RESUMEN
The present study investigated the effects of systemic or intra-dorsolateral periaqueductal gray (dlPAG) administration of CB1 agonists on behavioural changes induced in rats by predator (a live cat) exposure, a model of panic responses. Since nitric oxide (NO) and cannabinoid neurotransmission are proposed to interact in the dlPAG to modulate defensive responses, we also investigated if NO is involved in the biphasic effects of anandamide (AEA) injected into the dlPAG. The results showed that systemic administration of WIN55,212-2 or intra-dlPAG AEA attenuated the defensive behaviours caused by cat exposure. Both compounds produced biphasic curves. The cannabinoid receptor type 1 (CB1) antagonist AM251 prevented the panicolytic effect of AEA whereas a neuronal NOS inhibitor turned the ineffective high dose of AEA into an effective one. These results suggest that modulation of the cannabinoid system could be a target in the treatment of panic disorders. However, the biphasic effects of these compounds could limit their therapeutic potential.
Asunto(s)
Miedo/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/fisiología , Conducta Predatoria , Animales , Ácidos Araquidónicos/administración & dosificación , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/farmacología , Benzoxazinas/farmacología , Agonistas de Receptores de Cannabinoides/administración & dosificación , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Gatos , Relación Dosis-Respuesta a Droga , Endocannabinoides/administración & dosificación , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/farmacología , Inhibidores Enzimáticos/farmacología , Miedo/fisiología , Masculino , Microinyecciones , Morfolinas/farmacología , Naftalenos/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Ornitina/análogos & derivados , Ornitina/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas/administración & dosificación , Alcamidas Poliinsaturadas/antagonistas & inhibidores , Alcamidas Poliinsaturadas/farmacología , Pirazoles/farmacología , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismoRESUMEN
The ventral medial prefrontal cortex (vMPFC) comprises the prelimbic cortex (PL) and the infralimbic cortex (IL). Conflicting results have been reported from studies aiming to investigate the role played by the vMPFC in behavioral and autonomic responses evoked in rodents exposed to experimental protocols that promote defense responses. Acute restraint is an unavoidable stress situation that evokes marked and sustained cardiovascular changes, which are characterized by elevated blood pressure (BP) and intense heart rate (HR) increases. We report here a comparison between the effects of pharmacological inhibition of IL and PL neurotransmission on BP and HR responses evoked by acute restraint in rats. Bilateral microinjection of 200 nl of the unspecific synaptic blocker CoCl(2) (1 mM) into the PL increased HR response associated with restraint, without affecting the restraint-induced BP response. However, when local synapses in the IL were inhibited by bilateral injection of CoCl(2) into that area, the restraint-induced HR increases were significantly reduced, without a significant effect on the concomitant BP response. No responses were observed when CoCl(2) was microinjected into structures surrounding the vMPFC, such as the cingulate cortex area 1, the corpus callosum, or the tenia tecta. The present results confirm the involvement of the vMPFC in modulation of the tachycardiac response evoked by acute restraint but not of the restraint-evoked blood pressure response. They also indicate that the IL and PL areas have opposite roles in the cardiac response, facilitating and reducing, respectively, restraint-evoked tachycardiac responses.
Asunto(s)
Corteza Prefrontal/fisiopatología , Restricción Física , Estrés Psicológico/fisiopatología , Taquicardia/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Fármacos del Sistema Nervioso Central/farmacología , Cobalto/farmacología , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/fisiopatología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Microinyecciones , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacosRESUMEN
There is conflicting evidence concerning the role of the bed nucleus of the stria terminalis (BNST) in fear and anxiety-elicited behavior. Most of the studies investigating this role, however, employed irreversible lesions of this nucleus. The objective of the present study was to investigate the effects of an acute and reversible inactivation of the BNST in rats submitted to the Vogel conflict test (VCT) and contextual fear conditioning, two widely employed animal models that are responsive to prototypal anxiolytic drugs. Male Wistar rats were submitted to stereotaxic surgery to bilaterally implant cannulae into the BNST. Ten minutes before the test they received bilateral microinjections of cobalt chloride (CoCl(2)) (1 mM/100 nL), a nonselective synapse blocker. CoCl(2) produced anxiolytic-like effects in tests, increasing the number of punished licks in the VCT and decreasing freezing behavior and the increase in mean arterial blood pressure and heart rate of animals re-exposed to the context where they had received electrical foot shocks 24 h before. The results indicate that the BNST is engaged in behavioral responses elicited by punished stimuli and aversively conditioned contexts, reinforcing its proposed role in anxiety.
