Bed nucleus of the stria terminalis CB1 receptors and the FAAH enzyme modulate anxiety behavior depending on previous stress exposure.

The endocannabinoid (eCB) anandamide (AEA) is synthesized on-demand in the post-synaptic terminal and can act on presynaptic cannabinoid type 1 (CB1) receptors, decreasing the release of neurotransmitters, including glutamate. AEA action is ended through enzymatic hydrolysis via FAAH (fatty acid amid hydrolase) in the post-synaptic neuron. eCB system molecules are widely expressed in brain areas involved in the modulation of fear and anxiety responses, including the Bed Nucleus of the Stria Terminalis (BNST), which is involved in the integration of autonomic, neuroendocrine, and behavioral regulation. The presence of the CB1 and FAAH was described in the BNST; however, their role in the modulation of defensive reactions is not fully comprehended. In the present work we aimed at investigating the role of AEA and CB1 receptors in the BNST in modulating anxiety-related behaviors. Adult male Wistar rats received local BNST injections of the CB1 receptor antagonist AM251 (0.1-0.6 nmol) and/or the FAAH inhibitor (URB597; 0.001-0.1 nmol) and were evaluated in the elevated plus maze (EPM) test, with or without previous acute restraint stress (2 h) exposure, or in the contextual fear conditioning. We observed that although AM251 and URB597 had no effects on the EPM, they increased and decreased, respectively, the conditioned fear response. Supporting a possible influence of stress in these differences, URB597 was able to prevent the restraint stress-induced anxiogenic effect in the EPM. The present data, therefore, suggest that eCB signaling in the BNST is recruited during more aversive situations to counteract the stress effect.

Carotid dysfunction in senescent female mice is mediated by increased α1A-adrenoceptor activity and COX-derived vasoconstrictor prostanoids.

α-Adrenergic receptors are crucial regulators of vascular hemodynamics and essential pharmacological targets for cardiovascular diseases. With aging, there is an increase in sympathetic activation, which could contribute to the progression of aging-associated cardiovascular dysfunction, including stroke. Nevertheless, there is little information directly associating adrenergic receptor dysfunction in the blood vessels of aged females. This study determined the role of a-adrenergic receptors in carotid dysfunction of senescent female mice (accelerated-senescence prone, SAMP8), compared with a nonsenescent (accelerated-senescence prone, SAMR1). Vasoconstriction to phenylephrine (Phe) was markedly increased in common carotid artery of SAMP8 [area under the curve (AUC), 527 ± 53] compared with SAMR1 (AUC, 334 ± 30, P = 0.006). There were no changes in vascular responses to the vasoconstrictor agent U46619 or the vasodilators acetylcholine (ACh) and sodium nitroprusside (NPS). Hyperactivity to Phe in female SAMP8 was reduced by cyclooxygenase-1 and cyclooxygenase-2 inhibition and associated with augmented ratio of TXA2/PGI2 release (SAMR1, 1.1 ± 0.1 vs. SAMP8, 2.1 ± 0.3, P = 0.007). However, no changes in cyclooxygenase expression were seen in SAMP8 carotids. Selective α1A-receptor antagonism markedly reduced maximal contraction, whereas α1D antagonism induced a minor shift in Phe contraction in SAMP8 carotids. Ligand binding analysis revealed a threefold increase of α-adrenergic receptor density in smooth muscle cells (VSMCs) of SAMP8 vs. SAMR1. Phe rapidly increased intracellular calcium (Cai2+) in VSMCs via the α1A-receptor, with a higher peak in VSMCs from SAMP8. In conclusion, senescence intensifies vasoconstriction mediated by α1A-adrenergic signaling in the carotid of female mice by mechanisms involving increased Cai2+ and release of cyclooxygenase-derived prostanoids.NEW & NOTEWORTHY The present study provides evidence that senescence induces hyperreactivity of α1-adrenoceptor-mediated contraction of the common carotid. Impairment of α1-adrenoceptor responses is linked to increased Ca2+ influx and release of COX-derived vasoconstrictor prostanoids, contributing to carotid dysfunction in the murine model of female senescence (SAMP8). Increased reactivity of the common carotid artery during senescence may lead to morphological and functional changes in arteries of the cerebral microcirculation and contribute to cognitive decline in females. Because the elderly population is growing, elucidating the mechanisms of aging- and sex-associated vascular dysfunction is critical to better direct pharmacological and lifestyle interventions to prevent cardiovascular risk in both sexes.

Intermittent exposure to chlorpyrifos results in cardiac hypertrophy and oxidative stress in rats.

Forbidden in some countries due to its proven toxicity to humans, chlorpyrifos (CPF) still stands as an organophosphate pesticide (OP) highly used worldwide. Cardiotoxicity assessment is an unmet need in pesticide regulation and should be deeply studied through different approaches to better inform and generate an appropriate regulatory response to OP use. In the present study, we used our 4-week intermittent OP exposure model in rats to address the CPF effects on cardiac morphology allied with cardiovascular functional and biomolecular evaluation. Rats were intermittently treated with CPF at doses of 7 mg/kg and 10 mg/kg or saline (i.p.) and assessed for cardiac morphology (cardiomyocyte diameter and collagen content), cardiopulmonary Bezold-Jarisch reflex (BJR) function, cardiac autonomic tone, left ventricle (LV) contractility, cardiac expression of NADPH oxidase (Nox2), catalase (CAT), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2) and cardiac levels of advanced oxidation protein products (AOPP) and thiobarbituric acid reactive substances (TBARS). Plasma butyrylcholinesterase (BuChE) and brainstem acetylcholinesterase (AChE) were also measured. Intermittent exposure to CPF induced cardiac hypertrophy, increasing cardiomyocyte diameter and collagen content. An impairment of cardioinhibitory BJR responses and an increase in cardiac vagal tone were also observed in CPF-treated animals without changes in LV contractility. CPF exposure increased cardiac Nox-2, CAT, SOD1, and TBARS levels and inhibited plasma BuChE and brainstem AChE activities. Our data showed that intermittent exposure to CPF induces cardiac hypertrophy together with cardiovascular reflex impairment, imbalance of autonomic tone and oxidative stress, which may bring significant cardiovascular risk to individuals exposed to OP compounds seasonally.