RESUMO
A functional lateralization has been reported in control of emotional responses by the medial prefrontal cortex (mPFC). However, a hemisphere asymmetry in involvement of the mPFC in expression of fear conditioning responses has never been reported. Therefore, we investigated whether control by mPFC of freezing and cardiovascular responses during re-exposure to an aversively conditioned context is lateralized. For this, rats had guide cannulas directed to the mPFC implanted bilaterally or unilaterally in the right or left hemispheres. Vehicle or the non-selective synaptic inhibitor CoCl2 was microinjected into the mPFC 10 min before re-exposure to a chamber where the animals had previously received footshocks. A catheter was implanted into the femoral artery before the fear retrieval test for cardiovascular recordings. We observed that bilateral microinjection of CoCl2 into the mPFC reduced both the freezing behavior (enhancing locomotion and rearing) and arterial pressure and heart rate increases during re-exposure to the aversively conditioned context. Unilateral microinjection of CoCl2 into the right hemisphere of the mPFC also decreased the freezing behavior (enhancing locomotion and rearing), but without affecting the cardiovascular changes. Conversely, unilateral synaptic inhibition in the left mPFC did not affect either behavioral or cardiovascular responses during fear retrieval test. Taken together, these results suggest that the right hemisphere of the mPFC is necessary and sufficient for expression of freezing behavior to contextual fear conditioning. However, the control of cardiovascular responses and freezing behavior during fear retrieval test is somehow dissociated in the mPFC, being the former bilaterally processed.
Assuntos
Cobalto , Medo , Lateralidade Funcional , Córtex Pré-Frontal , Animais , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Masculino , Cobalto/farmacologia , Medo/fisiologia , Medo/efeitos dos fármacos , Ratos , Lateralidade Funcional/fisiologia , Lateralidade Funcional/efeitos dos fármacos , Emoções/fisiologia , Emoções/efeitos dos fármacos , Ratos Wistar , Frequência Cardíaca/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Microinjeções , Condicionamento Clássico/fisiologia , Condicionamento Clássico/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-ß oligomers (AßO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AßO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AßO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AßO (90 µM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AßO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AßO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AßO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AßO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AßO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Lignanas , Fármacos Neuroprotetores , Camundongos , Masculino , Animais , Peptídeos beta-Amiloides/metabolismo , Memantina/farmacologia , Antioxidantes/farmacologia , Doença de Alzheimer/patologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Lignanas/farmacologia , Furanos/farmacologia , Anti-Inflamatórios/farmacologia , Fármacos Neuroprotetores/farmacologia , Hipocampo/metabolismoRESUMO
The cardiac baroreflex is an autonomic neural mechanism involved in the modulation of the cardiovascular system. It influences the heart rate and peripheral vascular resistance to preserve arterial blood pressure within a narrow variation range. This mechanism is mainly controlled by medullary nuclei located in the brain stem. However, supramedullary areas, such as the ventral portion of medial prefrontal cortex (vMPFC), are also involved. Particularly, the glutamatergic NMDA/NO pathway in the vMPFC can facilitate baroreflex bradycardic and tachycardic responses. In addition, cannabinoid receptors in this same area can reduce or increase those cardiac responses, possibly through alteration in glutamate release. This vMPFC network has been associated to cardiovascular responses during stressful situations. Recent results showed an involvement of glutamatergic, nitrergic, and endocannabinoid systems in the blood pressure and heart rate increases in animals after aversive conditioning. Consequently, baroreflex could be modified by the vMPFC neurotransmission during stressful situations, allowing necessary cardiovascular adjustments. Remarkably, some mental, neurological and neurodegenerative disorders can involve damage in the vMPFC, such as posttraumatic stress disorder, major depressive disorder, Alzheimer's disease, and neuropathic pain. These pathologies are also associated with alterations in glutamate/NO release and endocannabinoid functions along with baroreflex impairment. Thus, the vMPFC seems to play a crucial role on the baroreflex control, either during pathological or physiological stress-related responses. The study of baroreflex mechanism under such pathological view may be helpful to establish causality mechanisms for the autonomic and cardiovascular imbalance found in those conditions. It can explain in the future the reasons of the high cardiovascular risk some neurological and neurodegenerative disease patients undergo. Additionally, the present work offers insights on the possible contributions of vMPFC dysfunction on baroreflex alterations, which, in turn, may raise questions in what extent other brain areas may play a role in autonomic deregulation under such pathological situations.
