Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex

RATIONALE: The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied. OBJECTIVE: The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex. METHODS: The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique. RESULTS: Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines. CONCLUSION: Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.     

Differential regulation of nicotinic receptor-mediated neurotransmitter release following chronic (-)-nicotine administration

The objective of this study was to compare nAChR-mediated neurotransmitter release from slices of rat striatum, frontal cortex and hippocampus following chronic (-)-nicotine (Nic) administration (tartrate salt, 2 mg/kg twice daily for 10 days). Binding studies were also conducted to measure changes in receptor density. Relative to saline-treated animals, the number of nAChRs measured by [(3)H]-cytisine (CYT) binding was significantly increased in all brain regions examined by 15% to 25% following chronic Nic administration. Using a relatively high throughput method to measure neurotransmitter release, we found that Nic, CYT, and (+/-)-epibatidine (EB) evoked similar concentration-dependent striatal [(3)H]-dopamine (DA) and hippocampal [(3)H]-norepinephrine (NE) release from both saline (rank order of potency for [(3)H]-DA: EB>CYT>Nic; pEC(50) values, EB (9 +/- 0.1), CYT (8 +/- 0.13), Nic (7.3 +/- 0.19); rank order potency for [(3)H]-NE: EB>Nic=CYT; pEC(50) values, EB (8 +/- 0.18), Nic (5.5 +/- 0.09), CYT (5.12 +/- 0.1)) -and Nic-treated animals (pEC(50) values [(3)H]-DA, EB (9.5 +/- 0.15), Nic (8 +/- 0.16, CYT (6.6 +/- 0.52); [(3)H]-NE, EB (8.4 +/- 0.23), Nic (5.19 +/- 0.1), CYT (5.18 +/- 0.29)). Although no change in potency was detected between the two treatment groups, the agonist efficacies in both tissues were significantly reduced by approximately 17-54% following chronic Nic administration. In contrast to striatum, treatment with Nic did not affect the maximal [(3)H]-DA response (efficacy) in the frontal cortex. However, as observed in the striatum, no change in agonist potency was observed in the frontal cortex following chronic Nic administration (pEC(50) values, saline; EB (9.2 +/- 0.2), >CYT (6.95 +/- 0.75) = Nic (6.9 +/- 0.16); Nic-treated, EB (9 +/- 0.42)>CYT (6.88 +/- 0.27) = Nic (7.1 +/- 0.17)). Chronic Nic treatment did not significantly affect KCl-evoked [(3)H]-NE release from hippocampus or [(3)H]-DA release from frontal cortex or striatum. Since previous work has demonstrated that different nAChR subtypes display various sensitivities to chronic Nic exposure, we suggest that the subtypes of nAChRs involved in regulating [(3)H]-DA release may be different in the striatum and frontal cortex. These results support findings from earlier studies comparing the pharmacology of nAChR-evoked striatal versus cortical [(3)H]-DA release.     

Cyclooxygenase inhibitors attenuate endothelin ET(B) receptor-mediated contraction in human temporal artery

Phendimetrazine is an effective and widely prescribed appetite suppressant. Preclinical findings show that phendimetrazine displays stimulant properties similar to amphetamine, but few studies have examined the neurochemical mechanism of the drug. In the present work, we characterize the activity of phendimetrazine and its putative metabolites [phenmetrazine, pseudophenmetrazine, and associated stereoisomers] at biogenic amine transporters. All drugs were tested in vitro using assays to measure uptake and release of [3H]dopamine, [3H]norepinephrine, and [3H]serotonin ([3H]5-HT) in rat brain synaptosomes. Selected drugs were tested in vivo using microdialysis to measure extracellular dopamine and serotonin (5-HT) in rat nucleus accumbens. Phendimetrazine itself had no effect on uptake or release of any transmitter. In contrast, the trans-configured N-demethylated metabolite, phenmetrazine, was a potent releaser of [3H]norepinephrine (EC(50)=50 nM) and [3H]dopamine (EC(50)=131 nM). The cis N-demethylated metabolite, pseudophenmetrazine, displayed modest potency at releasing [3H]norepinephrine (EC(50)=514 nM) and blocking [3H]dopamine re-uptake (IC(50)=2630 nM). All drugs tested were inactive or weak in the [3H]5-HT assays. When injected intravenously, phendimetrazine had minimal effects on extracellular transmitter levels, whereas phenmetrazine produced dose-related elevations in extracellular dopamine. The collective findings suggest that phendimetrazine is a "prodrug" that is converted to the active metabolite phenmetrazine, a potent substrate for norepinephrine and dopamine transporters.     

