Angiotensin-(1-7) Ang-(1-7), a counter-regulatory peptide of the renin-angiotensin system (RAS) exerts its effects through the G-protein-coupled receptor Mas, which is expressed in different tissues, ...including the brain. Ang-(1-7) has a broad range of effects beyond the well-described cardiovascular and renal actions, including the modulation of emotional and behavioural responses. In the present study we tested the hypothesis that Ang-(1-7) could attenuate the anxiety- and depression-like behaviours observed in transgenic hypertensive (mRen2)27 rats (TGRs). We also hypothesized that Ang-(1-7) could be involved in the anxiolytic-like effect induced by ACE (angiotensin-converting enzyme) treatment in these hypertensive rats. Therefore, TGRs and Sprague-Dawley rats were subjected to the Elevated Plus Maze (EPM) test, Forced Swimming Test (FST) and Novelty Suppressed Feeding (NSF). TGRs presented a decreased percentage of entries in the open arms of the EPM test, a phenotype reversed by systemic treatment with enalapril or intracerebroventricular infusion of Ang-(1-7). It is interesting that pre-treatment with A779, a selective Mas receptor antagonist, prevented the anxiolytic-like effect induced by the ACE inhibitor. In the NSF test, TGRs showed increased latency to eating, an indicative of a higher aversion in response to a new environment. These animals also showed increased immobility in the FST. Again, Ang-(1-7) reversed this phenotype. Thus, our data showed that Ang-(1-7) can modulate anxiety- and depression-like behaviours in TGRs and warrant further investigation as a new therapy for certain psychiatric disorders.
•Reduced anxiety-like behavior in transgenic rats with increased circulating Ang-(1–7).•PD123319 did not modify behavior in transgenic rats.•A779 reversed the reduced anxiety-like behavior in ...transgenic rats.•Activation of the Mas receptor exerts an anxiolytic-like effect.
Angiotensin-(1–7) Ang-(1–7), a counterregulatory peptide of the renin-angiotensin system (RAS), exerts its cardiovascular and renal functions through the G-protein-coupled receptor Mas. More recently, Ang-(1–7) has also been implicated in the control of emotional states related to fear and anxiety. Here, we tested the hypothesis that transgenic rats overexpressesing Ang-(1–7) (TGR) show reduced anxiety-like behavior in two distinct animals models, the Elevated Plus Maze (EPM) and Vogel Conflict Test (VCT). Sprague-Dawley rats (SDs) were used as controls. In addition, we also verified whether this phenotype depend on activation of the Mas receptor. In line with our hypothesis, TGR rats showed an increase in the percentage of time and entries in the open arms of the EPM. There was also an increase in the number of punished licks in VCT. These phenotypes were reversed by ICV injection of the Mas receptor antagonist, A779, but not by the AT2 and MrgD receptor antagonist, PD123319. These results suggest that chronic elevation of Ang-(1–7) levels results in a phenotype characterized by reduced anxiety-like behavior, possibly due to higher activation of the Mas receptor. Therefore, facilitation of the Ang-(1–7)/Mas receptor signaling may be further investigated as an additional strategy for the treatment of anxiety-related disorders.
One of the main goals in flux-cored arc welding processes is the optimization of bead geometry, in which multiple geometric characteristics of the welding bead are important; therefore, ...multiobjective optimization programming is often applied. However, several optimization problems that use stochastic programming do not consider the impact of the correlation between the output variables on their probabilistic constraints. In this context, this paper aims to present a multiobjective optimization method based on multivariate stochastic programming. To demonstrate the applicability of the proposal, we conducted a design of experiments to optimize a flux-cored arc welding process for stainless-steel claddings. The weighting-sums method was applied to formulate the multiobjective optimization problem. It was possible to formulate a multivariate probability distribution for the penetration and dilution. In addition, a 95% probability to meet the predefined specification limits of the geometric characteristics was achieved.
Bckground
Aripiprazole is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Recently, its peripheral analgesic component was evaluated, however, the mechanism involved in this ...effect is not fully established. Therefore, the aim of the study was to obtain pharmacological evidence for the involvement of the nitric oxide system in the peripheral antinociceptive effect induced by aripiprazole.
Methods
The hyperalgesia was induced via intraplantar injection of prostaglandin E2 in mice and the nociceptive thresholds were evaluated using the paw pressure test. All drugs were injected locally into the right hind paw.
Results
The PI3K inhibitor (AS605240), but not rapamycin (mTOR kinase inhibitor), reversed the peripheral antinociceptive effect induced by Aripiprazole. Antinociception was antagonized by the non‐selective inhibitor of the nitric oxide synthase (L‐NOarg). The same response was observed using the selective iNOS, but not with the selective nNOS inhibitors. The selective guanylyl cyclase enzyme inhibitor (ODQ) and the non‐selective potassium channel blocker tetraethylammonium were able to reverse the antinociceptive effect of aripiprazole. The same was seen using glibenclamide, an ATP‐dependent K+ channel blocker. However, calcium‐activated potassium channel blockers of small and high conductance, dequalinium chloride and paxilline, respectively, did not reverse this effect. The injection of cGMP‐specific phosphodiesterase type 5 inhibitor zaprinast, potentiated the antinociceptive effect induced by a low dose of aripiprazole.