Assuntos
Transtorno Depressivo Maior , Doenças Neurodegenerativas , Ratos , Animais , Ratos Wistar , Barorreflexo/fisiologia , Endocanabinoides/metabolismo , Transtorno Depressivo Maior/metabolismo , Doenças Neurodegenerativas/metabolismo , Frequência Cardíaca/fisiologia , Pressão Sanguínea/fisiologia , Córtex Pré-Frontal/metabolismo , Glutamatos/metabolismoRESUMO
Dysregulation of GABAergic neurotransmission has long been implicated in several psychiatric disorders, including schizophrenia, depression, and anxiety disorders. Alpha 5 subunit-containing GABAA receptors (α5-GABAAR), which are expressed mainly by pyramidal neurons in the hippocampus, have been proposed as a potential target to treat these psychiatric disorders. Here, we evaluated the effects produced by GL-II-73 and SH-053-2'F-R-CH3 (1, 5, and 10 mg/kg), two positive allosteric modulators of α5-GABAAR in behavioral tests sensitive to drugs with anxiolytic, antidepressant, and antipsychotic properties in male and female C57BL/6 mice. In both males and females, GL-II-73 produced an anxiolytic-like effect in the elevated plus-maze (EPM) and novelty-suppressed feeding and a rapid and sustained antidepressant-like effect in the forced swim test. GL-II-73 also induced antipsychotic-like effects in males indicated by attenuating MK-801-induced hyperlocomotion and prepulse inhibition (PPI) disruption. However, GL-II-73 per se increased locomotor activity and impaired fear memory extinction in males and females and PPI in males. On the other hand, SH-053-2'F-R-CH3 induced anxiolytic-like effects in the EPM and facilitated fear memory extinction in males. Contrary to GL-II-73, SH-053-2'F-R-CH3 attenuated MK-801-induced hyperlocomotion and PPI disruption in females but not in males. Neither of these drugs induced rewarding effects or impaired motor coordination. These findings suggest that GL-II-73 and SH-053-2'F-R-CH3 cause distinct sex-dependent behavioral responses and support continued preclinical research on the potential of positive allosteric modulators of α5-GABAAR for the treatment of psychiatric disorders.
Assuntos
Ansiolíticos , Antipsicóticos , Animais , Ansiolíticos/farmacologia , Benzodiazepinas/farmacologia , Maleato de Dizocilpina , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de GABA-A , Ácido gama-AminobutíricoRESUMO
Ventral medial prefrontal cortex (vMPFC) glutamatergic neurotransmission has a facilitatory role on cardiac baroreflex activity which is mediated by NMDA receptors activation. Corticotrophin releasing factor receptors type1 and 2 (CRF1 and CRF2), present in the vMPFC, are colocalized in neurons containing glutamate vesicles, suggesting that such receptors may be involved in glutamate release in this cortical area. Therefore, our hypothesis is that the CRF1 and CRF2 receptors can modulate the baroreflex bradycardic and tachycardic responses. In order to prove this assumption, male Wistar rats had bilateral stainless steel guide cannula implanted into the vMPFC, and baroreflex was activated by intravenous infusion of phenylephrine or sodium nitroprusside through a vein catheter. A second catheter was implanted into the femoral artery for cardiovascular measurements. The CRF1 receptor antagonist administration in either infralimbic cortex (IL) or prelimbic cortex (PL), vMPFC regions, was unable to change the bradycardic responses but increased the slope of the baroreflex tachycardic activity. Microinjection of the CRF2 receptor antagonist into the IL and PL did not alter ether bradycardic nor tachycardic baroreflex responses. The administration of the non-selective CRF receptors agonist, urocortin in these areas, did not modify bradycardic responses but decreased tachycardia slope of the baroreflex. CRF1 receptor antagonist administration prior to non-selective CRF agonist in vMPFC prevented the tachycardic responses reduction. However, CRF2 receptor antagonism could not prevent the effect of CRF receptors agonist. These results suggest that IL and PL CRF1 but not CRF2 receptors have an inhibitory role on the baroreflex tachycardic activity. Furthermore, they have no influence on baroreflex bradycardic activity.
