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RATIONALE: Chronic stress exposure disrupts the medial prefrontal cortex's (mPFC) ability to regulate impulses, leading to the loss of control over alcohol drinking in rodents, emphasizing the critical role of this forebrain area in regulating alcohol consumption. Moreover, chronic stress exposure causes lateralization of mPFC functions with volumetric and functional changes, resulting in hyperactivity in the right hemisphere and functional decrease in the left. OBJECTIVES: This study investigated the inhibitory role of the left prelimbic cortex (LPrL) on ethanol consumption induced by chronic social defeat stress (SDS) in male mice and to examine if inactivation of the LPrL causes disinhibition of the right mPFC, leading to an increase in ethanol consumption. We also investigated the role of lateralization and neurochemical alterations in the mPFC related to ethanol consumption induced by chronic SDS. To this end, we examined the activation patterns of ΔFosB, VGLUT2, and GAD67 in the left and right mPFC. RESULTS: Temporarily blocking the LPrL or right PrL (RPrL) cortices during acute SDS did not affect male mice's voluntary ethanol consumption in male mice. When each cortex was blocked in mice previously exposed to chronic SDS, ethanol consumption also remained unaffected. However, male mice with LPrL lesions during chronic SDS showed an increase in voluntary ethanol consumption, which was associated with enhanced ΔFosB/VGLUT2-positive neurons within the RPrL cortex. CONCLUSIONS: The results suggest that the LPrL may play a role in inhibiting ethanol consumption induced by chronic SDS, while the RPrL may be involved in the disinhibition of ethanol consumption.
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Consumo de Bebidas Alcoólicas , Córtex Pré-Frontal , Derrota Social , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Camundongos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Etanol/administração & dosagem , Etanol/farmacologia , Lateralidade Funcional/efeitos dos fármacos , Doença CrônicaRESUMO
Morphine withdrawal can trigger disruptions in neuronal pathways involved in the modulation and expression of anxiety and fear-related behaviors, particularly those involved in associative learning. When it comes to contextual fear, specific subdivisions of the medial prefrontal cortex (mPFC) regulate the expression of defensive behaviors through projections to specific amygdala (AM) nuclei, such as the prelimbic cortex (PrL). The basolateral nucleus (BLA) of the AM has been shown to be involved in the modulation and expression of associative memories of fear, including those associated with opiate withdrawal-related aversive events. The purpose of this study is to determine the role of GABA mechanisms in the PrL and BLA in startle potentiation and freezing behavior caused by morphine-precipitated withdrawal. Our findings show that morphine withdrawal promotes the emergence of contextual conditioned fear in animals when they are exposed to the same environment where the withdrawal sessions were performed. This suggests that the neural circuits underlying the organism's response to conditioned stressors and the circuits modulating the negative affective states induced by drug withdrawal may overlap. The pharmacological manipulation of GABAergic neurotransmission in the PrL and BLA can reverse contextual fear in morphine-withdrawn rats, an effect that appears to be mediated, at least in part, by GABAA receptors.
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Complexo Nuclear Basolateral da Amígdala , Tonsila do Cerebelo , Animais , Medo/fisiologia , Morfina/efeitos adversos , Córtex Pré-Frontal/fisiologia , Ratos , Receptores de GABA-A , Ácido gama-AminobutíricoRESUMO
The ability to retrieve contextual fear memories depends on the coordinated activation of a brain-wide circuitry. Transition from recent to remote memories seems to involve the reorganization of this circuitry, a process called systems consolidation that has been associated with time-dependent fear generalization. However, it is unknown whether emotional memories acquired under different stress levels can undergo different systems consolidation processes. Here, we explored the activation pattern and functional connectivity of key brain regions associated with contextual fear conditioning (CFC) retrieval after recent (2 days) or remote (28 days) memory tests performed in rats submitted to strong (1.0 mA footshock) or mild (0.3 mA footshock) training. We used brain tissue from Wistar rats from a previous study, where we observed that increasing training intensity promotes fear memory generalization over time, possibly due to an increase in corticosterone (CORT) levels during memory consolidation. Analysis of Fos expression across 8 regions of interest (ROIs) allowed us to identify coactivation between them at both timepoints following memory recall. Our results showed that strong CFC elicits higher Fos activation in the anterior insular and prelimbic cortices during remote retrieval, which was positively correlated with freezing along with the basolateral amygdala. Rats trained either with mild or strong CFC showed broad functional connectivity at the recent timepoint whereas only animals submitted to the strong CFC showed a widespread loss of coactivation during remote retrieval. Post-training plasma CORT levels are positively correlated with FOS expression during recent retrieval in strong CFC, but negatively correlated with FOS expression during remote retrieval in mild CFC. Our findings suggest that increasing training intensity results in differential processes of systems consolidation, possibly associated with increased post-training CORT release, and that strong CFC engages activity from the aIC, BLA and PrL - areas associated with the Salience Network in rats - during remote retrieval.