Conclusion
The results provide evidence that aripiprazole induces peripheral antinociceptive effects via PI3K/NO/cGMP/KATP pathway activation.
When 5-lipoxygenase (5-LO) is inhibited, roughly half of the CNS effect of the prototypic endocannabinoid anandamide (AEA) is lost. Therefore, we decided to investigate whether inhibiting this enzyme ...would influence physiological functions classically described as being under control of the endocannabinoid system. Although 5-LO inhibition by MK-886 reduced lipoxin A4 levels in the brain, no effect was found in the elevated plus maze (EPM), even at the highest possible doses, via i.p. (10 mg/kg,) or i.c.v. (500 pmol/2 µl) routes. Accordingly, no alterations in anxiety-like behavior in the EPM test were observed in 5-LO KO mice. Interestingly, aged mice, which show reduced circulating lipoxin A4 levels, were sensitive to MK-886, displaying an anxiogenic-like state in response to treatment. Moreover, exogenous lipoxin A4 induced an anxiolytic-like profile in the EPM test. Our findings are in line with other reports showing no difference between FLAP KO or 5-LO KO and their control strains in adult mice, but increased anxiety-like behavior in aged mice. We also show for the first time that lipoxin A4 affects mouse behavior. In conclusion, we propose an age-dependent relevancy of endogenous 5-LO derivatives in the modulation of anxiety-like behavior, in addition to a potential for exogenous lipoxin A4 in producing an anxiolytic-like state.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:Recently, we demonstrated that the antipsychotic dopaminergic and serotoninergic agonist aripiprazole induced peripheral antinociception. However, the mechanism underlying this effect has ...not been fully established. Here, our aim was to identify possible relationships between this action of aripiprazole and the endocannabinoid system.
METHODS:All drugs were given locally into the right hind paw of male Swiss mice weighing 30–35 g in a volume of 20 µL. The hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 μg). Aripiprazole was injected 10 minutes before the measurement, and an irreversible inhibitor of anandamide hydrolase (MAFP), an inhibitor for monoacylglycerol lipase (JZL184), and an anandamide reuptake inhibitor (VDM11) were given 10 minutes before the aripiprazole. Nociceptive thresholds were measured using an algesimetric apparatus in the third hour after prostaglandin E2 injection. Data were analyzed by ANOVA and Bonferroni tests.
RESULTS:The antinociceptive effect induced by aripiprazole (100 μg) was blocked by cannabinoid 1 or 2 receptor antagonists AM251 (40 μg P < .01, 80 μg P < .0001, and 160 μg P < .0001) and AM630 (100 μg P < .0001, 200 μg P < .0001, and 400 μg P < .0001), respectively. The peripheral antinociception induced by aripiprazole (25 μg) was enhanced by administration of the inhibitor of fatty acid amide hydrolase (MAFP, 0.5 μg P < .0001) or monoacylglycerol lipase (JZL184, 4 μg P < .0001). Moreover, a similar enhancement was observed with the anandamide reuptake inhibitor (VDM11, 2.5 μg P < .0001).
CONCLUSIONS:These results provide evidence for the involvement of the endocannabinoid system in peripheral antinociception induced by aripiprazole treatment.
Aripiprazole is an antipsychotic that acts by multiple mechanisms, including partial agonism at dopamine D2 and serotonin 5-HT1A receptors. Since these neurotransmitters also modulate pain and ...analgesia, we tested the hypothesis that systemic or local administration of aripiprazole induces antinociceptive responses. Systemic aripiprazole (0.1–10mg/kg; i.p.) injection in mice inhibited formalin-induced paw licking and PGE2-induced hyperalgesia in the paw pressure test. This effect was mimicked by intra-plantar administration (12.5–100µg/paw) in the ipsi, but not contralateral, paw. The peripheral action of aripiprazole (100µg/paw) was reversed by haloperidol (0.1–10µg/paw), suggesting the activation of dopamine receptors as a possible mechanism. Accordingly, quinpirole (25–100µg/paw), a full agonist at D2/D3 receptors, also reduced nociceptive responses.. In line with the partial agoniztic activity of aripiprazole, low dose of this compound inhibited the effect of quinpirole (both at 25µg/paw). Finally, peripheral administration of NAN-190 (0.1–10μg/paw), a 5-HT1A antagonist, also prevented aripiprazole-induced antinociception. In conclusion, systemic or local administration of aripiprazole induces antinociceptive effects. Similar to its antipsychotic activity, the possible peripheral mechanism involves dopamine D2 and serotoninergic 5-HT1A receptors. Aripiprazole and other dopaminergic modulators should be further investigated as new treatments for certain types of pain.