Assuntos
Barorreflexo , Frequência Cardíaca , Córtex Pré-Frontal/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Masculino , Córtex Pré-Frontal/fisiologia , Ratos , Ratos WistarRESUMO
The bed nucleus of the stria terminalis (BNST) is a forebrain structure, involved in the modulation of neuroendocrine, cardiovascular and autonomic responses. One of the responses is baroreflex activity, which consists in a neural mechanism responsible for keeping the blood pressure within a narrow range of variation. It has been reported that blockade of BNST α1-adrenoceptors increased the bradycardic component of baroreflex. In addition, such receptors are able to modulate glutamate release in this structure. Interestingly, BNST NMDA receptor antagonism and neuronal nitric oxide synthase (nNOS) inhibition led to the same effect of the α1-adrenoceptors blockade on baroreflex bradycardic response. Therefore, the hypothesis of the present study is that BNST noradrenergic transmission interacts with NMDA/NO pathway through α1 adrenoceptors to modulate the baroreflex activity. Male Wistar rats had stainless steel guide cannulas bilaterally implanted in the BNST. Subsequently, a catheter was inserted into the femoral artery for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. Injection of the noradrenaline reuptake inhibitor reboxetine in the BNST did not modify the tachycardic, but significantly decreased the bradycardic component of baroreflex. Administration of an α1, but not an α2 antagonist into the BNST prior to reboxetine prevented this effect. Likewise, previous injection of NMDA/NO pathway blockers inhibited the effect of reboxetine on bradycardic response. In conclusion, it was demonstrated for the first time the existence of an interaction between BNST noradrenergic, glutamatergic and nitrergic neurotransmissions in the modulation of bradycardic baroreflex response.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Barorreflexo , Coração/inervação , Óxido Nítrico/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleos Septais/metabolismo , Animais , Pressão Arterial , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Frequência Cardíaca , Masculino , Neurotransmissores/farmacologia , Ratos Wistar , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Núcleos Septais/efeitos dos fármacos , Fatores de TempoRESUMO
The medial amygdaloid nucleus (MeA) is a key neural structure in triggering physiologic and behavioral control during aversive situations. However, MeA role during stress exposure has not yet been fully elucidated. Thus, in the present study, we investigated the involvement of the MeA opioid neurotransmission in the modulation of autonomic, neuroendocrine and behavioral responses evoked by acute restraint stress (RS). The bilateral microinjection of naloxone (non-selective opioid antagonist) into the MeA potentiated RS-evoked autonomic responses and increased plasma corticosterone levels, in a dose-dependent manner. However, no effects were observed in RS-evoked increases on plasma oxytocin levels and anxiogenic-like behavior. Similar to naloxone, MeA pretreatment with the selective κ-opioid antagonist (nor-BNI) also enhanced heart rate and corticosterone increases induced by RS, whereas treatment with selective µ- or δ-opioid antagonists did not affect the physiologic and behavioral responses caused by RS. The present results showed MeA κ-opioid receptors modulate heart rate and corticosterone increases evoked by acute RS, reinforcing the idea of an inhibitory role exerted by MeA during aversive situations .
Assuntos
Complexo Nuclear Corticomedial , Receptores Opioides kappa , Animais , Frequência Cardíaca , Ratos , Ratos Wistar , Estresse PsicológicoRESUMO
Insular cortex is a brain structure involved in the modulation of autonomic activity and cardiovascular function. The nitric oxide/cyclic guanosine-3',5'-monophosphate pathway is a prominent signaling mechanism in the central nervous system, controlling behavioral and physiological responses. Nevertheless, despite evidence regarding the presence of nitric oxide-synthesizing neurons in the insular cortex, its role in the control of autonomic and cardiovascular function has never been reported. Thus, the present study aimed to investigate the involvement of nitric oxide/cyclic guanosine-3',5'-monophosphate pathway mediated by neuronal nitric oxide synthase (nNOS) activation within the insular cortex in the modulation of baroreflex responses in unanesthetized rats. For this, we evaluated the effect of bilateral microinjection of either the nitric oxide scavenger carboxy-PTIO, the selective neuronal nitric oxide synthase inhibitor Nω-Propyl-l-arginine or the soluble guanylate cyclase inhibitor ODQ into the insular cortex on the bradycardia evoked by blood pressure increases in response to intravenous infusion of phenylephrine, and the tachycardia caused by blood pressure decreases evoked by intravenous infusion of sodium nitroprusside. Bilateral microinjection of either NPLA or carboxy-PTIO into the insular cortex increased the reflex bradycardic response, whereas the reflex tachycardia was decreased by these treatments. Bilateral microinjection of the soluble guanylate cyclase inhibitor into the insular cortex did not affect any parameter of baroreflex function evaluated. Overall, our findings provide evidence that insular cortex nitrergic signaling, acting via neuronal nitric oxide synthase, plays a prominent role in control of baroreflex function. However, control of reflex responses seems to be independent of soluble guanylate cyclase activation.
