RESUMEN

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/metabolismo

RESUMEN

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/genética

RESUMEN

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/genética

RESUMEN

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.

Asunto(s)

Sistema Cardiovascular/fisiopatología , Hemodinámica/fisiología , Hemorragia/complicaciones , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de Glutamato/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar

RESUMEN

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.

Asunto(s)

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/agonistas

RESUMEN

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.

Asunto(s)

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 fármacos

RESUMEN

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.

Asunto(s)

Barorreflejo/fisiología , Corazón/fisiología , Corteza Prefrontal/fisiología , Canales Catiónicos TRPV/fisiología , Animales , Capsaicina/análogos & derivados , Capsaicina/farmacología , Masculino , Ratas Wistar , Canales Catiónicos TRPV/antagonistas & inhibidores

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/metabolismo

RESUMEN

The dorsal hippocampus (DH) is a structure of the limbic system that is involved in emotional, learning and memory processes. There is evidence indicating that the DH modulates cardiovascular correlates of behavioral responses to stressful stimuli. Acute restraint stress (RS) is an unavoidable stress situation that evokes marked and sustained autonomic changes, which are characterized by elevated blood pressure (BP), intense heart rate (HR) increase and a decrease in cutaneous temperature. In the present study, we investigated the involvement of an N-methyl-D-aspartate (NMDA) glutamate receptor/nitric oxide (NO) pathway of the DH in the modulation of autonomic (arterial BP, HR and tail skin temperature) responses evoked by RS in rats. Bilateral microinjection of the NMDA receptor antagonist AP-7 (10 nmol/500 nL) into the DH attenuated RS-evoked autonomic responses. Moreover, RS evoked an increase in the content of NO2/NO3 in the DH, which are products of the spontaneous oxidation of NO under physiological conditions that can provide an indirect measurement of NO production. Bilateral microinjection of N-propyl-L-arginine (0.1 nmol/500 nL; N-propyl, a neuronal NO synthase (nNOS) inhibitor) or carboxy-PTIO (2 nmol/500 nL; c-PTIO, an NO scavenger) into the DH also attenuated autonomic responses evoked by RS. Therefore, our findings suggest that a glutamatergic system present in the DH is involved in the autonomic modulation during RS, acting via NMDA receptors and nNOS activation. Furthermore, the present results suggest that NMDA receptor/nNO activation has a facilitatory influence on RS-evoked autonomic responses.

Asunto(s)

Hipocampo/fisiopatología , Óxido Nítrico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/fisiopatología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Presión Arterial/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Depuradores de Radicales Libres/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Nitratos/metabolismo , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/metabolismo , Nitritos/metabolismo , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Restricción Física , Transducción de Señal/efectos de los fármacos , Temperatura Cutánea/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Cola (estructura animal)

RESUMEN

Stimulation of cannabinoid CB1 receptors or inhibition of nitric oxide synthase (NOS) in the dorsolateral periaqueductal gray (dlPAG) decreases anxiety-like behavior. Moreover, activation of CB1 receptors attenuates flight responses induced by nitric oxide (NO) donors in the dlPAG, suggesting that endocannabinoids and NO could interact to control defensive responses such as anxiety-like behavior. To test this hypothesis male Wistar rats received intra-dlPAG microinjections of anandamide (AEA) or NO inhibitors and were tested in the elevated plus maze (EPM). Combined administration of low and ineffective doses of AEA and the NO scavenger (c-Ptio), the nNOS inhibitor (NPA) or the soluble guanylate cyclase inhibitor (ODQ) induced anxiolytic-like effects. The CB1 receptor antagonist AM251, but not the GABAA receptor antagonist bicuculline, attenuated the effect induced by AEA+c-Ptio combination. No effect, however, was found when anxiolytic doses of these same drugs were administered together. Combination of higher, ineffective doses of AEA and c-Ptio, NPA or ODQ was again anxiolytic. The effect of the former combination was prevented by low and ineffective doses of the GABAA receptor antagonist bicuculline or the GABA synthesis inhibitor L-allilglycine, suggesting that they depend on GABAA-mediated neurotransmission. AM251 was also able to attenuate this effect, indicating that in the presence of NO inhibition, the resultant anxiolytic-like effect could be due to AEA action on CB1 receptors. The present results suggest that the AEA and nitrergic systems exert a complex functional interaction in the dlPAG to modulate anxiety behavior, probably interfering, in addition to glutamate, also with GABAergic mechanisms.