Asunto(s)
Ansiolíticos/farmacología , Miedo/efectos de los fármacos , Núcleos Septales/efectos de los fármacos , Analgésicos Opioides/farmacología , Animales , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Reacción de Prevención/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Calcio/metabolismo , Cobalto , Conflicto Psicológico , Ingestión de Líquidos/efectos de los fármacos , Masculino , Microinyecciones , Morfina/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Técnicas Estereotáxicas , Sinapsis/efectos de los fármacosRESUMEN
RATIONALE: Conditioned fear to context causes freezing and cardiovascular changes in rodents and has been used to measure anxiety. It also activates the dorsolateral column of the periaqueductal gray (dlPAG). Microinjections of cannabinoid agonists into the dlPAG produced anxiolytic-like effects in the elevated plus maze, but the effects of these treatments on fear conditioning remains unknown. OBJECTIVE: The objective of this study was to verify if intra-dlPAG injection of the CB1 cannabinoid receptor agonist anandamide (AEA) or the anandamide transport inhibitor AM404 would attenuate behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats submitted to a contextual fear-conditioning paradigm. MATERIALS AND METHODS: Male Wistar rats with cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Fifteen minutes before the test, the animals received a first intra-dlPAG injection of vehicle or AM251, a CB1 receptor antagonist (100 pmol/200 nl), followed 5 min later by vehicle, AEA (5 pmol/200 nl) or AM404 (50 pmol/200 nl). Freezing and cardiovascular responses were recorded for 10 min. RESULTS: Freezing and cardiovascular responses were reduced by administration of either AEA or AM404 into the dlPAG before re-exposition to the aversively conditioned context. These effects were abolished when the animals were locally pretreated with AM251. The latter drug, even at a higher dose (300 pmol), was ineffective when administered alone into the dlPAG. CONCLUSION: The results suggest that facilitation of endocannabinoid-mediated neurotransmission in the dlPAG, through activation of local CB1 receptors, attenuates the expression of contextual fear responses.
Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Miedo/psicología , Sustancia Gris Periacueductal/fisiología , Receptor Cannabinoide CB1/agonistas , Animales , Ácidos Araquidónicos/metabolismo , Ácidos Araquidónicos/farmacología , Presión Sanguínea/efectos de los fármacos , Endocannabinoides , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Microinyecciones , Inhibidores de la Captación de Neurotransmisores/farmacología , Sustancia Gris Periacueductal/anatomía & histología , Sustancia Gris Periacueductal/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/metabolismo , Alcamidas Poliinsaturadas/farmacología , Pirazoles/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidoresRESUMEN
Conflicting results have been obtained in studies aimed at investigating the role of the ventral portion of the medial prefrontal cortex (vMPFC), which comprise the prelimbic cortex (PL) and infralimbic cortex (IL), on anxiety responses in rodents evoked by animal models such as fear conditioning, elevated plus maze or social interaction. This may reflect the use of different lesion techniques and/or experimental paradigms based on distinct behaviors properties. Among the latter, the Vogel punished-licking test has been widely used to measure anxiety. However, the role of the vMPFC on anxiety-like behavior evoked by the Vogel model has not been evaluated. Thus, the present study verified the effects of acute and reversible bilateral inhibition of the vMPFC on the behavioral responses in the Vogel conflict test. After 24 h of water deprivation, male Wistar rats were subjected to an initial 3-min non-punished (pretest) drinking session. After an additional 24-h period of water deprivation they were exposed to a 3-min punished-licking session (test).Bilateral microinjections of lidocaine 2% (200 nL) or CoCl(2) (1 mM/200 nL) into the PL or IL produced similar anticonflict effects, increasing the number of punished licks. No responses were observed when lidocaine 2% was microinjected into vMPFC surrounding structures such as the cingulate cortex area 1, the corpus callosum and the tenia tecta. In control experiments the drugs did not change the number of unpunished licks nor had any effect in the tail-flick test. The present results, therefore, indicate that the vMPFC is involved in the behavioral responses elicited by punished stimuli.
