pressure increased from rest similarly during all conditions ( P > 0.05). Importantly, no sex-related differences were found in any variables during experiments. These findings demonstrate, for the first time, that the GABAergic mechanisms significantly contribute to the muscle mechanoreflex-mediated HR responses at the onset of exercise in humans. NEW & NOTEWORTHY We found that passive and voluntary cycling evokes similar increases in heart rate and that these responses were enhanced after diazepam administration, a benzodiazepine that enhances GABAA activity. These findings suggest that the GABAergic system may contribute to the muscle mechanoreflex-mediated vagal withdrawal at the onset of exercise in humans.
Assuntos
Encéfalo/efeitos dos fármacos , Diazepam/administração & dosagem , Exercício Físico/fisiologia , Agonistas de Receptores de GABA-A/administração & dosagem , Neurônios GABAérgicos/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Coração/inervação , Fusos Musculares/metabolismo , Músculo Quadríceps/inervação , Reflexo/efeitos dos fármacos , Adolescente , Adulto , Pressão Arterial/efeitos dos fármacos , Ciclismo , Encéfalo/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Feminino , Neurônios GABAérgicos/metabolismo , Humanos , Masculino , Músculo Quadríceps/metabolismo , Distribuição Aleatória , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Fatores de Tempo , Adulto Jovem , Ácido gama-Aminobutírico/metabolismoRESUMO
Episodic memory was initially believed to be unique to humans. However, studies demonstrate that nonhuman species discriminate items based on the triad what, where and when. Here we addressed the role of the dorsal hippocampal subfield CA1 in an integrative what-where-when task in Wistar rats. We performed bilateral inactivation of dorsal CA1 with the GABAA agonist muscimol previously to the task. As expected, sham-operated animals recollected an integrative memory for objects (what), their places (where) and temporal order (when). However, the inactivation of CA1 impaired the performance of the three components of episodic-like memory. In addition, total time of objects exploration and distance traveled were not different between groups, indicating that rats had similar levels of motivation, thus, alterations in exploration does not account for impaired locomotor performance. Altogether, our data provides evidence that CA1 plays an important role in episodic-like memory.
Assuntos
Região CA1 Hipocampal/fisiologia , Memória Episódica , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Comportamento Exploratório , Agonistas de Receptores de GABA-A/administração & dosagem , Masculino , Muscimol/administração & dosagem , Ratos WistarRESUMO
Previous studies from our group have shown that cytotoxic lesions in the ventral portion of the anteromedial thalamic nucleus (AMv), one of the main targets of the hypothalamic predator-responsive circuit, strongly impairs contextual fear responses to an environment previously associated with a predator. The AMv is in a position to convey information to cortico-hippocampal-amygdalar circuits involved in the processing of fear memory. However, it remains to be determined whether the nucleus is involved in the acquisition or subsequent expression of contextual fear. In the present investigation, we addressed this question by inactivating the rat AMv with muscimol either prior to cat exposure or prior to exposure to the cat-related context. Accordingly, AMv pharmacological inactivation prior to cat exposure did not interfere with innate fear responses, but it drastically reduced contextual conditioning to the predator-associated environment. On the other hand, AMv inactivation prior to exposure to the environment associated with the predator threat did not affect contextual fear responses. The behavioral results were further supported by the demonstration that AMv inactivation prior to cat exposure also blocked the activation of sites critically involved in the expression of anti-predatory contextual defensive responses (i.e., the dorsal premammillary nucleus and the dorsolateral periaqueductal gray) in animals exposed to the predator-associated context. The AMv projections were also examined, and the results of this investigation outline important paths that can influence hippocampal circuitry and raise new ideas for anterior thalamic-hippocampal paths involved in emotional learning.
Assuntos
Núcleos Anteriores do Tálamo/fisiologia , Medo/fisiologia , Memória/fisiologia , Animais , Núcleos Anteriores do Tálamo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Gatos , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Hipotálamo Posterior/efeitos dos fármacos , Hipotálamo Posterior/fisiologia , Masculino , Memória/efeitos dos fármacos , Muscimol/administração & dosagem , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Comportamento Predatório , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos WistarRESUMO
Previously we showed that activation of the Nucleus of the Solitary Tract (NTS)-Nucleus Paragigantocellularis (PGi)-Locus coeruleus (LC) pathway, which theoretically culminates with norepinephrine (NE) release in dorsal hippocampus (CA1 region) and basolateral amygdala (BLA) is necessary for the consolidation of object recognition (OR) memory. Here we show that, while the microinjection of the beta-noradrenergic receptor blocker timolol into CA1 impairs OR memory consolidation, the microinjection of norepinephrine (NE) promotes the persistence of this type of memory. Further, we show that OR consolidation is attended by an increase of norepinephrine (NE) levels and of the expression of brain derived neurotrophic factor (BDNF) in hippocampus, which are impaired by inactivation of the NTS-PGi-LC pathway by the infusion of muscimol into the NTS.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , Norepinefrina/fisiologia , Reconhecimento Psicológico/fisiologia , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Agonistas de Receptores de GABA-A/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Muscimol/administração & dosagem , N-Metilaspartato/administração & dosagem , Norepinefrina/administração & dosagem , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia , Timolol/administração & dosagemRESUMO
The medial prefrontal cortex (mPFC) is known for its role in decision making and memory processing, including the participation in the formation of extinction memories. However, little is known regarding its contribution to aversive memory consolidation. Here we demonstrate that neural activity and protein synthesis are required in the dorsal mPFC for memory formation of a conditioned taste aversion (CTA) task and that this region is involved in the retrieval of recent and remote long-term CTA memory. In addition, both NMDA receptor and CaMKII activity in dorsal mPFC are needed for CTA memory consolidation, highlighting the complexity of mPFC functions.