Asunto(s)

Ansiedad/tratamiento farmacológico , Ácidos Araquidónicos/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Endocannabinoides/uso terapéutico , Óxido Nítrico Sintasa/metabolismo , Sustancia Gris Periacueductal/fisiología , Alcamidas Poliinsaturadas/uso terapéutico , Animales , Ansiedad/metabolismo , Apomorfina/análogos & derivados , Apomorfina/farmacología , Bicuculina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Oxadiazoles/farmacología , Sustancia Gris Periacueductal/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB1

RESUMEN

The medial amygdaloid nucleus (MeA) is a sub-region of the amygdaloid complex that has been described as participating in food intake regulation. Serotonin has been known to play an important role in appetite and food intake regulation. Moreover, serotonin 5-HT(2C) and 5-HT(1A) receptors appear to be critical in food intake regulation. We investigated the role of the serotoninergic system in the MeA on feeding behavior regulation in rats. The current study examined the effects on feeding behavior regulation of the serotonin reuptake inhibitor, zimelidine, administered directly into the MeA or given systemically, and the serotoninergic receptors mediating its effect. Our results showed that microinjection of zimelidine (0.2, 2 and 20 nmol/100 nL) into the MeA evoked dose dependent hypophagic effects in fasted rats. The selective 5-HT(1A) receptor antagonist WAY-100635 (18.5 nmol/100 nL) or the 5-HT(1B) receptor antagonist SB-216641 microinjected bilaterally into the MeA did not change the hypophagic effect evoked by local MeA zimelidine treatment. However, microinjection of the selective 5-HT(2C) receptor antagonist SB-242084 (10 nmol/100 nL) was able to block the hypophagic effect of zimelidine. Moreover, microinjection of the 5-HT(2C) receptor antagonist SB-242084 into the MeA also blocked the hypophagic effect caused by zimelidine administered systemically. These results suggest that MeA 5-HT(2C) receptors modulate the hypophagic effect caused by local MeA administration as well as by systemic zimelidine administration. Furthermore, 5-HT(2C) into the MeA could be a potential target for systemic administration of zimelidine.

Asunto(s)

Amígdala del Cerebelo/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Receptor de Serotonina 5-HT2C/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Zimeldina/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Masculino , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología

RESUMEN

Dynamic exercise evokes sustained blood pressure and heart rate (HR) increases. Although it is well accepted that there is a CNS mediation of cardiovascular adjustments during dynamic exercise, information on the role of specific CNS structures is still limited. The bed nucleus of the stria terminalis (BST) is involved in exercise-evoked cardiovascular responses in rats. However, the specific neurotransmitter involved in BST-related modulation of cardiovascular responses to dynamic exercise is still unclear. In the present study, we investigated the role of local BST adrenoceptors in the cardiovascular responses evoked when rats are submitted to an acute bout of exercise on a rodent treadmill. We observed that bilateral microinjection of the selective α1-adrenoceptor antagonist WB4101 into the BST enhanced the HR increase evoked by dynamic exercise without affecting the mean arterial pressure (MAP) increase. Bilateral microinjection of the selective α2-adrenoceptor antagonist RX821002 reduced exercise-evoked pressor response without changing the tachycardiac response. BST pretreatment with the nonselective ß-adrenoceptor antagonist propranolol did not affect exercise-related cardiovascular responses. BST treatment with either WB4101 or RX821002 did not affect motor performance in the open-field test, which indicates that effects of BST adrenoceptor antagonism in exercise-evoked cardiovascular responses were not due to changes in motor activity. The present findings are the first evidence showing the involvement of CNS adrenoceptors in cardiovascular responses during dynamic exercise. Our results indicate an inhibitory influence of BST α1-adrenoceptor on the exercise-evoked HR response. Data also point to a facilitatory role played by the activation of BST α2-adrenoceptor on the pressor response to dynamic exercise.

Asunto(s)

Tolerancia al Ejercicio/fisiología , Condicionamiento Físico Animal/fisiología , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Núcleos Septales/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Dioxanos/farmacología , Tolerancia al Ejercicio/efectos de los fármacos , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Ratas , Núcleos Septales/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología

RESUMEN

Reversible inactivation of the ventral portion of medial prefrontal cortex (vMPFC) of the rat brain has been shown to induce anxiolytic-like effects in animal models based on associative learning. The role of this brain region in situations involving innate fear, however, is still poorly understood, with several contradictory results in the literature. The objective of the present work was to verify in male Wistar rats the effects of vMPFC administration of cobalt chloride (CoCl(2)), a selective inhibitor of synaptic activity, in rats submitted to two models based on innate fear, the elevated plus-maze (EPM) and light-dark box (LDB), comparing the results with those obtained in two models involving associative learning, the contextual fear conditioning (CFC) and Vogel conflict (VCT) tests. The results showed that, whereas CoCl(2) induced anxiolytic-like effects in the CFC and VCT tests, it enhanced anxiety in rats submitted to the EPM and LDB. Together these results indicate that the vMPFC plays an important but complex role in the modulation of defensive-related behaviors, which seems to depend on the nature of the anxiety/fear inducing stimuli.