Aggression-associated changes in murine olfactory tubercle bioamines

The relationship between changes in regional brain bioamine levels and the expression of intraspecies aggressive behavior was evaluated in two murine models. In one study, normal male mice were maintained either in aggregate (i.e., normal, intraspecies social behavioral controls) or isolated (i.e., developed, non-social intraspecies aggressive 'fighter' behavior) housing environments, and the accompanying changes in both olfactory tubercle (OT) and hypothalamic (HYPOTH), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) concentration indices quantitated by high-performance liquid chromatography (HPLC) for analysis of behavior-related alterations in localized bioamine deposition loci. Intact mice which had been housed in isolation cages and which exhibited aggressive, intraspecies reflexive-biting ('fighter') behavior when introduced to a novel (stimulus) animal, exhibited significant (P<0.05) elevations in NE levels, and depressed DA concentrations, in the OT regions relative to aggregated controls, indicating an intrinsic social influence on the maintenance of basal adrenergic indices at this neural locus. No changes in 5-HT levels were indicated between control and aggressive, isolated 'fighter' groups in either OT or HYPOTH loci. In addition, the NE and DA levels in the HYPOTH samples of both control and aggressive groups were found to be comparable. In the second study, utilizing an alternate type of aggression-induced murine model, changes in bioamine parameters were determined from samples obtained from aggregated, olfactory-bulbectomized (Obx) mice which are recognized to exhibit an overt, intraspecies, reflexive-biting behavior as compared to sham-operated (control) mice housed under identical conditions. In these studies, Obx-mice exhibited a significant increase in 5-HT levels in the OT relative to sham-operated controls, but similar NE and DA concentrations. In addition, all hypothalamic bioamine indices were found to be comparable between control and Obx groups. These data, collected for both isolation-developed, and experimentally-induced (i.e., OBX), intraspecies aggressive models, indicate that the distinctive types of aggressive behaviors displayed by these two murine models are accompanied by specific alterations in regional bioamine levels within the OT of these groups, relative to controls. These data suggest that the specific type of overt aggressive behavior demonstrated by these models may be causally related to the identified changes in bioamine concentrations in the forebrain regions of the CNS, in loci recognized to participate in environmental recognition and social processing activities.     

Norepinephrine‐induced diastolic dysfunction with aortic valve opening under calcium‐loading in rats

Heart failure associated with a high plasma level of norepinephrine (NE) has an extremely poor prognosis with NE being the most powerful predictor of all‐cause mortality. An increase in the diastolic intracellular calcium level (Ca²⁺) occurs in left ventricular dysfunction; however, the cause‐and‐effect relationships among Ca²⁺loading, high plasma NE, and an increase in diastolic ventricular pressure is unclear. Here, we examined the relationship between diastolic dysfunction and NE with and without Ca²⁺loading in rats. Animals were studied in four groups: Ca²⁺loading for 45 min (Ca²⁺group), NE alone for 25 min (30 µg/kg/min NE for 25 min; NE group), Ca²⁺loading and NE for 25 min after Ca²⁺loading (Ca²⁺‐NE group), and a vehicle group. Hemodynamics were examined using a micromanometer‐tipped pressure catheter, and diastolic function was studied using Doppler echocardiography. Significantly increased left ventricular end‐diastolic pressure (LVEDP) and decreased E and Ea waves and deceleration time (DCT) were found in the Ca²⁺‐NE group, compared with the Ca²⁺and NE groups. There were no changes in left ventricular pressure (LVP) and LV ejection fraction (EF) among the four groups. NE‐induced diastolic contracture (NEIDC) with aortic valve opening occurred in the diastole when LVP overshot the aortic pressure after co‐administration of NE and Ca²⁺after Ca²⁺loading, and pulmonary hemorrhage was observed in all animals of the Ca²⁺‐NE group. The results support the suggestion that NE may be an important factor in the development of diastolic dysfunction in ischemic heart disease. Drug Dev. Res. 67:511–518, 2006. © 2006 Wiley‐Liss, Inc.     

Effect of novel stressors on gene expression of tyrosine hydroxylase and monoamine transporters in brainstem noradrenergic neurons of long-term repeatedly immobilized rats

Responses of central noradrenergic (NE) neurons to stressors like immobilization (IMO), cold exposure, insulin-induced hypoglycemia, and cellular glucoprivation caused by 2-deoxy-D-glucose (2-DG) were investigated in intact and long-term repeatedly immobilized (LTR, 2 h daily IMO for 41 days) rats. Expression of tyrosine hydroxylase (TH), norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT2) genes were determined by using in situ hybridization histochemistry in brainstem A1, A2, A5 and locus coeruleus (LC) neurons. TH mRNA levels were increased by single IMO or 2-DG administration in all areas studied. Cold was effective only in LC and A2 neurons while insulin had no effect. LTR immobilization elevated TH mRNA levels in all investigated cell groups. These elevations were equally high to those elicited by a single IMO in each noradrenergic group, except the LC where LTR IMO was less effective than the single IMO. The levels of NET and VMAT2 mRNAs were elevated only in the A1 and A2 cell groups of LTR IMO rats. A newly applied IMO in LTR rats did not alter TH, NET, and VMAT2 mRNA levels in any NE cell group investigated. Novel stressors like cold and 2-DG exaggerated the increased TH mRNA levels only in the LC of LTR IMO rats, unlike in the other NE cell groups. The present data indicate that repeated exposure of rats to homotypic stressor induces an adaptation of NE neurons, whereas single exposure of such animals to heterotypic novel stressor produces an exaggerated response of the system at the level of TH (in LC) and NET (in A1, A2) gene expression.     

