RESUMO
BACKGROUND: The dorsal hippocampus has a central role in modulating cardiovascular responses and behavioral adaptation to stress. The dorsal hippocampus also plays a key role in stress-associated mental disorders. The endocannabinoid system is widely expressed in the dorsal hippocampus and modulates defensive behaviors under stressful conditions. The endocannabinoid anandamide activates cannabinoid type 1 receptors and is metabolized by the fatty acid amide hydrolase enzyme. AIMS: We sought to verify whether cannabinoid type 1 receptors modulate stress-induced cardiovascular changes, and if pharmacological fatty acid amide hydrolase inhibition in the dorsal hippocampus would prevent the cardiovascular responses and the delayed anxiogenic-like behavior evoked by restraint stress in rats via cannabinoid type 1 receptors. METHODS: Independent groups received intra-dorsal-hippocampal injections of N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-hpyrazole-3-carboxamide (AM251; cannabinoid type 1 receptor antagonist/inverse agonist, 10-300 pmol) and/or cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597; fatty acid amide hydrolase inhibitor, 10 pmol) before the restraint stress session. Cardiovascular response during restraint stress or later behavioral parameters were evaluated. RESULTS: Acute restraint stress altered the cardiovascular response, characterized by increased heart rate and mean arterial pressure, as well as decreased tail cutaneous temperature. It also induced a delayed anxiogenic-like effect, evidenced by reduced open arm exploration in the elevated plus maze 24 h after stress. AM251 exacerbated the stress-induced cardiovascular responses after injection into the dorsal hippocampus. In contrast, local injection of URB597 prevented the cardiovascular response and the delayed (24 h) behavioral consequences of restraint stress, effects attenuated by pretreatment with AM251. CONCLUSION: Our data corroborate previous results indicating that the hippocampal endocannabinoid system modulates the outcome of stress exposure and suggest that this could involve modulation of the cardiovascular response during stress exposure.
Assuntos
Ansiedade , Pressão Arterial/fisiologia , Comportamento Animal/fisiologia , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/fisiologia , Frequência Cardíaca/fisiologia , Hipocampo/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Estresse Psicológico , Amidoidrolases/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/etiologia , Ansiedade/metabolismo , Ácidos Araquidônicos/farmacologia , Pressão Arterial/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Agonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/administração & dosagem , Carbamatos/farmacologia , Modelos Animais de Doenças , Endocanabinoides/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Restrição Física/efeitos adversos , Temperatura Cutânea/efeitos dos fármacos , Temperatura Cutânea/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
The dorsolateral periaqueductal grey (dlPAG) plays an essential role in unconditioned fear responses and could also be involved in the expression of contextual fear responses. Activation of glutamate N-methyl-D-aspartate (NMDA) receptors and the nitric oxide (NO) pathway in this region facilitates anxiety-like responses. In the present study we investigated if antagonism of NMDA receptors or inhibition of the NO pathway in the dlPAG would attenuate behavioral and cardiovascular responses of rats submitted to a contextual fear-conditioning paradigm. Male Wistar rats with unilateral cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Ten min before the test the animals received an intra-dlPAG injection of vehicle, AP7 (NMDA receptor antagonist), N-propyl-L-arginine (neuronal NO synthase inhibitor), carboxy-PTIO (NO scavenger) or 1H-[1,2,4] oxadiazolol [4,3-a]quinoxalin-1-one (ODQ) (guanylate cyclase inhibitor). Freezing and cardiovascular responses were recorded continuously for 10 min. Intra-dlPAG administration of AP7 before re-exposure to the aversively conditioned context attenuated these responses. Similar effects were observed after the NO synthase inhibitor, NO scavenger or guanylate cyclase inhibitor. Our findings suggest that activity of dlPAG NMDA/NO/cyclic guanosine monophosphate (cGMP) pathway facilitates the expression of contextual fear responses.
Assuntos
Condicionamento Psicológico/fisiologia , GMP Cíclico/metabolismo , Medo/fisiologia , N-Metilaspartato/metabolismo , Óxido Nítrico/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Transdução de Sinais/fisiologia , Animais , Coração/fisiopatologia , Masculino , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
The bed nucleus of the stria terminalis (BNST) is a heterogeneous and complex limbic forebrain structure, which plays an important role in controlling autonomic, neuroendocrine and behavioral responses. The BNST is thought to serve as a key relay connecting limbic forebrain structures to hypothalamic and brainstem regions associated with autonomic and neuroendocrine functions. Its control of physiological and behavioral activity is mediated by local action of numerous neurotransmitters. In the present review we discuss the role of the BNST in control of both autonomic and neuroendocrine function. A description of BNST control of cardiovascular and hypothalamus-pituitary-adrenal axisactivity at rest and during physiological challenges (stress and physical exercise) is presented. Moreover, evidence for modulation of hypothalamic magnocellular neurons activity is also discussed. We attempt to focus on the discussion of BNST neurochemical mechanisms. Therefore, the source and targets of neurochemical inputs to BNST subregions and their role in control of autonomic and neuroendocrine function is discussed in details.
RESUMO
BACKGROUND: Several studies had demonstrated the involvement of the dorsolateral portion of periaqueductal grey matter (dlPAG) in defensive responses. This region contains a significant number of neurons containing the enzyme nitric oxide synthase (NOS) and previous studies showed that non-selective NOS inhibition or glutamate NMDA-receptor antagonism in the dlPAG caused anxiolytic-like effects in the elevated plus maze. METHODS: In the present study we verified if the NMDA/NO pathway in the dlPAG would also involve in the behavioral suppression observed in rats submitted to the Vogel conflict test. In addition, the involvement of this pathway was investigated by using a selective nNOS inhibitor, Nomega-propyl-L-arginine (N-Propyl, 0.08 nmol/200 nL), a NO scavenger, carboxy-PTIO (c-PTIO, 2 nmol/200 nL) and a specific NMDA receptor antagonist, LY235959 (4 nmol/200 nL). RESULTS: Intra-dlPAG microinjection of these drugs increased the number of punished licks without changing the number of unpunished licks or nociceptive threshold, as measure by the tail flick test. CONCLUSION: The results indicate that activation of NMDA receptors and increased production of NO in the dlPAG are involved in the anxiety behavior displayed by rats in the VCT.