Assuntos
Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Córtex Pré-Frontal/fisiologia , Percepção Gustatória/fisiologia , Animais , Benzilaminas/administração & dosagem , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Emetina/administração & dosagem , Agonistas de Receptores de GABA-A/administração & dosagem , Masculino , Consolidação da Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Muscimol/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Inibidores da Síntese de Proteínas/administração & dosagem , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Percepção Gustatória/efeitos dos fármacos , Valina/administração & dosagem , Valina/análogos & derivadosRESUMO
We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)âlocus coeruleusâhippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 µg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 µg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 µg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 µg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 µg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTSâlocus coeruleusâHIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning.
Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Epinefrina/fisiologia , Extinção Psicológica/fisiologia , Hipocampo/fisiologia , Locus Cerúleo/fisiologia , Norepinefrina/fisiologia , Transdução de Sinais/fisiologia , Núcleo Solitário/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Epinefrina/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Medo/fisiologia , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/efeitos dos fármacos , Locus Cerúleo/efeitos dos fármacos , Masculino , Muscimol/administração & dosagem , Muscimol/farmacologia , Norepinefrina/administração & dosagem , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacosRESUMO
This study investigated whether perinatal exposure to picrotoxin, a GABAA antagonist, modifies the effect of muscimol, a GABAA agonist, on the sexual behavior of adult male rats. Two hours after birth and then once daily during the next 9 days of lactation, dams received picrotoxin (0.75 mg/kg subcutaneously) or saline (1 ml/kg subcutaneously). The adult male offspring from the picrotoxin and saline groups received saline (1 ml/kg intraperitoneally) or muscimol (1 mg/kg intraperitoneally), and 15 min later, their sexual behavior was assessed. Muscimol treatment in the saline-exposed group increased the mount and intromission latencies. However, these effects were absent in the picrotoxin-exposed groups. The latencies to first ejaculation, postejaculatory mount, and intromission were decreased in both picrotoxin-exposed groups relative to the saline-exposed groups. The picrotoxin+muscimol-treated rats required more intromissions to ejaculate and the picrotoxin-exposed groups made more ejaculations than the saline-exposed groups. Thus, muscimol treatment did not increase the mount and intromission latencies following picrotoxin exposure, but increased the ejaculation frequency, which did not differ between the picrotoxin+muscimol and the picrotoxin+saline groups. These data indicate that perinatal picrotoxin treatment interfered with GABAA receptor development.
Assuntos
Antagonistas GABAérgicos/farmacologia , Muscimol/farmacologia , Picrotoxina/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Feminino , Antagonistas GABAérgicos/administração & dosagem , Agonistas de Receptores de GABA-A/administração & dosagem , Agonistas de Receptores de GABA-A/farmacologia , Injeções Subcutâneas , Lactação , Masculino , Muscimol/administração & dosagem , Picrotoxina/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismoRESUMO
Hippocampus is hypothesized to play a temporary role in the retrieval of context memories. Similarly, previous studies have reported that the expression of context memories becomes more generalized as memory ages. We report, first, that contextual fear memory expression changes from being sensitive to dorsal hippocampus inactivation by muscimol at 2 days post-conditioning, to insensitive at 28 days, and second, that over the same period rats lose their ability to discriminate between a novel and conditioned context. Furthermore, we show that repeated brief memory reactivation sessions prevent memory from becoming both hippocampus-independent and generalized.
Assuntos
Comportamento Animal/fisiologia , Região CA1 Hipocampal/fisiologia , Medo/fisiologia , Rememoração Mental/fisiologia , Fatores Etários , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Eletrochoque , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/administração & dosagem , Rememoração Mental/efeitos dos fármacos , Muscimol/administração & dosagem , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The blockade of the inhibitory mechanisms for sodium intake with GABAergic activation in the lateral parabrachial nucleus (LPBN) induces strong ingestion of water and hypertonic NaCl in satiated and normovolemic rats. A question that remains is if the activity of facilitatory mechanisms, like angiotensin II, is necessary for sodium and water intake induced by muscimol (GABA(A) receptor agonist) injected into the LPBN. Therefore, in the present study, we investigated the effects of the blockade of angiotensinergic AT(1) receptors with losartan injected i.c.v. on 0.3 M NaCl and water intake induced by muscimol injected into the LPBN in satiated and normovolemic rats. Male Holtzman rats with stainless steel cannulas implanted bilaterally into the LPBN and unilaterally into the lateral ventricle were used. Bilateral injections of muscimol (0.5 nmol/0.2 µl) into the LPBN combined with i.c.v. injection of vehicle induced 0.3 M NaCl (31.7 ± 1.8 ml/240 min, vs. saline: 0.4 ± 0.3 ml/240 min) and water intake (21.5 ± 1.9 ml/240 min, vs. saline: 0.8 ± 0.2 ml/240 min). Losartan (50 and 100 µg/1.0 µl) injected i.c.v. reduced the effects of LPBN-muscimol on 0.3 M NaCl (18.9 ± 1.9 and 9.9 ± 1.7 ml/240 min, respectively) and water intake (9.8 ± 1.7 and 5.1 ± 1.1 ml/240 min, respectively). The results suggest that the activation of central AT(1) angiotensinergic receptors is essential for hypertonic NaCl and water intake induced by the blockade of the inhibitory mechanisms with muscimol injected into the LPBN in satiated and normovolemic rats.