Asunto(s)
Ansiedad/psicología , Reacción de Prevención/fisiología , Conflicto Psicológico , Sistema Límbico/fisiología , Corteza Prefrontal/fisiología , Análisis de Varianza , Anestésicos Locales/farmacología , Animales , Ansiedad/fisiopatología , Reacción de Prevención/efectos de los fármacos , Cobalto/farmacología , Lidocaína/farmacología , Sistema Límbico/efectos de los fármacos , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neurotoxinas/farmacología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Corteza Prefrontal/efectos de los fármacos , Castigo/psicología , Ratas , Ratas Endogámicas WKY , Estadísticas no ParamétricasRESUMEN
The purinergic system consists of two large receptor families - P2X and P2Y. Both are activated by adenosine triphosphate (ATP), although presenting different functions. These receptors are present in several brain regions, including those involved in emotion and stress-related behaviors. Hence, they seem to participate in fear- and anxiety-related responses. However, few studies have investigated the purinergic system in threatening situations, as observed in contextual fear conditioning (CFC). Therefore, this study investigated the involvement of purinergic receptors in the expression and extinction of aversive memories. C57Bl/6 background mice were submitted to the CFC protocol. Wildtype (WT) mice received i.p. injection of either a nonselective P2 receptor (P2R) antagonist, P178 (10 or 30 mg/kg); a selective P2X7 receptor (P2X7R) antagonist, A438079 (10 mg/kg); a selective P2Y1 receptor (P2Y1R) antagonist, MRS2179 (10 mg/kg); or vehicle 10 min prior to or immediately after the extinction session. Additionally, P2X7R KO mice were tested in the CFC protocol. After P2R antagonist treatment, contextual fear recall increased, while acquisition of extinction was impaired. Similar results were observed with the selective P2X7R antagonist, but not with the selective P2Y1R antagonist. Interestingly, P2X7R KO mice showed increased contextual fear recall, associated with impaired acquisition of extinction, in accordance with pharmacologic P2X7R antagonism. Our results suggest that specific pharmacological or genetic blockade of P2X7R promotes anxiogenic-like effects, along with deficits in extinction learning. Thus, these receptors could present an alternative treatment of stress-related psychiatric disorders.
Asunto(s)
Condicionamiento Psicológico/fisiología , Miedo/fisiología , Memoria/fisiología , Receptores Purinérgicos P2X7/metabolismo , Análisis de Varianza , Animales , Condicionamiento Psicológico/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Miedo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Agonistas Purinérgicos/farmacología , Antagonistas del Receptor Purinérgico P2X/farmacología , Piridoxal/farmacología , Receptores Purinérgicos P2X7/genéticaRESUMEN
Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.
Asunto(s)
Antidepresivos/metabolismo , Ansiedad/enzimología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Prefrontal/metabolismo , Serina Endopeptidasas/deficiencia , Animales , Conducta Animal , Simulación por Computador , Condicionamiento Psicológico , Miedo , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/farmacología , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismoRESUMEN
The bed nucleus of stria terminalis (BST) has been reported to be involved in central cardiovascular control in rat. We presently report on the cardiovascular effects of carbachol (CBH) microinjection into the BST as well as on local receptor and peripheral mechanisms involved in their mediation. Microinjection of CBH (0.1 to 3 nmol/100 nL) into the BST of anesthetized rats caused dose-related pressor and bradycardiac responses. The cardiovascular response evoked by 1 nmol of CBH was blocked by local microinjection of the nonselective muscarinic receptor antagonist atropine (3 nmol) or the selective M(2)-muscarinic receptor antagonist 4-DAMP (2 nmol). Microinjection of the selective M(1)-muscarinic receptor antagonist pirenzepine (6 nmol) did not affect cardiovascular responses to CBH, suggesting their mediation by local BST M(2)-muscarinic receptors. Cardiovascular responses to CBH microinjected in the BST were markedly reduced in urethane-anesthetized rats. The pressor response was potentiated by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and blocked by i.v. pretreatment with the vasopressin antagonist dTyr(CH2)5(Me)AVP (50 microg/kg), suggesting involvement of circulating vasopressin in response mediation. In conclusion, results suggest that microinjection of CBH in the BST activates local M(2)-muscarinic receptor evoking pressor and bradycardiac responses, which are mediated by acute vasopressin release into circulation.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Núcleos Septales/efectos de los fármacos , Animales , Arginina Vasopresina/antagonistas & inhibidores , Arginina Vasopresina/farmacología , Atropina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Microinyecciones/métodos , Antagonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Tartrato de Pentolinio/farmacología , Piperidinas/farmacología , Ratas , Ratas WistarRESUMEN
The dorsal portion of the periaqueductal gray area (dPAG) is involved in behavioral and cardiovascular control. We report the effect of acute and reversible dPAG blockade by local microinjection of either lidocaine or CoCl2 on the baroreflex response of unanesthetized rats. Acute and reversible blockade evoked by lidocaine microinjection into the dPAG did not affect the bradycardic response to mean arterial pressure (MAP) increases evoked by i.v. infusion of phenylephrine. However, lidocaine increased baroreflex gain and tachycardic reflex in response to MAP decreases evoked by i.v. infusion of sodium nitroprusside, thus suggesting an action on the sympathetic component of the baroreflex. The effects of dPAG synapses blockade caused by CoCl2 were similar to those observed after lidocaine microinjection. CoCl2 microinjection also increased baroreflex gain and tachycardiac responses to MAP decreases without affecting the parasympathetic baroreflex component. In conclusion, our data point to a dPAG tonic inhibitory involvement in baroreflex control, specifically modulating the sympathetic baroreflex component. Temporary dPAG ablation by local microinjection of lidocaine increased the sympathetic baroreflex component. Because CoCl2 microinjection had similar effects on the baroreflex, this modulation involves local synaptic neurotransmission within the dPAG.