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In C57BL/6 J mice, systemic inflammation was induced by administering bacterial LPS (1 mg/kg) intraperitoneally. In response, animals exhibited hypokinesia, piloerection, and a slight decrease in body temperature accompanied by increased serum levels of the proinflammatory cytokine TNF-α. 24 h after the immunogenic challenge, acute cortical slices were prepared, and whole-cell patch-clamp recordings were performed in morphologically identified prelimbic neurons of the mice's prefrontal cortex. Electrophysiologic alterations included changes in the kinetics parameters of the fast-inactivating sodium and slow-inactivating potassium currents. In current-clamp mode, our recordings revealed alterations in several conductances that shape the intrinsic excitability of prelimbic neurons. The action potential exhibited changes in latency, amplitude, and the rheobase current to elicit firing discharge. Likewise, phase plots of the action potentials uncovered alterations in the repetitive firing of prelimbic neurons. Consistent with these changes, the afterhyperpolarization conductance and the slowly decaying, calcium-dependent after-hyperpolarization current that follows an action potential were decreased in response to systemic LPS. Our data demonstrate that immune activation alters the ionic currents that shape the intrinsic excitability and predicts dysregulation of non-synaptic forms of neuronal plasticity modulated by the intrinsic excitability of prefrontal cortex neurons.
Assuntos
Potássio , Sódio , Potenciais de Ação/fisiologia , Animais , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Potássio/fisiologiaRESUMO
Memory extinction has been used in behavioral therapy to treat post-traumatic stress disorders. It was demonstrated that memory reactivation before extinction could facilitate this process. However, the mechanisms involved are still unclear. Here, we investigated the participation of two regions of the ventromedial prefrontal cortex (vmPFC), the infralimbic (IL) and prelimbic (PL), in the memory reactivation modulatory effect of fear extinction. We confirmed that the reactivation facilitates the fear extinction in an inhibitory aversive task; however, when the muscimol (a GABAergic agonist) is infused in IL or PL vmPFC after reactivation, extinction's facilitation was not observed. These findings support the idea that the reactivation can modulate the fear extinction process, facilitating it, and that this effect requires the activation of both IL and PL regions of vmPFC.
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Aprendizagem da Esquiva/fisiologia , Extinção Psicológica/fisiologia , Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Muscimol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Although stimuli that are associated often overlap in time, previous events can also predict the occurrence of a later aversive stimulus and be associated with it to better guide future behavior. Associations of stimuli separated in time have been studied using discrete stimulus as the conditioned stimulus (CS) in trace conditioning or, more recently in our lab, using the context as the CS in contextual fear conditioning with temporal discontinuity (CFC-5s), a task that simultaneously includes the processing of time and space components. It is thought that fear memories are encoded by the strengthening of synaptic connections in a distributed neural network. However, it is unclear how this temporal factor, which may differentially require the maintenance of the stimulus over time, affects the interactivity between brain regions to form the association. Because the prelimbic cortex (PL) and the hippocampus have been individually engaged in trace conditioning, they may functionally interact to encode associations separated in time. This is anatomically supported by direct ipsilateral projections from the ventral hippocampal CA1 region (vCA1) to PL. The aim of the present study was to investigate the effect of the functional disconnection of vCA1 and PL on CFC-5s using pre-training asymmetric reversible inactivation with muscimol. For comparison, we also observed its effect on contextual fear conditioning (CFC). Results showed that the functional disconnection impaired the encoding of the CFC-5s, an association of stimuli separated in time, while did not affect the CFC, an association of stimuli overlapped in time. In addition, the preserved connection in one hemisphere was sufficient to support the encoding of CFC-5s. The time interval by itself did not increase freezing responses and both CFC and CFC tasks had similar generalization and higher freezing responses than unconditioned groups. These findings suggest that the time factor alters the requirement of the interactivity of the brain regions underlying fear conditioning and extend the relevance of hippocampal-prefrontal interactions in memory.
