The brain noradrenergic system has been implicated in the expression of defensive behaviors elicited by acute stress. The dorsal periaqueductal gray area (dPAG) is a key structure involved in the behavioral and cardiovascular responses elicited by fear and anxiety situations. Although there are noradrenergic terminals in the dPAG, few studies have investigated the role of noradrenaline (NA) in the dPAG on anxiety modulation. The aim of this study was to evaluate the effect of NA microinjection into the dPAG of rats subjected to two animal models of anxiety, the elevated plus-maze and the Vogel conflict test. Male Wistar rats implanted with a guide cannula aimed at the dPAG received microinjections of NA (3, 15, or 45 nmol/0.05 microl) or artificial cerebral spinal fluid into the dPAG immediately before being exposed to the elevated plus-maze or the Vogel conflict test. NA increased the exploration of the open arms and the number of enclosed arm entries in the elevated plus-maze. The increase in open arm exploration remained significant after being subjected to an analysis of covariance using the latter variable as covariate. Moreover, the NA microinjection into the dPAG did not increase general exploratory activity of animals subjected to the open-field test, indicating that the increase in open arm exploration cannot be attributed to a nonspecific increase in exploratory activity. In the Vogel test, the NA microinjection into the dPAG increased the number of punished licks without changing the number of nonpunished licks or interfering with the tail-flick test. The results, therefore, indicate that the NA microinjection into the dPAG produces anxiolytic-like effects, suggesting its possible involvement in the anxiety modulation.
The medial amydaloid nucleus (MeA) modulates several physiological and behavioral processes, including autonomic changes during aversive situations. The restraint stress (RS) causes significant increase in neuronal activity of the MeA when compared to other amygdaloid nuclei. In addition, the opioid system participates of the mediating cardiovascular responses, including those associated with aversive situations. Based on the facts mentioned above, the hypothesis of this study is that the MeA opioid neurotransmission is involved in the modulation of cardiovascular and endocrine responses evoked by RS. Male Wistar rats (240‐280g) were used. Guide cannulae were implanted bilaterally in the MeA for drug injection and a polyethylene catheter was implanted in the femoral artery for mean arterial pressure (MAP) and heart rate (HR) record. 10 minutes before microinjection of drugs or vehicle into the MeA, rats were subjected to RS. EDTA plasma were used to measured the corticosterone level by ELISA.Increasing doses of the naloxone into the MeA, at dose‐dependent manner, potentiated the increase of MAP (r2=0.2096, df=18, P<0.05) and tachycardia (r2=0.1704, df=18, P<0.05) and the decrease of tail temperature (r2=0.2462, df=18, P<0.05) caused by RS. Also, MeA treatment with naloxone potentiated the increase in corticosterone levels (F4,22= 3.49; P=0.24) at 0.03 and 3nmol/100nL of opioid antagonist. In conclusion, opioid neurotransmission mediates the MeA inhibitory influence on restraint‐evoked cardiovascular and endocrine changes. Financial Support: FAPESP, CAPES and FAEPA.
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) has properties that go beyond its antidepressant effects and alters mechanisms involved in the regulation of vasomotor tone. While there are many studies demonstrating the acute effects of fluoxetine in the vasculature, studies on the chronic effects of this SSRI are still limited. Here we postulated that chronic treatment with fluoxetine enhances vascular reactivity to vasodilator stimuli by increasing nitric oxide (NO) signaling. The effects of chronic treatment with fluoxetine on vascular reactivity were determined in resistance mesenteric arteries from Wistar rats, which were treated with (I) vehicle (water for 21 days) or (II) fluoxetine (10 mg/kg/day for 21 days in the drinking water). Fluoxetine treatment increased endothelium-dependent (pEC50, Veh = -7.08±0.07; Fluox = -7.4±0.11, p<0.05) and -independent relaxant response (pEC50, Veh = -7.75±0.08; Fluox = -8.5 ± 0.11, p<0.05). Fluoxetine also increased vascular NOx (NO metabolites) levels (Veh = 1.2±0.13 μM/μg; Fluox = 2.0 ± 0.13 μM/μg, p <0.05), nitric oxide sintase (NOS) activity (Fluox = 76%) and phosphorylation of endothelial NOS (eNOS) at serine1177 [arbitrary units (a.u.), Veh = 0.36±0.10; Fluox = 1.2 ± 0.08, p <0.05]. Fluoxetine treatment did not change neuronal NOS (nNOS) or soluble guanylate cyclase (sGC) expression neither vascular responses to cyclic guanosine monophosphate (cGMP) or sGC activators. However, pinacidil- (KATP channels activator)-induced relaxation was increased by fluoxetine treatment (pEC50, Veh = -5.9±0.12; Fluox = -6.5±0.17, p>0.05). In conclusion, chronic treatment with fluoxetine increases endothelium-dependent and -independent relaxation response in resistance mesenteric arteries by mechanisms that involve increased NOS activity, NO generation and KATP channels activation. These effects may contribute to the cardiovascular side effects associated with fluoxetine treatment.
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