Asunto(s)
Barorreflejo/fisiología , Sustancia Gris Periacueductal/citología , Sinapsis/fisiología , Anestésicos Locales/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Cobalto/farmacología , Estado de Conciencia , Frecuencia Cardíaca/efectos de los fármacos , Lidocaína/farmacología , Masculino , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Wistar , Análisis de Regresión , Sinapsis/efectos de los fármacos , Factores de Tiempo , Oligoelementos/farmacologíaRESUMEN
The medical properties of Cannabis sativa is known for centuries. Since the discovery and characterization of the endogenous cannabinoid system, several studies have evaluated how cannabinoid compounds and, particularly, how the modulation of the endocannabinoid (eCB) system influences a wide range of functions, from metabolic to mental disorders. Cannabinoids and eCB system often exert opposite effects on several functions, such as anxiety. Although the mechanisms are not completely understood, evidence points to different factors influencing those effects. In this chapter, the recent advances in research about the relationship between eCB system and anxiety disorders in humans, as well as in animal models, will be discussed. The recent data addressing modulation of the eCBs in specific brain areas, such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray, will be summarized. Finally, data from animal models addressing the mechanisms through which the eCB system modulates anxiety-related behavior dependent on stressful situations, such as the involvement of different receptors, distinct eCBs, modulation of neurotransmitters release, HPA axis and immune system activation, and plastic mechanisms, will also be discussed.
Asunto(s)
Trastornos de Ansiedad/metabolismo , Ansiedad/metabolismo , Encéfalo/metabolismo , Endocannabinoides/metabolismo , Neuronas/metabolismo , Neuroprotección , Receptores de Cannabinoides/metabolismo , Animales , Ansiedad/genética , Ansiedad/inmunología , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/inmunología , Encéfalo/inmunología , Endocannabinoides/inmunología , Miedo , Predisposición Genética a la Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/metabolismo , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Neuronas/inmunología , Especificidad de Órganos , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/metabolismo , Polimorfismo de Nucleótido Simple , Receptores de Cannabinoides/química , Receptores de Cannabinoides/genéticaRESUMEN
We have reported that l-glutamate (l-glu) microinjections into ventral portion of medial prefrontal cortex (vMPFC) caused tachycardia and blood pressure increase in unanesthetized rats. In the present study, we report the subtype of vMPFC glutamatergic receptor mediating the response as well as the possible involvement of nitric oxide (NO) in these cardiovascular responses. Microinjection of 200nL of l-glu (81nmol) into the vMPFC of unanesthetized rats caused long-lasting pressor and tachycardic responses which were abolished by pretreatment with 4nmol of the specific NMDA receptor antagonist AP7. The response was not affected by 4nmol of the non-NMDA receptor antagonist NBQX. Local pretreatment with 80nmol of the unspecific nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME) or 0.08nmol of the specific neuronal NOS (nNOS) inhibitor N(omega)-Propyl-l-arginine (N-Propyl) blocked l-glu effects. Microinjection of the NO donor sodium nitroprusside (SNP: 3, 9, 27 or 81nmol) in the vMPFC caused dose-related long-lasting pressor and tachycardic responses in unanesthetized rats, which were similar to those caused by l-glu. These results suggest that cardiovascular responses evoked by local injection of l-glu into the vMPFC of unanesthetized rats are caused by activation of a local NMDA receptor-NO pathway.