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Aprendizagem por Associação/fisiologia , Região CA1 Hipocampal/fisiologia , Córtex Cerebral/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Muscimol/farmacologia , Ratos , Ratos WistarRESUMO
The mechanisms underlying chronic and neuropathic pain pathology involve peripheral and central sensitisation. The medial prefrontal cortex (mPFC) seems to participate in pain chronification, and glutamatergic neurotransmission may be involved in this process. Thus, the aim of the present work was to investigate the participation of the prelimbic (PrL) area of the mPFC in neuropathic pain as well as the role of N-methyl D-aspartate (NMDA) glutamate receptors in neuropathic pain induced by a modified sciatic nerve chronic constriction injury (CCI) protocol in Wistar rats. Neural inputs to the PrL cortex were inactivated by intracortical treatment with the synapse blocker cobalt chloride (CoCl2, 1.0 mM/200 nL) 7, 14, 21, or 28 days after the CCI or sham procedure. The glutamatergic agonist NMDA (0.25, 1 or 4 nmol) or the selective NMDA receptor antagonist LY235959 (2, 4 or 8 nmol) was microinjected into the PrL cortex 21 days after surgery. CoCl2 administration in the PrL cortex decreased allodynia 21 and 28 days after CCI. NMDA at 1 and 4 nmol increased allodynia, whereas LY235959 decreased mechanical allodynia at the highest dose (8 nmol) microinjected into the PrL cortex. These findings suggest that NMDA receptors in the PrL cortex participate in enhancing the late phase of mechanical allodynia after NMDA-induced increases and LY235959-induced decreases in allodynia 21 days after CCI. The glutamatergic system potentiates chronic neuropathic pain by NMDA receptor activation in the PrL cortex. Mechanism of neuropathic pain. The infusion of CoCl2, a synapse activity blocker, into the prelimbic (PrL) division of the medial prefrontal cortex (mPFC) decreased the severity of mechanical allodynia, showing the late participation of the limbic cortex. The glutamatergic system potentiates chronic neuropathic pain via NMDA receptor activation in the PrL cortex.
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Neuralgia/metabolismo , Nervos Periféricos/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cobalto/farmacologia , Hiperalgesia/tratamento farmacológico , Isoquinolinas/farmacologia , Masculino , N-Metilaspartato/farmacologia , Neuralgia/tratamento farmacológico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacosRESUMO
BACKGROUND:: Serotonin plays an important role in the regulation of anxiety, acting through complex modulatory mechanisms within distinct brain structures. Serotonin can act through complex negative feedback mechanisms controlling the neuronal activity of serotonergic circuits and downstream physiologic and behavioral responses. Administration of serotonin or the serotonin 1A receptor agonist, (±)-8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), into the prefrontal cortex, inhibits anxiety-like responses. The prelimbic area of the prefrontal cortex regulates serotonergic neurons within the dorsal raphe nucleus and is involved in modulating anxiety-like behavioral responses. AIMS:: This study aimed to investigate the serotonergic role within the prelimbic area on anxiety- and panic-related defensive behavioral responses. METHODS:: We investigated the effects of serotonin within the prelimbic area on inhibitory avoidance and escape behaviors in the elevated T-maze. We also extended the investigation to serotonin 1A, 2A, and 2C receptors. RESULTS:: Intra-prelimbic area injection of serotonin or 8-OH-DPAT induced anxiolytic effects without affecting escape behaviors. Previous administration of the serotonin 1A receptor antagonist, WAY-100635, into the prelimbic area counteracted the anxiolytic effects of serotonin. Neither the serotonin 2A nor the serotonin 2C receptor preferential agonists, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and 6-chloro-2-(1-piperazinyl) pyrazine (MK-212), respectively, affected behavioral responses in the elevated T-maze. CONCLUSION:: Facilitation of serotonergic signaling within the prelimbic area of rats induced an anxiolytic effect in the elevated T-maze test, which was mediated by local serotonin 1A receptors. This inhibition of anxiety-like defensive behavioral responses may be mediated by prelimbic area projections to neural systems controlling anxiety, such as the dorsal raphe nucleus or basolateral amygdala.
