Hypothalamic endocannabinoid signalling modulates aversive responses related to panic attacks.

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB1 and CB2 antagonists (AM251 and AM630, respectively), and mimicked by CB1 and CB2 agonists (ACEA and JWH133, respectively). URB602 also prevented the cardiovascular effects of DMH-stimulation in anaesthetised animals. None of the treatments modified blood corticosterone levels. In conclusion, facilitation of 2-AG-signalling in the DMH modulates panic-like responses. The possible mechanisms comprise activation of both CB1 and CB2 receptors in this brain region.

Bed nucleus of the stria terminalis NMDA receptors and nitric oxide modulate contextual fear conditioning in rats.

The bed nucleus of the stria terminalis (BNST) modulates anxiety-like responses, including conditioned emotional responses. Evidence suggests that glutamatergic neurotransmission in the BNST plays a role in the modulation of defensive responses. However, little is known about the involvement of glutamate NMDA receptor activation within the BNST, and its resultant increase in nitric oxide (NO) levels, in the expression of contextual fear conditioning (CFC). We investigated whether the antagonism of NMDA receptors or the reduction of NO levels in the BNST would attenuate behavioral and autonomic responses (i.e. increase in arterial pressure and heart rate, and decrease in tail cutaneous temperature) of rats submitted to a CFC paradigm. Intra-BNST infusion of AP7, an NMDA receptor antagonist, attenuated both behavioral and autonomic changes induced by CFC. Similar results were observed with NPLA and c-PTIO, an nNOS inhibitor and an NO scavenger, respectively. A positive correlation between BNST NO levels and the time spent in freezing behavior was also observed for animals submitted to the CFC. These findings indicate that the expression of CFC involves a facilitation of BNST NMDA receptor-NO signaling. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

Aptidão física e nível habitual de atividade física associados à saúde cardiovascular em adultos e idosos / Physical fitness and habitual level of physical activity associated with cardiovascular health in adults and elderly

O nível habitual de atividade física (NHAF) vem sendo utilizado para estabelecer uma relação entre estilo de vida ativo e saúde cardiovascular. No entanto, a avaliação da aptidão física permitiria a avaliação real das condições físicas do indivíduo, podendo assim apresentar melhores relações com a saúde cardiovascular. Objetivos: Relacionar o NHAF e aptidão física com a saúde cardiovascular de adultos e idosos e verificar a associação da prática regular de exercícios físicos supervisionada com os diferentes níveis de aptidão física. Método: Foram avaliados 213 adultos e idosos (> 50 anos) participantes de projetos comunitários. Os participantes realizaram as seguintes avaliações: NHAF por meio do questionário IPAQ, aptidão física por meio de uma bateria de testes motores que permitiu o cálculo do Índice de Aptidão Funcional Geral (IAFG), pressão arterial, perfil lipídico e índice de massa corporal. Resultados: O modelo linear generalizado evidenciou um maior número de diferenças com relação às variáveis relacionadas à saúde cardiovascular quando os participantes foram subdivididos em grupos tendo o IAFG como variável independente, comparado ao NHAF. O teste exato de Fisher evidenciou que os grupos de IAFG classificados como “bom” e “muito bom” apresentaram maior proporção de indivíduos com prática regular de exercícios físicos superior a 6 meses, com destaque para um maior número realizando a prática com supervisão (p<0,0001). Conclusão: O IAFG apresenta melhor associação com a saúde cardiovascular do que o NHAF e o tempo de prática e a supervisão estão associados ao nível de aptidão física...

The habitual level of physical activity (HLPA) has been used to establish the relation between active lifestyle and cardiovascular health. However, the assessment of physical fitness would review the actual physical condition of the individual, and thus can have better relations with cardiovascular health. Objectives: Relate HLPA and physical fitness with cardiovascular health of adults and elderly and to verify the association of supervised regular physical exercise with different levels of fitness. Method: 213 adults and elderly (> 50 years) participating in community projects were evaluated. The HLPA were assessed by the IPAQ and physical fitness through a battery of motor tests that allowed the calculation of the General Functional Fitness Index (GFFI). Blood pressure, lipid profile and body mass index were considered as indicators of cardiovascular health. Results: The generalized linear model showed a greater number of differences with respect to variables related to cardiovascular health when participants were subdivided having GFFI as an independent variable, compared to HLPA. The Fisher exact test showed that the groups GFFI classified as “good” and “very good” showed a higher proportion of individuals with regular practice for more than 6 months exercise, especially for a larger number performing the practice under supervision (p <0.0001). Conclusion: The GFFI has better association with cardiovascular health than HLPA and time of practice and supervision are associated with the level of physical fitness...

Anti-aversive role of the endocannabinoid system in the periaqueductal gray stimulation model of panic attacks in rats.