Assuntos
Barorreflexo/fisiologia , Córtex Cerebral/metabolismo , GMP Cíclico/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia , Animais , Barorreflexo/efeitos dos fármacos , Benzoatos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/farmacologia , Masculino , Oxidiazóis/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
We evaluate whether acute restraint stress may affect the oxidative state of the cardiorenal system and the possible contribution of angiotensin II/AT1 receptors in such response. Male Wistar rats were restrained for 60 min within wire mesh chambers. Some rats were treated with losartan (selective AT1 receptor antagonist, 10 mg/kg, p.o., gavage) 30 min before being stressed. Biochemical analyses were conducted after the 60-min period of restraint. Treatment with losartan prevented the increase in mean arterial pressure (MAP), but not heart rate (HR) induced by acute stress. Phenylephrine-induced contraction of endothelium-intact aortas was not affected by acute stress. Losartan prevented the increase in both superoxide anion (O2â¢-) and hydrogen peroxide (H2O2) levels induced by acute stress in the aorta and renal cortex. Similarly, the augmented activity of superoxide dismutase (SOD) induced by acute stress in the aorta and renal cortex was prevented by losartan. Enhanced levels of O2â¢- and thiobarbituric acid reactive species (TBARS) were detected in the left ventricle (LV) of stressed rats, but losartan did not prevent these responses. Similarly, losartan did not inhibited stress-induced decrease in the concentration of nitrate/nitrite (NOx) and H2O2 in the left ventricle. Stress increased ROS generation and affected the enzymatic antioxidant system in the cardiorenal system. In addition to its well-known cardiovascular changes during acute stress, angiotensin II also induces ROS generation in the cardiorenal system in a tissue-specific manner. The increase in oxidative stress mediated by angiotensin II/AT1 receptors could be one mechanism by which acute stress predisposes to cardiorenal dysfunctions.
Assuntos
Peróxido de Hidrogênio , Estresse Psicológico , Angiotensina II , Animais , Pressão Sanguínea , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismoRESUMO
Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB1 and CB2 antagonists (AM251 and AM630, respectively), and mimicked by CB1 and CB2 agonists (ACEA and JWH133, respectively). URB602 also prevented the cardiovascular effects of DMH-stimulation in anaesthetised animals. None of the treatments modified blood corticosterone levels. In conclusion, facilitation of 2-AG-signalling in the DMH modulates panic-like responses. The possible mechanisms comprise activation of both CB1 and CB2 receptors in this brain region.