Asunto(s)
Ácido Glutámico/farmacología , Hemodinámica/efectos de los fármacos , Óxido Nítrico/fisiología , Corteza Prefrontal/fisiología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/administración & dosificación , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Microinyecciones , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
To explore the ventral medial prefrontal cortex (vMPFC) involvement in behavioral and autonomic fear-conditioned responses to context, vMPFC synaptic transmission was temporarily inhibited by bilateral microinjections of 200 nL of the nonselective synapse blocker CoCl(2) (1 mM). Behavioral activity (freezing, motor activity and rearing) as well as evoked cardiovascular responses (arterial pressure and heart rate) was analyzed. Rats were pre-exposed to the footshock chamber (context) and shock stimulus was used unconditioned stimulus. During re-exposure to context, conditioned rats spent 80% of the session in freezing while non-conditioned rats (no shock group) spent less than 15% of the session time in freezing. Conditioned rats had significantly lower activity scores than non-conditioned animals. Exposure to context increased mean arterial pressure (MAP) and heart rate (HR) of both groups. MAP and HR of the conditioned animals were markedly increased and remained at a high and stable level, whereas MAP and HR increases in non-conditioned animals were less pronounced and declined during the session. CoCl(2) microinjected in the vMPFC significantly reduced freezing and attenuated MAP and HR increase of the conditioned group. Cobalt-induced vMPFC inhibition also significantly reduced MAP and HR increase observed in non-conditioned animals, without any behavioral changes. The effect of vMPFC acute ablation on MAP and HR did not seem to be specific to the fear response because they were also evident in non-conditioned animals. The results indicate that vMPFC integrity is crucial for expression of fear-conditioned responses to context, such as freezing and cardiovascular changes, suggesting that fear-conditioned responses to context involve cortical processing prior to amygdalar output. They also indicate a cardiovascular response observed during re-exposure of non-conditioned rats to the context is completely dependent on vMPFC integrity.
Asunto(s)
Conducta Animal/fisiología , Sistema Cardiovascular , Condicionamiento Psicológico/fisiología , Miedo , Neuronas/fisiología , Corteza Prefrontal/citología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Cobalto/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Electrochoque/efectos adversos , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Microinyecciones/métodos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The lateral septal area (LSA) is involved in central cardiovascular control. In the present study, we report on the cardiovascular effects of noradrenaline (NA) injection into the LSA of unanesthetized rats, as well as on local receptors and peripheral mechanisms involved in their mediation. Microinjections of NA (9, 15, 21, 27 or 45 nmol) caused long-lasting, dose-related pressor and bradycardic responses in unanesthetized rats. No responses were observed when the dose of 21 nmol of NA was microinjected into medial septal area or lateral ventricle suggesting a main action at the LSA. No changes were observed in arterial pressure and heart rate when NA was injected in the LSA of anesthetized rats. The effects of 21 nmol of NA were abolished by local pretreatment with 10 nmol of the specific alpha1-receptor antagonist WB 4101, but were not affected by pretreatment with 10 nmol of the specific alpha2-receptor antagonist RX 821002. The magnitude of pressor response to NA in the LSA was increased by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and significantly reduced by i.v. pretreatment with the V1-vasopressin receptor antagonist dTyr (CH2)5(Me) AVP (50 microg/kg). No pressor response to NA was observed in hypophysectomized rats. The present observation of alpha1-adrenoceptor-mediated pressor responses after local injection of NA confirms earlier evidence of a LSA involvement in central cardiovascular control. Pretreatment with the alpha1-adrenoceptor antagonist WB-4101 did not affect baseline blood pressure or heart rate suggesting no tonic involvement of septal adrenergic mechanisms suggesting a modulatory LSA influence on cardiovascular control. Additionally, the blockade of the pressor response by the i.v. pretreatment with a V1-vasopressin antagonist indicates that noradrenergic LSA mechanisms modulate vasopressin release.