2-Arachidonoylglycerol and anandamide are the main endocannabinoids, which act through cannabinoid type-1 and type-2 receptors. Among its many functions, anandamide modulates anxiety-like behaviors ...in the ventromedial prefrontal cortex. The role of 2-arachidonoylglycerol in this region, however, has remained unclear. Here, we verified whether intra- ventromedial prefrontal cortex injection of 2-arachidonoylglycerol or URB602, a monoacylglycerol lipase inhibitor (responsible for 2-arachidonoylglycerol hydrolysis), induce anxiolytic-like effects in Wistar rats. Since activation of metabotropic glutamate receptor type 5 promotes diacylglycerol lipase-α-mediated 2-arachidonoylglycerol synthesis, we also verified if the blockade of this receptor impairs the anxiolytic-like effect induced by URB 602. 2-Arachidonoylglycerol reduced anxiety-like response in rats exposed to the Elevated Plus Maze test, an effect mimicked by URB602. Cannabinoid type-1 and type-2 receptor antagonists prevented these effects. The pre-treatment with an ineffective dose of MPEP, a metabotropic glutamate receptor type 5 antagonist, also attenuated the anxiolytic-like effect of URB602. Moreover, immunofluorescence microscopy revealed co-expression of metabotropic glutamate receptor type 5 and diacylglycerol lipase-α in several neurons in slices from the ventromedial prefrontal cortex. Altogether, our results implicate 2-arachidonoylglycerol and both cannabinoid receptors on anxiety-related behaviors mediated by ventromedial prefrontal cortex. Further, these data support a role for the coupling between metabotropic glutamate receptor type 5 activation and 2-arachidonoylglycerol signalling as a mechanism modulating aversive responses.
For many persons worldwide, mental health is inseparably linked with spirituality and religion (S&R), yet psychiatrists have repeatedly expressed doubts regarding their preparedness to address ...patients' spirituality or religion appropriately. In recent decades, medical educators have developed and implemented curricula for teaching S&R-related competencies to psychiatry residents. The authors reviewed the literature to understand the scope and effectiveness of these educational initiatives.
The authors searched 8 databases to identify studies for a scoping review and a systematic review. The scoping review explored educational approaches (topics, methods) used in psychiatry residency programs to teach S&R-related competencies. The systematic review examined changes in psychiatry trainees' competencies and/or in patient outcomes following exposure to these educational interventions.
Twelve studies met criteria for inclusion in the scoping review. All reported providing residents with both (1) a general overview of the intersections between mental health and S&R and (2) training in relevant interviewing and assessment skills. Seven of these studies-representing an estimated 218 postgraduate psychiatry trainees and at least 84 patients-were included in the systematic review. Residents generally rated themselves as being more competent in addressing patients' S&R-related concerns following the trainings. One randomized controlled trial found that patients with severe mental illness who were treated by residents trained in S&R-related competencies attended more appointments than control patients.
S&R-related educational interventions appeared generally well tolerated and appreciated by psychiatry trainees and their patients; however, some topics (e.g., Alcoholics Anonymous) received infrequent emphasis, and some experiential teaching methodologies (e.g., attending chaplaincy rounds) were less frequently used for psychiatry residents than for medical students. The positive association between teaching S&R-related competencies to psychiatry residents and patient appointment attendance merits further study. Future trainings should supplement classroom learning with experiential approaches and incorporate objective measures of resident competence.
The basolateral amygdala (BLA) is critical in the control of the sympathetic output during stress. Studies demonstrated the involvement of the renin-angiotensin system components in the BLA. ...Angiotensin-(1–7) Ang-(1–7), acting through Mas receptors, reduces stress effects. Considering that angiotensin-converting enzyme 2 (ACE2) is the principal enzyme for the production of Ang-(1–7), here we evaluate the cardiovascular reactivity to acute stress after administration of the ACE2 activator, diminazene aceturate (DIZE) into the BLA. We also tested whether systemic treatment with DIZE could modify synaptic activity in the BLA and its effect directly on the expression of the N-methyl-d-aspartate receptors (NMDARs) in NG108 neurons in-vitro. Administration of DIZE into the BLA (200 pmol/100 nL) attenuated the tachycardia to stress (ΔHR, bpm: vehicle = 103 ± 17 vs DIZE = 49 ± 7 p = 0.018); this effect was inhibited by Ang-(1–7) antagonist, A-779 (ΔHR, bpm: DIZE = 49 ± 7 vs A-779 + DIZE = 100 ± 15 p = 0.04). Systemic treatment with DIZE attenuated the excitatory synaptic activity in the BLA (Frequency (Hz): vehicle = 2.9 ± 0.4 vs. DIZE =1.8 ± 0.3 p < 0.04). NG108 cells treated with DIZE demonstrated decreased expression of l subunit NMDAR-NR1 (NR1 expression (a.u): control = 0.534 ± 0.0593 vs. DIZE = 0.254 ± 0.0260) of NMDAR and increases of Mas receptors expression. These data demonstrate that DIZE attenuates the tachycardia evoked by acute stress. This effect results from a central action in the BLA involving activation of Mas receptors. The ACE2 activation via DIZE treatment attenuated the frequency of excitatory synaptic activity in the basolateral amygdala and this effect can be related with the decreases of the NMDAR-NR1 receptor expression.
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