Assuntos
Núcleo Hipotalâmico Dorsomedial/fisiopatologia , Endocanabinoides/fisiologia , Transtorno de Pânico/fisiopatologia , Animais , Ácidos Araquidônicos/farmacologia , Benzamidas/farmacologia , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Canabinoides/farmacologia , Carbamatos/farmacologia , Corticosterona/sangue , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Indóis/farmacologia , Masculino , Microinjeções , N-Metilaspartato/antagonistas & inibidores , Transtorno de Pânico/induzido quimicamente , Transtorno de Pânico/prevenção & controle , Piperidinas/farmacologia , Pirazóis/farmacologia , RatosRESUMO
We investigated the involvement of nitrergic neurotransmission within the paraventricular nucleus of the hypothalamus (PVN) in modulation of local neuronal activation, autonomic and neuroendocrine responses and behavioral consequences of acute restraint stress in rats. Bilateral microinjections of the selective neuronal nitric oxide (NO) synthase (nNOS) inhibitor Nw-Propyl-L-arginine (NPLA) or the NO scavenger carboxy-PTIO into the PVN reduced arterial pressure and heart rate increases, as well as the fall in cutaneous tail temperature induced by restraint stress. PVN injection of either NPLA or carboxy-PTIO also inhibited restraint-induced increases in anxiety-related behaviors in the elevated plus-maze 24â¯h later. Local microinjection of NPLA or carboxy-PTIO into the PVN reduced the number of c-fos-immunoreactive neurons in the dorsal parvocellular, ventromedial, medial parvocellular and lateral magnocelllular portions of the PVN in animals subjected to restraint stress. However, neither NPLA nor carboxy-PTIO into the PVN affected restraint-induced increases in plasma corticosterone concentration. The present results indicate that PVN nitrergic neurotransmission acting via nNOS activation has a facilitatory influence on autonomic responses to acute restraint and the delayed emotional consequences of restraint stress. Our results also provide evidence of a prominent role of local nitrergic neurotransmission in PVN neuronal activation during stress.
Assuntos
Óxido Nítrico Sintase Tipo I/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Restrição Física/fisiologia , Estresse Psicológico/metabolismo , Transmissão Sináptica/fisiologia , Animais , Sistema Nervoso Autônomo/metabolismo , Corticosterona/sangue , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Restrição Física/psicologiaRESUMO
Schizophrenia patients typically exhibit prominent negative symptoms associated with deficits in extinction recall and decreased ventromedial prefrontal cortex activity (vmPFC, analogous to medial PFC infralimbic segment in rodents). mPFC activity modulates the activity of basolateral amygdala (BLA) and this connectivity is related to extinction. mPFC and BLA activity has been shown to be altered in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. However, it is unknown if there are alterations in extinction processes in this model. Therefore, we investigated extinction and the role of mPFC-BLA balance in MAM rats. Male offspring of pregnant rats treated with Saline or MAM (20 mg/kg; i.p.) on gestational day 17 were used in fear conditioning (contextual/tone) and electrophysiological experiments (mPFC-BLA plasticity). No difference was observed in conditioning, extinction, and test sessions in contextual fear conditioning. However, MAM-treated rats demonstrated impairment in extinction learning and recall in tone fear conditioning. Furthermore, high frequency stimulation (HFS) of the BLA decreased spike probability in the mPFC of saline-treated rats but not in MAM rats. NMDA antagonist microinjected into the BLA disrupted extinction learning and recall in control rats, resulting in a similar deficit as that observed in MAM-treated rats. These data demonstrate extinction impairment in the MAM model that is analogous to that observed in schizophrenia patients, that was probably due to disruption in the regulation of mPFC activity by glutamatergic neurotransmission in the BLA.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Feminino , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
The ventral medial prefrontal cortex (vMPFC) facilitates the cardiac baroreflex response through N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) formation by neuronal NO synthase (nNOS) and soluble guanylate cyclase (sGC) triggering. Glutamatergic transmission is modulated by the cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid type 1 (TRPV1) receptors, which may inhibit or stimulate glutamate release in the brain, respectively. Interestingly, vMPFC CB1 receptors decrease cardiac baroreflex responses, while TRPV1 channels facilitate them. Therefore, the hypothesis of the present study is that the vMPFC NMDA/NO pathway is regulated by both CB1 and TRPV1 receptors in the modulation of cardiac baroreflex activity. In order to test this assumption, we used male Wistar rats that had stainless steel guide cannulae bilaterally implanted in the vMPFC. Subsequently, a catheter was inserted into the femoral artery, for cardiovascular recordings, and into the femoral vein for assessing baroreflex activation. The increase in tachycardic and bradycardic responses observed after the microinjection of a CB1 receptors antagonist into the vMPFC was prevented by an NMDA antagonist as well as by the nNOS and sGC inhibition. NO extracellular scavenging also abolished these responses. These same pharmacological manipulations inhibited cardiac reflex enhancement induced by TRPV1 agonist injection into the area. Based on these results, we conclude that vMPFC CB1 and TRPV1 receptors inhibit or facilitate the cardiac baroreflex activity by stimulating or blocking the NMDA activation and NO synthesis.