Asunto(s)
Presión Sanguínea/fisiología , Norepinefrina/fisiología , Receptores Adrenérgicos alfa 1/metabolismo , Núcleos Septales/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Sistema Cardiovascular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Microinyecciones , Norepinefrina/administración & dosificación , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Análisis de Regresión , Núcleos Septales/efectos de los fármacos , Estadísticas no ParamétricasRESUMEN
The medial prefrontal cortex (MPFC) and specifically its ventral portion (vMPFC) have been reported to modulate autonomic responses. On the cardiovascular system, this modulation is characterized by an influence on arterial blood pressure, regional blood flow as well as cardiac sympathetic and parasympathetic responses. The vMPFC also modulates baroreflex activity. Several neurotransmitters are present in the vMPFC. Among them L-glutamate, acetylcholine and noradrenaline are involved with cardiovascular modulation. In the present review, we describe evidences on the mechanisms involved in the vMPFC-related cardiovascular modulation.
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Sistema Cardiovascular/inervación , Corteza Prefrontal/fisiología , Acetilcolina/metabolismo , Animales , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/fisiología , Ácido Glutámico/metabolismo , Frecuencia Cardíaca/fisiología , Norepinefrina/metabolismo , Ratas , Aprendizaje Inverso/fisiologíaRESUMEN
Cannabinoid type 1 (CB1) and Transient Potential Vanilloid type 1 (TRPV1) receptors in the dorsolateral periaqueductal gray (dlPAG) matter are involved in the modulation of conditioned response. Both CB1 and TRPV1 receptors are related to glutamate release and nitric oxide (NO) synthesis. It was previously demonstrated that both NMDA glutamate receptors and NO are involved in the conditioned emotional response. Therefore, one aim of this work was to verify whether dlPAG CB1 and TRPV1 receptors modulate the expression of contextual conditioned emotional response. Moreover, we also investigated the involvement of NMDA receptors and the NO pathway in this response. Male Wistar rats with local dlPAG guide cannula were submitted to contextual fear conditioning. Following 24 h, a polyethylene catheter was implanted in the femoral artery for cardiovascular recordings. After an additional 24 h, drugs were administered in the dlPAG and freezing behavior and autonomic responses were recorded during chamber re-exposure. Both a CB1 antagonist (AM251) and a TRPV1 agonist (Capsaicin; CPS) increased the expression of a conditioned emotional response. This response was prevented by an NMDA antagonist, a preferential neuronal NO synthase inhibitor, an NO scavenger and a soluble guanylate cyclase inhibitor (sGC). Furthermore, pretreatment with a TRPV1 antagonist also prevented the increased conditioned emotional response induced by AM251. Considering that GABA can counterbalance glutamate effects, we also investigated whether GABAA receptors were involved in the effect of a higher dose of AM251. Pretreatment with a GABAA receptor antagonist caused an increased conditioned emotional response by AM251. Our results support the possibility that dlPAG CB1 and TRPV1 receptors are involved in the expression of conditioned emotional response through the NMDA/NO/sGC pathway. Moreover, the opposite effects exerted by GABA and glutamate could produce different outcomes of drugs modulating eCBs.
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Condicionamiento Clásico/fisiología , Miedo/fisiología , Sustancia Gris Periacueductal/fisiología , Receptor Cannabinoide CB1/fisiología , Canales Catiónicos TRPV/fisiología , Animales , Capsaicina/administración & dosificación , Masculino , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/fisiología , Piperidinas/administración & dosificación , Pirazoles/administración & dosificación , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología , Transducción de Señal , Guanilil Ciclasa Soluble/antagonistas & inhibidores , Guanilil Ciclasa Soluble/fisiología , Canales Catiónicos TRPV/agonistasRESUMEN
Here we report the involvement of N-Methyl-d-Aspartate (NMDA) and non-NMDA glutamate receptors from the paraventricular nucleus of the hypothalamus (PVN) in the mediation of cardiovascular changes observed during hemorrhage and post-bleeding periods. In addition, the present study provides further evidence of the involvement of circulating vasopressin and cardiac sympathetic activity in cardiovascular responses to hemorrhage. Systemic treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP (50 µg/kg, i.v.) increased the latency to the onset of hypotension during hemorrhage and slowed post-bleeding recovery of blood pressure. Systemic treatment with the ß1-adrenergic receptor antagonist atenolol (1 mg/kg, i.v.) also increased the latency to the onset of hypotension during hemorrhage. Moreover, atenolol reversed the hemorrhage-induced tachycardia into bradycardia. Bilateral microinjection of the selective NMDA glutamate receptor antagonist LY235959 (2 nmol/100 nL) into the PVN blocked the hypotensive response to hemorrhage and reduced the tachycardia during the post-hemorrhage period. Systemic treatment with dTyr(CH2)5(Me)AVP inhibited the effect of LY235959 on hemorrhage-induced hypotension, without affecting the post-bleeding tachycardia. PVN treatment with the selective non-NMDA receptor antagonist NBQX (2 nmol/100 nL) reduced the recovery of blood pressure to normal levels in the post-bleeding phase and reduced hemorrhage-induced tachycardia. Combined blockade of both NMDA and non-NMDA glutamate receptors in the PVN completely abolished the hypotensive response in the hemorrhage period and reduced the tachycardiac response in the post-hemorrhage period. These results indicate that local PVN glutamate neurotransmission is involved in the neural pathway mediating cardiovascular responses to hemorrhage, via an integrated control involving autonomic nervous system activity and vasopressin release into the circulation.