Asunto(s)

Trastornos de Ansiedad/fisiopatología , Aprendizaje por Asociación/fisiología , Miedo/fisiología , Corteza Prefrontal/fisiología , Animales , Trastornos de Ansiedad/inducido químicamente , Aprendizaje por Asociación/efectos de los fármacos , Cobalto/toxicidad , Masculino , Modelos Animales , Neurotoxinas/toxicidad , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología

RESUMEN

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 fármacos

RESUMEN

BACKGROUND AND PURPOSE: Control of food intake is a complex behaviour which involves many interconnected brain structures. The present work assessed if the noradrenergic system in the lateral septum (LS) was involved in the feeding behaviour of rats. EXPERIMENTAL APPROACH: In the first protocol, the food intake of rats was measured. Then non-food-deprived animals received either 100 nL of 21 nmol of noradrenaline or vehicle unilaterally in the LS 10 min after local 10 nmol of WB4101, an alpha(1)-adrenoceptor antagonist, or vehicle. In the second protocol, different doses of WB4101 (1, 10 or 20 nmol in 100 nL) were microinjected bilaterally into the LS of rats, deprived of food for 18 h and food intake was compared to that of satiated animals. KEY RESULTS: One-sided microinjection of noradrenaline into the LS of normal-fed rats evoked food intake, compared with vehicle-injected control animals, which was significantly reduced by alpha(1)-adrenoceptor antagonism. In a further investigation, food intake was significantly higher in food-deprived animals, compared to satiated controls. Pretreatment of the LS with WB4101 reduced food intake in only food-deprived animals in a dose-related manner, suggesting that the LS noradrenergic system was involved in the control of food intake. CONCLUSION AND IMPLICATIONS: Activation by local microinjection of noradrenaline of alpha(1)-adrenoceptors in the LS evoked food intake behaviour in rats. In addition, blockade of the LS alpha(1)-adrenoceptors inhibited food intake in food-deprived animals, suggesting that the LS noradrenergic system modulated food intake behaviour and satiation.

Asunto(s)

Ingestión de Alimentos , Conducta Alimentaria/fisiología , Receptores Adrenérgicos alfa 1/fisiología , Tabique del Cerebro/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacología , Animales , Dioxanos/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Privación de Alimentos/fisiología , Masculino , Microinyecciones , Norepinefrina/farmacología , Ratas , Ratas Wistar , Saciedad/fisiología , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/patología

RESUMEN

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 fármacos

RESUMEN

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 & inhibidores

RESUMEN

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 Paramétricas

RESUMEN

The bed nucleus of the stria terminalis (BST) is a limbic structure involved in regulating the hypothalamic-pituitary-adrenal axis as well as in central cardiovascular control. We report here on cardiovascular effects caused by microinjection of noradrenaline (NA) in the BST of the rat brain and the peripheral mechanisms involved in their mediation. Injection of NA (3, 7, 10, 15, 30, or 45 nmol in 100 nl) in the BST of unanesthetized rats caused long-lasting dose-related pressor and bradycardiac responses. No responses were observed when the dose of 10 nmol NA was microinjected into surrounding structures, such as the anterior commissure, the stria terminalis, the fornix, and the internal capsule, indicating a predominant action at the BST. Additionally, microinjection of 50 nmol tyramine, an indirectly acting sympathomimetic amine, caused similar pressor response, indicating local NA release in the BST. Responses to NA microinjection in the BST were markedly reduced in urethane-anesthetized rats, favoring the idea of a central action without significant leakage to the peripheral circulation. The pressor response was potentiated by i.v. pretreatment with the ganglion blocker pentolinium and blocked by i.v. pretreatment with the selective V(1)-vasopressin antagonist dTyr(CH(2))(5)(Me)AVP, suggesting its mediation by vasopressin release into circulation. The bradycardiac response to NA microinjected into the BST was also abolished by pretreatment with the vasopressin antagonist, indicating its reflex origin. In conclusion, results indicate that microinjection of NA into the BST evokes pressor responses, which are mediated by acute vasopressin release.

Asunto(s)

Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Norepinefrina/fisiología , Núcleos Septales/fisiología , Análisis de Varianza , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Microinyecciones , Norepinefrina/administración & dosificación , Ratas , Ratas Wistar , Núcleos Septales/efectos de los fármacos , Estadísticas no Paramétricas , Tiramina/administración & dosificación , Tiramina/fisiología

RESUMEN

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 Wistar