Assuntos
Barorreflexo , Coração/fisiologia , Córtex Pré-Frontal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Frequência Cardíaca , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Canais de Cátion TRPV/agonistasRESUMO
Although it is well-established that severe poisoning by organophosphorus (OP) compounds strongly affects the cardiorespiratory system, the effects of sub-lethal exposure to these compounds on the neural control of cardiovascular function are poorly explored. The aim of this study was to evaluate the effects of acute sub-lethal exposure to chlorpyrifos (CPF), a commonly used OP insecticide, on three basic reflex mechanisms involved in blood pressure regulation, the peripheral chemoreflex, the baroreflex and the Bezold-Jarisch reflex. Adult male Wistar rats were injected intraperitoneally with a single dose of CPF (30â¯mg/kg) or saline (0.9%). 24â¯h after injections, cardiovascular reflexes were tested in awake rats. Potassium cyanide (KCN) and phenylbiguanide (PBG) were injected intravenously to activate the chemoreflex and the Bezold-Jarisch reflex, respectively. The baroreflex was activated by phenylephrine and sodium nitroprusside infusions. Blood samples were taken for measurements of butyrylcholinesterase (BChE) activity while acetylcholinesterase (AChE) activity was measured in brainstem samples. Animals treated with CPF presented signs of intoxication such as ataxia, tremor, lacrimation, salivation, tetany, urination and defecation. The hypertensive and the bradycardic responses of the chemoreflex as well as the hypotensive and bradycardic responses of the Bezold-Jarisch reflex were attenuated in CPF treated animals (Pâ¯<â¯0.05). Concerning the baroreflex responses, CPF treatment reduced the bradycardia plateau, the range and the gain of the reflex (Pâ¯<â¯0.05). Plasma BChE and brainstem AChE were both reduced significantly after CPF treatment (Pâ¯<â¯0.05). Our results showed that acute sub-lethal exposure to CPF impairs the cardiovascular responses of homeostatic and defensive cardiovascular reflexes. These effects are associated with a marked inhibition of plasma BChE and brainstem AChE.
Assuntos
Barorreflexo/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Clorpirifos/toxicidade , Acetilcolinesterase/sangue , Acetilcolinesterase/metabolismo , Animais , Tronco Encefálico/enzimologia , Butirilcolinesterase/sangue , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/toxicidade , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Inseticidas/toxicidade , Masculino , Projetos Piloto , Ratos , Ratos Wistar , Testes de Toxicidade AgudaRESUMO
Anandamide, an endocannabinoid, inhibits aversive responses by activating the CB1 cannabinoid receptor. At high concentrations, however, anandamide may exert pro-aversive activities mediated by the transient receptor potential vanilloid type-1 channel (TRPV1). Accordingly, N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the anandamide-hydrolysing enzyme fatty acid amide hydrolase (FAAH) and the TRPV1 channel, induces anxiolytic-like effects. Here we tested the hypothesis that AA-5-HT inhibits the expression of contextual fear conditioning by facilitating CB1 receptor signalling in the dorsal hippocampus of mice. Intraperitoneal injection of AA-5-HT (0.1, 0.3, 1 mg/kg) inhibited the retrieval of contextual fear memory (freezing response). The effect of AA-5-HT (0.3 mg/kg) was prevented by systemic injection of the CB1 receptor antagonist, AM251 (1.0 mg/kg), and mimicked by simultaneous FAAH inhibition (URB597, 0.3 mg/kg) and TRPV1 blockage (SB366791, 1 mg/kg). Injection of AA-5-HT (0.125, 0.25, 0.5 nmol) into the dorsal hippocampus also reduced freezing. Finally, the effect of systemic AA-5-HT (0.3 mg/kg) was prevented by intra-hippocampal injection of AM251 (1 nmol). In conclusion, dual FAAH and TRPV1 blockage inhibits contextual fear memory by facilitating anandamide-induced CB1 receptor activation in the dorsal hippocampus. This approach may lead to new pharmacological treatments for traumatic memories and related psychiatric disorders.