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The prelimbic cortex (PL) is an important structure in the neural pathway integrating stress responses. Brain angiotensin is involved in cardiovascular control and modulation of stress responses. Blockade of angiotensin receptors has been reported to reduce stress responses. Acute restraint stress (ARS) is a stress model, which evokes sustained blood pressure increase, tachycardia, and reduction in tail temperature. We therefore hypothesized that PL locally generated angiotensin and angiotensin receptors modulate stress autonomic responses. To test this hypothesis, we microinjected an angiotensin-converting enzyme (ACE) inhibitor or angiotensin antagonists into the PL, prior to ARS. Male Wistar rats were used; guide cannulas were bilaterally implanted in the PL for microinjection of vehicle or drugs. A polyethylene catheter was introduced into the femoral artery to record cardiovascular parameters. Tail temperature was measured using a thermal camera. ARS was started 10 min after PL treatment with drugs. Pretreatment with ACE inhibitor lisinopril (0.5 nmol/100 nL) reduced the pressor response, but did not affect ARS-evoked tachycardia. At a dose of 1 nmol/100 nL, it reduced both ARS pressor and tachycardic responses. Pretreatment with candesartan, AT1 receptor antagonist reduced ARS-evoked pressor response, but not tachycardia. Pretreatment with PD123177, AT2 receptor antagonist, reduced tachycardia, but did not affect ARS pressor response. No treatment affected ARS fall in tail temperature. Results suggest involvement of PL angiotensin in the mediation of ARS cardiovascular responses, with participation of both AT1 and AT2 receptors. In conclusion, results indicate that PL AT1-receptors modulate the ARS-evoked pressor response, while AT2-receptors modulate the tachycardic component of the autonomic response.
Assuntos
Pressão Sanguínea/fisiologia , Córtex Cerebral/metabolismo , Frequência Cardíaca/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Estresse Psicológico/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Lobo Límbico/efeitos dos fármacos , Lobo Límbico/metabolismo , Masculino , Ratos , Ratos Wistar , Restrição Física/fisiologia , Restrição Física/psicologia , Estresse Psicológico/psicologiaRESUMO
It has been found that the medial prefrontal cortex (mPFC) is involved in memory encoding of aversive events, such as inhibitory avoidance (IA) training. Dissociable roles have been described for different mPFC subregions regarding various memory processes, wherein the anterior cingulate cortex (ACC), prelimbic cortex (PL), and infralimbic cortex (IL) are involved in acquisition, retrieval, and extinction of aversive events, respectively. On the other hand, it has been demonstrated that intense training impedes the effects on memory of treatments that typically interfere with memory consolidation. The aim of this work was to determine if there are differential effects on memory induced by reversible inactivation of neural activity of ACC, PL, or IL produced by tetrodotoxin (TTX) in rats trained in IA using moderate (1.0 mA) and intense (3.0 mA) foot-shocks. We found that inactivation of ACC has no effects on memory consolidation, regardless of intensity of training. PL inactivation impairs memory consolidation in the 1.0 mA group, while no effect on consolidation was produced in the 3.0 mA group. In the case of IL, a remarkable amnestic effect in LTM was observed in both training conditions. However, state-dependency can explain the amnestic effect of TTX found in the 3.0 mA IL group. In order to circumvent this effect, TTX was injected into IL immediately after training (thus avoiding state-dependency). The behavioral results are equivalent to those found after PL inactivation. Therefore, these findings provide evidence that PL and IL, but not ACC, mediate LTM of IA only in moderate training.