Central monoamine activity in genetically distinct strains of mice following a psychogenic stressor: effects of predator exposure

The effects of psychogenic stressors, rat exposure and fox urine odor, on central monoamine functioning was assessed in two inbred strains of mice, BALB/cByJ and C57BL/6ByJ, thought to be differentially reactive to stressors. These stressors markedly increased NE utilization, as reflected by MHPG accumulation, in the locus coeruleus, hippocampus, prefrontal cortex and central amygdala. Likewise, the 5-HT metabolite, 5-HIAA, was elevated in hippocampus, prefrontal cortex and central amygdala, and to some extent DOPAC accumulation was increased in the prefrontal cortex. In most brain regions, the neurochemical effects of the stressors were comparable in the two mouse strains. However, central amygdala 5-HIAA elevations as well as DOPAC increases in the prefrontal cortex elicited by fox odor were greater in C57BL/6ByJ than in BALB/cByJ mice. Although BALB/cByJ mice are more behaviorally reactive than C57BL/6ByJ mice, and also show greater corticosterone elevations in response to neurogenic and systemic stressors, it was previously shown that differential corticosterone changes were not elicited by a predator exposure. Taken together with earlier findings, it appears that despite greater behavioral reactivity/anxiety, the strain-specific neurochemical changes elicited may be situation-specific such that the profile apparent in response to neurogenic and systemic stressors may not be evident in response to predator-related threats.     

比较多巴胺与去甲肾上腺素对感染性休克血流动力学和氧代谢的影响

目的比较多巴胺与去甲肾上腺素对感染性休克患者血流动力学和氧代谢的影响。方法44例早期感染性休克患者经过充足的液体复苏使肺动脉楔压(PAWP)维持在1.6～2kPa之间,随机分为多巴胺组(Dopa组)和去甲肾上腺素组(NE组)。分别加用多巴胺或去甲肾上腺素,使平均动脉压(MAP)维持>10.7kPa。分别测定并计算应用多巴胺或去甲肾上腺素前(T0)、用药后1h(T1)、4h(T2)、8h(T3)、16h(T4)、24h(T5)和48h(T6)各个时间点的血流动力学指标[包括心率(HR)、外周血管阻力指数(SVRI)、心脏指数(CI)、肺动脉楔压(PAWP)及平均肺动脉压(MPAP)]和氧和指标[包括氧供指数(DO2I)、氧耗指数(VO2I)及氧摄取率(O2ext)]。结果(1)用药后2组同一时间点的HR、CI相比,NE组显著低于Dopa组(P<0.05);NE组的SVRI明显高于Dopa组(P<0.05)。(2)Dopa组的DO2I比NE组明显增加(P<0.05),NE组的VO2I、O2ext和Dopa组同一时间点相比明显增高(P<0.05)。结论对于早期感染性休克患者,去甲肾上腺素比多巴胺能更好的维持血流动力学稳定,它可以增加脏器灌注,提高O2ext,改善氧代谢。     

新型镇痛药——盐酸他喷他朵

盐酸他喷他朵是一种新型的具有双重功效的中枢止痛剂,它既是μ型阿片受体激动剂同时又抑制中枢去甲肾上腺素再摄取,是迄今为止研发的第一个同时具有上述两种药理作用的单一分子药物。该药镇痛谱广,包括各种急性和慢性疼痛。对各种疼痛模型中包括神经病理性痛在内的多种大鼠疼痛模型有效,镇痛作用是吗啡的1/2～1/3。临床应用副反应轻微,耐受良好。     

单胺类递质在大鼠癫痫发作心脏损伤中的作用

目的:观察癫痫发作前、发作时及发作后血浆去甲肾上腺素(NE)及血清心肌肌钙蛋白I(cTnI)含量以及心脏病理变化。探讨癫痫发作致心脏损害的发生、发展机制。方法:健康Wistar大鼠40只随机分成癫痫组(EP)和对照组(Control)。癫痫由青霉素诱导发作,动态监测大鼠癫痫发作时和发作后不同时间点血浆NE含量及血清cTnI水平的变化。NE的测定采用高效液相-电化学法,cTnI的测定采用光化学发光法。结果:大鼠癫痫发作时血浆NE明显升高,NE升高持续约1h以上。癫痫发作后1h血清cTnI水平开始升高,12h达高峰,随后逐渐下降。心脏病理检查证实癫痫发作可引起心脏损害。结论:癫痫发作时NE含量升高在癫痫发作致心脏损害过程中起重要作用。