Assuntos
Amidoidrolases/antagonistas & inibidores , Ácidos Araquidônicos/farmacologia , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Serotonina/análogos & derivados , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Endocanabinoides/farmacologia , Hipocampo/metabolismo , Masculino , Camundongos , Alcamidas Poli-Insaturadas/farmacologia , Serotonina/farmacologiaRESUMO
Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms. Wistar rats were treated with vehicle (water) or chronic fluoxetine (10mg/kg/day) for 21 days. Blood pressure (BP) and heart rate were measured. Vascular reactivity was evaluated in perfused mesenteric arterial beds (MAB) and in mesenteric resistance arteries. Protein expression by western blot analysis or immunohistochemistry, ß-arrestin recruitment by BRET and calcium influx by FLIPR assay. Fluoxetine treatment decreased phenylephrine (PE)-induced, but not electrical-field stimulation (EFS)-induced vasoconstriction. Fluoxetine-treated rats exhibited increased KCl-induced vasoconstriction, which was abolished by prazosin. Desipramine, an inhibitor of norepinephrine (NA) reuptake, increased EFS-induced vasoconstrictor response in vehicle-treated, but not in fluoxetine-treated rats. Chronic treatment did not alter vascular expression of α1 adrenoceptor, phosphorylation of PKCα or ERK 1/2 and RhoA. On the other hand, vascular contractions to calcium (Ca2+) as well as Ca2+ influx in mesenteric arteries were increased, while intracellular Ca2+ storage was decreased by the chronic treatment with fluoxetine. In vitro, fluoxetine decreased vascular contractions to PE, EFS and Ca2+, but did not change ß-arrestin activity. In conclusion, chronic treatment with fluoxetine decreases sympathetic-mediated vascular responses by mechanisms that involve inhibition of NA release/reuptake and decreased Ca2+ stores.
Assuntos
Fluoxetina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sinapses/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Cálcio/metabolismo , Estimulação Elétrica , Frequência Cardíaca/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , beta-Arrestinas/metabolismoRESUMO
The bed nucleus of the stria terminalis (BNST) modulates anxiety-like responses, including conditioned emotional responses. Evidence suggests that glutamatergic neurotransmission in the BNST plays a role in the modulation of defensive responses. However, little is known about the involvement of glutamate NMDA receptor activation within the BNST, and its resultant increase in nitric oxide (NO) levels, in the expression of contextual fear conditioning (CFC). We investigated whether the antagonism of NMDA receptors or the reduction of NO levels in the BNST would attenuate behavioral and autonomic responses (i.e. increase in arterial pressure and heart rate, and decrease in tail cutaneous temperature) of rats submitted to a CFC paradigm. Intra-BNST infusion of AP7, an NMDA receptor antagonist, attenuated both behavioral and autonomic changes induced by CFC. Similar results were observed with NPLA and c-PTIO, an nNOS inhibitor and an NO scavenger, respectively. A positive correlation between BNST NO levels and the time spent in freezing behavior was also observed for animals submitted to the CFC. These findings indicate that the expression of CFC involves a facilitation of BNST NMDA receptor-NO signaling. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.
Assuntos
Medo/fisiologia , Óxido Nítrico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Núcleos Septais/fisiologia , Animais , Pressão Arterial , Sistema Nervoso Autônomo/fisiologia , Condicionamento Clássico/fisiologia , Frequência Cardíaca , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/fisiologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Núcleos Septais/metabolismoRESUMO
Stress is a response of the organism to homeostasis-threatening stimuli and is coordinated by two main neural systems: the hypothalamic-pituitary-adrenal and the autonomic nervous system. Acute restraint stress (RS) is a model of unavoidable stress, which is characterized by autonomic responses including an increase in mean arterial pressure (MAP) and heart rate (HR), as well as a drop in tail temperature. The prelimbic cortex (PL) has been implicated in the modulation of functional responses caused by RS. The present study aimed to evaluate the role of PL GABAergic neurotransmission in the modulation of autonomic changes induced by RS. Bilateral microinjection of the GABAA receptor antagonist bicuculline methiodide into the PL reduced pressor and tachycardic responses evoked by RS, in a dose-dependent manner, without affecting the tail temperature drop evoked by RS. In order to investigate which peripheral autonomic effector modulated the reduction in RS-cardiovascular responses caused by the blockade of PL GABAA receptors, rats were intravenously pretreated with either atenolol or homatropine methylbromide. The blockade of the cardiac sympathetic nervous system with atenolol blunted the reducing effect of PL treatment with bicuculline methiodide on RS-evoked pressor and tachycardic responses. The blockade of the parasympathetic nervous system with homatropine methylbromide, regardless of affecting the beginning of the tachycardic response, did not impact on the reduction of RS-evoked tachycardic and pressor responses caused by the PL treatment with bicuculline methiodide. The present results indicate that both cardiac sympathetic and parasympathetic activities are involved in the reduction of RS-evoked cardiovascular responses evidenced after the blockade of PL GABAA receptors by bicuculline methiodide.