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Hormones highly influence female behaviors. However, research on this topic has not usually considered the variable hormonal status. The prelimbic cortex (PrL) is commonly engaged in fear learning. Connections from and to this region are known to be critical in regulating anxiety, in which serotonin (5-HT) plays a fundamental role, particularly through changes in 5-HT1A receptors functioning. Also, hormone fluctuations can greatly influence anxiety in humans and anxiety-related behavior in rodents, and this influence involves the functioning of 5-HT brain systems. The present investigation sought to determine whether fluctuations in ovarian hormones relative to the estrous cycle would influence the expression of learned fear in female rats previously selected as low- (LA) or high-anxious (HA). Furthermore, we investigate the role of the 5-HT system of the PrL, particularly the 5-HT1A receptors, as a possible modulator of estrous cycle influence on the expression of learned fear through intra-PrL microinjections of 5-HT itself or the full 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamine)tetralin). Behavioral changes were assessed using the fear-potentiated startle (FPS) procedure. The results showed that fear intensity is associated with hormonal decay, being more accentuated during the estrus phase. This increase in fear levels was found to be negatively correlated with the expression of potentiated startle. In rats prone to anxiety and tested during the proestrus and estrus phases, 5-HT mechanisms of the PrL seem to play a regulatory role in the expression of learned fear. These results were not replicated in the LA rats. Similar but less intense results were found regarding the early and late diestrus. Our data indicate that future studies on this subject need to take into account the dissociation between low- and high-responsive females to understand how hormones affect emotional behavior.
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8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Ansiedade/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Medo/fisiologia , Aprendizagem/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Animais , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Córtex Cerebral/metabolismo , Medo/efeitos dos fármacos , Feminino , Ratos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologiaRESUMO
Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have structural homology with classic opioids, but constitute a distinct neurotransmitter system because they lack affinity for the opioid peptides and receptors. This neurotransmission is implicated in several physiologic processes, but the role played by NOP receptors during stress situations remains unclear. The acute restraint stress (RS) is a model of unavoidable stress, characterized by sustained increases in mean arterial pressure (MAP), heart rate (HR) and a drop in tail temperature. On another side, the prelimbic (PL) and infralimbic (IL) cortices, subdivisions of the medial prefrontal cortex (MPFC), are implicated in the modulation of functional responses caused by RS. Considering that, the objective of the present study was to investigate the involvement of PL and IL NOP receptors in the control of autonomic responses induced by RS. Bilateral microinjection of nociceptin (NOP agonist) into the PL reduced the cardiovascular responses evoked by RS. Bilateral microinjection of UPF-101 (NOP antagonist) into the PL potentiated the pressor and tachycardiac responses evoked by RS, in a dose-dependent manner. Local pretreatment with UPF-101 blocked the RS-evoked changes following nociceptin administration into the PL. None of these treatments affected the drop in tail temperature induced by RS. Otherwise, the administration of nociceptin or UPF-101 into the IL had no effect on RS-evoked autonomic changes. To investigate the peripheral mechanism involved in the increase in the RS-evoked cardiovascular responses induced by the blockade of PL NOP receptors, rats were intravenous pretreated with either homatropine or atenolol. The intravenous treatment with homatropine blunted the increase in the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101, while the intravenous treatment with atenolol did not affect the RS-evoked pressor and tachycardiac response induced by the PL treatment with UPF-101. In conclusion, our study shows an influence of the PL N/OFQ neurotransmission, but not the IL NOP receptors, in the control of cardiovascular responses observed during acute stress, by increasing cardiac parasympathetic activity.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Peptídeos Opioides/administração & dosagem , Peptídeos Opioides/fisiologia , Córtex Pré-Frontal/fisiopatologia , Receptores Opioides/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores Opioides/agonistas , Restrição Física , Receptor de Nociceptina , NociceptinaRESUMO
The aim of the present study was to investigate the role of glucocorticoids in medial prefrontal cortex (mPFC) activity and the expression of contextual conditioned fear (freezing). Rats were pretreated with vehicle or metyrapone, a corticosterone synthesis blocker, and exposed to a context previously paired with footshocks. Freezing and Fos-protein expression in different mPFC regions were assessed. Exposure to the aversive context led to increased freezing and Fos expression in the prelimbic (PrL), anterior cingulate areas 1 and 2 (Cg1/Cg2). Pretreatment with metyrapone decreased freezing and Fos expression in these areas. Administration of spironolactone, an MR antagonist, in the PrL before the test decreased freezing. Pretreatment with RU38486, a glucocorticoid receptor (GR) antagonist, reduced this effect of spironolactone, suggesting that the effects of this MR antagonist may be attributable to a redirection of endogenous corticosterone actions to GRs. Consistent with this result, the decrease in freezing that was induced by intra-PrL injections of corticosterone was attenuated by pretreatment with RU38486 but not spironolactone. These findings indicate that corticosterone release during aversive conditioning influences mPFC activity and the retrieval of conditioned fear memory indicating the importance of balance between MR:GR-mediated effects in this brain region in this process.