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Sistema Cardiovascular/fisiopatología , Hemodinámica/fisiología , Hemorragia/complicaciones , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de Glutamato/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas WistarRESUMEN
RATIONALE: Basal forebrain cholinergic neurons modulate the activation of cortical neurons by several stimuli such as fear and anxiety. However, the role of the muscarinic receptor in the medial prefrontal cortex (MPFC) in the modulation of the conditioned emotional response (CER) evoked in the model contextual conditioned fear remains unclear. OBJECTIVES: The objective of this study is to test the hypothesis that inhibition of the muscarinic receptor in ventral MPFC modulates CER observed during animal's re-exposure to the aversive context. METHODS: Rats implanted with cannulae aimed at the prelimbic (PL) or the infralimbic (IL) were submitted to a high-intensity contextual fear conditioning protocol. Before the test session, they received microinjections of the hemicholinium (choline reuptake blocker), atropine (muscarinic antagonist), J104129 fumarate (M1-M3 muscarinic antagonists), pirenzepine (M1 muscarinic antagonist), neostigmine (inhibitor acetylcholinesterase enzyme), or the systemic administration of the FG7142 (inverse benzodiazepine agonist). Additional independent groups received the neostigmine or FG7142 before the ineffective doses of J104129 fumarate in the low-intensity protocol of contextual fear conditioning. RESULTS: In the high-intensity protocol, the administration of hemicholinium (1 nmol), atropine (0.06-6 nmol), J104129 fumarate (6 nmol), or pirenzepine (6 nmol) attenuated the expression of CER in rats. However, in the low-intensity protocol, only J10129 fumarate (0.06 nmol) reduced the expression of the CER. Finally, neostigmine (0.1-1 nmol) or FG7142 (8 mg/Kg) increased CER expression, an effect inhibited by the low dose of the J10129 fumarate. CONCLUSIONS: These results indicated that the blockade of M3 muscarinic receptor in the vMPFC attenuates the CER expression.
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Condicionamiento Psicológico , Miedo/psicología , Corteza Prefrontal/metabolismo , Receptor Muscarínico M3/metabolismo , Animales , Benzodiazepinas/agonistas , Inhibidores de la Colinesterasa/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Emociones , Masculino , Antagonistas Muscarínicos/farmacología , Sistema Nervioso Parasimpático/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Receptor Muscarínico M3/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
The medial prefrontal cortex (MPFC) is involved in cardiovascular control and baroreflex modulation. Recent studies indicated that stimulation of MPFC muscarinic receptors causes hypotensive responses whereas stimulation of alpha1- but not of alpha2-adrenoceptors causes pressor responses in unanesthetized rats. It has also been shown that the MPFC is involved in the modulation of the parasympathetic component of the baroreflex in rats. We report that bilateral injections of CoCl2 in the ventral portion of the MPFC (vMPFC) reduced the parasympathetic component of the baroreflex, thus confirming the involvement of local synapses. We further evaluated the effect of the pharmacologic block of vMPFC alpha1- or alpha2-adrenoceptors and muscarinic receptors on the vMPFC-related modulation of the parasympathetic component of the baroreflex in unanesthetized rats. Bilateral microinjections of 10 nmol of the selective alpha1-adrenoceptor antagonist WB4101 or 10 nmol of the selective alpha2-adrenoceptors antagonist RX821002 into the MPFC did not affect the baroreflex. Bilateral microinjections of 9 nmol of the muscarinic antagonist atropine also did not affect baroreflex activity. The present results indicate that although vMPFC alpha-adrenergic and muscarinic receptors are involved in cardiovascular regulation, they do not mediate the vMPFC-related modulation of the parasympathetic component of the baroreflex.