Assuntos
Sistema Límbico/fisiopatologia , Receptores de GABA-A/metabolismo , Estresse Psicológico/fisiopatologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Atenolol/farmacologia , Bicuculina/administração & dosagem , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Antagonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/farmacologia , Masculino , Microinjeções , Parassimpatolíticos/farmacologia , Ratos , Ratos Wistar , Restrição Física , Transmissão Sináptica , Taquicardia/induzido quimicamente , Taquicardia/fisiopatologia , Tropanos/farmacologiaRESUMO
The cannabinoid receptor type 1 (CB1) is highly expressed in the dorsal portion of hippocampus - a brain region that has been involved in the control of conditioned emotional response (CER) in the contextual fear conditioning (CFC) model. These responses are characterized by increased freezing behavior and autonomic parameters. Moreover, CB1 receptors activation negatively modulate the release of several neurotransmitters, including glutamate and GABA, which also have been related to modulation of CER. Therefore, our aim was to investigate the involvement of CB1 receptors in the dorsal hippocampus on CER expression. Independent groups of male Wistar rats submitted to the contextual fear conditioning received bilateral intra-hippocampal injections (500 nL/side) of the following drugs or vehicle before re-exposure to the aversive context: AM251 (CB1 antagonist; 0.1, 0.3 and 1nmol); AP7 (NMDA antagonist; 1nmol)+AM251 (0.3nmol); NPLA (0.01nmol; nNOS inhibitor)+AM251 (0.3nmol); Bicuculline (1.3pmol; GABAA antagonist)+AM251 (0.1 and 1nmol). In the present paper, AM251 (0.3nmol) increased CER, while this response was prevented by both AP7 and NPLA pretreatment. After pretreatment with Bicuculline, the lower and higher ineffective doses of AM251 were able to increase the CER, supporting the balance between GABAergic and glutamatergic mechanisms controlling this response. Our results suggest that increased CER evoked by CB1 blockade in the dorsal hippocampus depends on NMDA receptor activation and NO formation. Moreover, a fine-tune control promoted by GABAergic and glutamatergic mechanisms in this brain area modulate the CER after CB1 blockade.
Assuntos
Medo/psicologia , Hipocampo/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Animais , Bicuculina/farmacologia , Condicionamento Psicológico , Emoções/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Glutamatos/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologiaRESUMO
Baroreflex activity is a neural mechanism responsible for short-term adjustments in blood pressure (BP). Several supramedullary areas, which send projections to the medulla, are able to control this reflex. In this context, the ventrolateral part of the periaqueductal grey matter (vlPAG), which is a mesencephalic structure, has been suggested to regulate the cardiovascular system. However, its involvement in baroreflex control has never been addressed. Therefore, our hypothesis is that the vlPAG neurotransmission is involved in baroreflex cardiac activity. Male Wistar rats had stainless steel guide cannulae unilaterally or bilaterally implanted in the vlPAG. Afterward, a catheter was inserted into the femoral artery for BP and HR recording. A second catheter was implanted into the femoral vein for baroreflex activation. When the nonselective synaptic blocker cobalt chloride (CoCl2 ) was unilaterally injected into the vlPAG, in either the left or the right hemisphere, it increased the tachycardic response to baroreflex activation. However, when CoCl2 was bilaterally microinjected into the vlPAG it decreased the tachycardic response to baroreflex stimulation. This work shows that vlPAG neurotransmission is involved in modulation of the tachycardic response of the baroreflex. Moreover, we suggest that the interconnections between the vlPAG of both hemispheres are activated during baroreflex stimulation. In this way, our work helps to improve the understanding about brain-heart circuitry control, emphasizing the role of the autonomic nervous system in such modulation.