Assuntos
Condicionamento Psicológico/fisiologia , Medo/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Condicionamento Psicológico/efeitos dos fármacos , Corticosterona/administração & dosagem , Corticosterona/metabolismo , Inibidores Enzimáticos/farmacologia , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Antagonistas de Hormônios/farmacologia , Masculino , Metirapona/farmacologia , Mifepristona/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologiaRESUMO
The prelimbic cortex (PL), a limbic structure, sends projections to areas involved in the control of cardiovascular responses. Stimulation of the PL with acetylcholine (ACh) evokes depressor and tachycardiac responses mediated by local PL muscarinic receptors. Early studies demonstrated that stimulation of muscarinic receptors induced nitric oxide (NO) synthesis and cyclic guanosine cyclic monophosphate (cGMP) formation. Hence, this study investigates which PL muscarinic receptor subtype is involved in the cardiovascular response induced by ACh and tests the hypothesis that cardiovascular responses caused by muscarinic receptor stimulation in the PL are mediated by local NO and cGMP formation. PL pretreatment with J104129 (an M3 receptor antagonist) blocked the depressor and tachycardiac response evoked by injection of ACh into the PL. Pretreatment with either pirenzepine (an M1 receptor antagonist) or AF-DX 116 (an M2 and M4 receptor antagonist) did not affect cardiovascular responses evoked by ACh. Moreover, similarly to the antagonism of PL M3 receptors, pretreatment with N(ω)-propyl-L-arginine (an inhibitor of neuronal NO synthase), carboxy-PTIO(S)-3-carboxy-4-hydroxyphenylglicine (an NO scavenger), or 1H-[1,2,4]oxadiazolol-[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) blocked both the depressor and the tachycardiac response evoked by ACh. The current results demonstrate that cardiovascular responses evoked by microinjection of ACh into the PL are mediated by local activation of the M3 receptor-NO-guanylate cyclase pathway.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Córtex Cerebral/metabolismo , Guanilato Ciclase/metabolismo , Óxido Nítrico/metabolismo , Receptor Muscarínico M3/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Colinérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
Several lines of evidence indicate that the dorsal hippocampus (dH) and medial prefrontal cortex (mPFC) regulate contextual fear conditioning. The prelimbic (PrL), infralimbic (IL) and the anterior cingulate cortex (ACC) subregions of the mPFC likely play distinct roles in the expression of fear. Moreover, studies have highlighted the role of serotonin (5-hydroxytryptamine, 5-HT)- and γ-aminobutyric acid (GABA)-mediated mechanisms in the modulation of innate fear in the mPFC. The present study characterized dH-mPFC pathways and investigated the role of serotonergic and GABAergic mechanisms of the PrL, IL and ACC-area 1 (Cg1) in the elaboration of contextual fear conditioning using fear-potentiated startle (FPS) and freezing behavior in Rattus norvegicus. The results of neurotracing with microinjections of biotinylated dextran amine into the dH revealed a neural link of the dH with the PrL and ACC. Intra-PrL injections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and the GABAA receptor-selective agonist muscimol reduced contextual FPS and freezing responses. Intra-Cg1 injections of muscimol but not 8-OH-DPAT decreased FPS and freezing responses. However, neither intra-IL injections of a 5-HT1A agonist nor of a GABAA agonist affected these defensive responses. Labeled neuronal fibers from the dH reached the superficial layers of the PrL cortex and spread to the inner layers of PrL and Cg1 cortices, supporting the pharmacological findings. The present results confirmed the involvement of PrL and Cg1 in the expression of FPS and freezing responses to aversive conditions. In addition, PrL serotoninergic mechanisms play a key role in contextual fear conditioning. This study suggests that PrL, IL and Cg1 distinctively contribute to the modulation of contextual fear conditioning.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Biotina/análogos & derivados , Condicionamento Psicológico/fisiologia , Dextranos , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Lobo Límbico/anatomia & histologia , Lobo Límbico/efeitos dos fármacos , Lobo Límbico/fisiologia , Masculino , Muscimol/farmacologia , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Marcadores do Trato Nervoso , Córtex Pré-Frontal/anatomia & histologia , Córtex Pré-Frontal/fisiologia , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de GABA-A/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