RATIONALE: Direct activation of the cannabinoid CB1 receptor in the dorsolateral periaqueductal gray (dlPAG) inhibits anxiety- and panic-related behaviours in experimental animals. It has remained unclear, however, whether the local endocannabinoid signalling is recruited as a protective mechanism against aversive stimuli. OBJECTIVES: The present study tested the hypothesis that the endocannabinoid system counteracts aversive responses in the dlPAG-stimulation model of panic attacks. METHODS: All drugs were infused into the dlPAG of rats. Local chemical stimulation with N-methyl-D-aspartate (NMDA, 1 nmol) was employed to induce panic-like behavioural and cardiovascular responses in freely moving and anaesthetized animals, respectively. The neuronal activity in the dlPAG was investigated by c-Fos immunohistochemistry. RESULTS: The selective CB1 receptor agonist, ACEA (0.005-0.5 pmol), prevented the NMDA-induced panic-like escape responses. More interestingly, increasing the local levels of endogenous anandamide with a fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3-3 nmol), prevented both the behavioural response and the increase in blood pressure induced by NMDA. The effect of URB597 (3 nmol) was reversed by the CB1 receptor antagonist, AM251 (0.1 nmol). Moreover, an otherwise ineffective and sub-threshold dose of NMDA (0.5 nmol) was able to induce a panic-like response if local CB1 receptors were previously blocked by AM251 (0.1 nmol). Finally, URB597 prevented the NMDA-induced neuronal activation of the dlPAG. CONCLUSIONS: The endocannabinoid system in the dlPAG attenuates the behavioural, cellular and cardiovascular consequences of aversive stimuli. This process may be considered for the development of additional treatments against panic and other anxiety-related disorders.

The expression of contextual fear conditioning involves activation of a NMDA receptor-nitric oxide-cGMP pathway in the dorsal hippocampus of rats.

The dorsal portion of the hippocampus is a limbic structure that is involved in fear conditioning modulation in rats. Moreover, evidence shows that the local dorsal hippocampus glutamatergic system, nitric oxide (NO) and cGMP modulate behavioral responses during aversive situations. Therefore, the present study investigated the involvement of dorsal hippocampus NMDA receptors and the NO/cGMP pathway in contextual fear conditioning expression. Male Wistar rats were submitted to an aversive contextual conditioning session and 48 h later they were re-exposed to the aversive context in which freezing, cardiovascular responses (increase of both arterial pressure and heart rate) and decrease of tail temperature were recorded. The intra-dorsal hippocampus administration of the NMDA receptor antagonist AP7, prior to the re-exposure to the aversive context, attenuated fear-conditioned responses. The re-exposure to the context evoked an increase in NO concentration in the dorsal hippocampus of conditioned animals. Similar to AP7 administration, we observed a reduction of contextual fear conditioning after dorsal hippocampus administration of either the neuronal NO synthase inhibitor N-propyl-L-arginine, the NO scavenger c-PTIO or the guanylate cyclase inhibitor ODQ. Therefore, the present findings suggest the possible existence of a dorsal hippocampus NMDA/NO/cGMP pathway modulating the expression of contextual fear conditioning in rats.

D-cycloserine injected into the dorsolateral periaqueductal gray induces anxiolytic-like effects in rats.

D-cycloserine (DCS) is a partial agonist of the glycine site coupled to the NMDA receptor (NMDAR). As a consequence, depending on the doses used it can function as an agonist or antagonist at this site. In rodents, anxiolytic-like effects have been observed after the systemic administration of high doses of DCS. The brain sites of these effects have not been investigated. Direct brain injection of glycine site antagonists or agonists into the dorsolateral periaqueductal gray (dlPAG), a brain structure involved in the modulation of defensive-related behaviors, produces anxiolytic- or anxiogenic-like effects, respectively. The present study investigated if the dlPAG could be a brain site of the anxiolytic effects observed after DCS systemic administration. Male Wistar rats received intra-dlPAG injections of DCS (25, 50, 100 or 200 nmol) and were exposed to the elevated plus-maze (EPM) or to the light-dark box. DCS, at the dose of 200 nmol, increased open arm exploration and the time spent in the light compartment, respectively. Based on this result we tested the effects of intra-dlPAG DCS (200 nmol) administration in animals submitted to the Vogel conflict tests. Anxiolytic-like effect was also observed in this test indicated by the increase of punished responses. The drug did not change locomotor activity, discarding potential confounding factors. These results indicated that administration of DCS, a partial agonist of the NMDAR-associated glycine site, into the dlPAG induces anxiolytic-like effects in different models, pointing to a possible site of action of this compound.

The dorsolateral periaqueductal grey N-methyl-D-aspartate/nitric oxide/cyclic guanosine monophosphate pathway modulates the expression of contextual fear conditioning in rats.

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.

Both α1- and ß1-adrenoceptors in the bed nucleus of the stria terminalis are involved in the expression of conditioned contextual fear.

BACKGROUND AND PURPOSE: The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats. EXPERIMENTAL APPROACH: Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context. KEY RESULTS: L-propranolol, a non-selective ß-adrenoceptor antagonist, and phentolamine, a non-selective α-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with CGP20712, a selective ß(1) -adrenoceptor antagonist, and WB4101, a selective α(1) -antagonist, but not with ICI118,551, a selective ß(2) -adrenoceptor antagonist or RX821002, a selective α(2) -antagonist. CONCLUSIONS AND IMPLICATIONS: These findings support the idea that noradrenergic neurotransmission in the BNST via α(1) - and ß(1) -adrenoceptors is involved in the expression of conditioned contextual fear.