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Barorreflejo/fisiología , Idazoxan/análogos & derivados , Sistema Nervioso Parasimpático/fisiología , Corteza Prefrontal/fisiología , Receptores Adrenérgicos alfa/fisiología , Receptores Muscarínicos/fisiología , Animales , Atropina/farmacología , Cobalto/farmacología , Dioxanos/farmacología , Idazoxan/farmacología , Masculino , Fenilefrina/farmacología , Ratas , Ratas WistarRESUMEN
BACKGROUND AND PURPOSE: The ventral portion of the medial prefrontal cortex (vMPFC) comprises the infralimbic (IL), prelimbic (PL) and dorsopenducular (DP) cortices. The IL and PL regions facilitate the baroreceptor reflex arc. This facilitatory effect on the baroreflex is thought to be mediated by vMPFC glutamatergic transmission, through NMDA receptors. The glutamatergic transmission can be modulated by other neurotransmitters, such as the endocannabinoids, which are agonists of the TRPV1 receptor. TRPV1 channels facilitate glutamatergic transmission in the brain. Thus, we hypothesized that TRPV1 receptors in the vMPFC enhance the cardiac baroreflex response. EXPERIMENTAL APPROACH: Stainless steel guide cannulae were bilaterally implanted into the vMPFC of male Wistar rats. Afterwards, a catheter was inserted into the femoral artery, for recording MAP and HR, and into the femoral vein for assessing baroreflex activation. KEY RESULTS: Microinjections of the TRPV1 receptor antagonists capsazepine and 6-iodo-nordihydrocapsaicin (6-IODO) into the vMPFC reduced the cardiac baroreflex activity in unanaesthetized rats. Capsaicin microinjected into the vMPFC increased the cardiac baroreflex activity in unanaesthetized rats. When an ineffective dose of the TRPV1 receptor antagonist 6-IODO was used, the capsaicin-induced increase in the cardiac baroreflex response was abolished. The higher doses of capsaicin administered into the vMPFC after the ineffective dose of 6-IODO displaced the dose-response curve of the baroreflex parameters to the right, with no alteration in the maximum effect of capsaicin. CONCLUSIONS AND IMPLICATIONS: The results of the present study show that stimulation of the TRPV1 receptors in the vMPFC increases the cardiac baroreceptor reflex response.
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Barorreflejo/fisiología , Corazón/fisiología , Corteza Prefrontal/fisiología , Canales Catiónicos TRPV/fisiología , Animales , Capsaicina/análogos & derivados , Capsaicina/farmacología , Masculino , Ratas Wistar , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
The ventral portion of the medial prefrontal cortex (vMPFC) that comprises the prelimbic and infralimbic cortex is involved in arterial blood pressure and heart rate control. In the present study, we attempted to verify the effect of an acute and reversible blockade of vMPFC activity by local bilateral microinjections of either lidocaine (a local anesthetic) or CoCl2 (a nonselective synapse blocker) on the baroreflex response of unanesthetized rats. Bilateral microinjection of lidocaine into the vMPFC did not affect the tachycardiac response to mean arterial pressure (MAP) decreases caused by i.v. infusion of sodium nitroprusside or the baroreflex gain in unanesthetized rats. However, lidocaine caused a reversible shift of the reflex threshold pressure toward higher (MAP) increases in response to i.v. infusion of phenylephrine, thus indicating an action on the parasympathetic component of the baroreflex. The effects of the blockade of local synapses in the vMPFC by CoCl2 were similar to those observed after the acute ablation of that area caused by lidocaine. Bilateral microinjection of CoCl2 into the vMPFC also caused a shift of the reflex threshold pressure bradycardiac responses to MAP increases toward higher MAP values, without affecting the baroreflex gain. In conclusion, our data indicate that the vMPFC is involved in baroreflex control, and more specifically in the modulation of the parasympathetic baroreflex component. The temporary ablation of this area by local microinjections of lidocaine caused a shift of the reflex threshold pressure toward higher MAP values, which is compatible with the idea that the vMPFC has a modulatory action on the baroreflex. The observation that CoCl2 and lidocaine microinjections had similar effects on the baroreflex also suggests that this modulation involves local synaptic neurotransmission within the vMPFC.