The prelimbic cortex (PL) is involved in the control of behavioral and autonomic responses to stress. The present study aimed to investigate whether opioid neurotransmission in the PL modulates autonomic responses evoked by restraint stress (RS). Bilateral microinjection of 0.03, 0.3 and 3 nmol/100 nL of the nonselective opioid antagonist naloxone into the PL reduced pressure and tachycardiac responses evoked by RS. However, no effects were observed after its injection at doses of 0.003 and 30 nmol/100 nL, thus resulting in an inverted U-shaped dose-inhibition curve. Similar to naloxone, the selective µ-opioid antagonist CTAP, and the selective κ-opioid antagonist nor-BNI, also reduced MAP and HR increases induced by RS when injected into the PL, whereas treatment with the selective δ-opioid antagonist naltrindole did not affect the pressor and tachycardiac response caused by RS. Blockade of opioid neurotransmission in the PL did not affect the fall in tail temperature and increase in body temperature induced by RS. The present results confirm the involvement of PL opioid neurotransmission in the modulation of cardiovascular responses evoked during the exposure to an aversive situation, and suggest that responses observed after the blockade of local opioid receptors is due to alterations in PL neuronal activity. Furthermore, these results suggest that a distinct circuitry is involved in modulation of the sympathetic output to different vascular territories.
Assuntos
Pressão Arterial/fisiologia , Córtex Cerebral/fisiopatologia , Frequência Cardíaca/fisiologia , Receptores Opioides/metabolismo , Estresse Psicológico/fisiopatologia , Taquicardia/fisiopatologia , Animais , Pressão Arterial/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/fisiologia , Córtex Cerebral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Masculino , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos Wistar , Restrição Física , Estresse Psicológico/tratamento farmacológico , Taquicardia/tratamento farmacológicoRESUMO
Interactions between the prelimbic cortex and the basolateral amygdala underlie fear memory processing, mostly through acquiring and consolidating the learning of a conditioned fear. More recently, studies highlighted the role of the dorsal periaqueductal gray (DPAG) in the modulation of learning fear responses. In addition, extensive data in the literature have signaled the importance of serotonin (5-HT) on fear and anxiety. In the present study, the role of 5-HT neurotransmission of the prelimbic cortex, basolateral amygdala or the DPAG on the unconditioned and conditioned fear responses in rats previously selected as low- (LA) or high-anxious (HA) were assessed through local infusions of 5-HT itself (10nmol/0.2µl) or the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT - 0.3µg/0.2µl). Behavioral analysis was conducted using the fear-potentiated startle (FPS) procedure. Dependent variables recorded were the latency and amplitude of the unconditioned startle response and FPS. Our findings suggest that, on the prelimbic cortex, 5-HT modulates the expression of conditioned fear response in HA rats and this modulation is dependent on 5-HT1A receptors. This is not true, however, for the basolateral amygdala or the DPAG. In these regions LA but not HA rats were susceptible to the anxiolytic-like effect of 5-HT1A receptor activation. It is thought that the expression of conditioned fear in HA subjects may be dependent on other 5-HT receptors, as the 5-HT1B subtype, and/or changes in other systems such as the GABA and glutamate neurotransmitters. These results increase our understanding of the rostrocaudal influence of 5-HT on the unconditioned and conditioned fear responses in LA and HA subjects and, to some extent, are in disagreement with the theoretical current that emphasizes the role of 5-HT on anxiety, mainly at the subcortical and midbrain levels.
Assuntos
Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Ansiedade/tratamento farmacológico , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Encéfalo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Individualidade , Masculino , Testes Neuropsicológicos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiopatologia , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology.