Effects of chronic treatment of rats with "designer" amphetamines on brain regional monoamines.

(+)-Amphetamine and two structurally related analogues, 4-methoxyamphetamine and a recent "designer drug," 4-ethoxyamphetamine, were given to rats via subcutaneous osmotic minipumps for 1-14 days. Regional brain levels of the drugs as well as monoamine neurotransmitters and some of their major acidic metabolites were determined. Amphetamine produced depletions of dopamine in the striatum after at least 3 days of treatment but not in the nucleus accumbens of olfactory tubercle, even after 14 days of treatment. In contrast, the two ring-substituted amphetamine analogues increased levels of the monoamines and decreased levels of their acid metabolites. These data indicate that the two ring-substituted amphetamine analogues, at least one of which is a potent hallucinogen, have potent monoamine oxidase inhibition properties that are sustained during chronic treatment. Furthermore, these two compounds do not share amphetamine's regionally selective neurotoxic effects on dopamine-releasing terminals, even though brain and striatal drug levels are the same or higher than those of amphetamine.     

The use of brain slices in central nervous system pharmacology

Brain slice preparations have most frequently been employed to answer questions of a biochemical or physiological nature. Nevertheless, in vitro brain slices also have considerable value as pharmacological tools with which to study the physiological actions of neurotransmitters and drugs on the central nervous system. Several aspects of the slice preparation facilitate this type of analysis. Because drugs can be applied and tested in a relatively quantitative manner, many classical pharmacological techniques (e.g., dose-response curves, tests for competitive vs. noncompetitive antagonism) can be used to examine drug responses. At the simplest level, these techniques facilitate the differentiation of specific (primarily receptor-mediated) and nonspecific actions of drugs and neurotransmitters. As another consequence, the electrophysiological actions of drugs can be directly compared to their biochemical effects in vitro (receptor binding, activation or inhibition of adenylate cyclase, etc.). Ultimately, parallel studies of this type can be used to establish mechanisms of action for various neurotransmitters, particularly those that may employ biochemical substrates as second messengers. In this paper we describe in general terms many of the advantages of the slice preparation as a neuropharmacological tool. Some of the criteria useful in determining the involvement of various receptors in drug-induced changes in electrophysiological responses are discussed in detail. Finally, the responses of hippocampal slices to various adrenergic agents are used to illustrate the way in which various features of this preparation can be exploited pharmacologically. The results of these experiments constitute a significant advance in terms of our understanding of the neuropharmacology of catecholamine responses in this brain region.     

Presenilin-1/Presenilin-2双基因敲除小鼠脑中单胺类神经递质变化的研究

条件性presenilins双基因敲除小鼠(dKO小鼠)表现出类似阿尔茨海默症(AD)的大部分神经退行性病症,如Tau 蛋白磷酸化、神经元凋亡、皮层萎缩以及认知能力受损等．为探讨presenilins功能缺失、神经退行性症状与单胺类递质变化的相关性,利用毛细管电泳法检测6、9和12月龄dKO小鼠皮层、海马及其他前脑部位中各单胺类神经递质的含量．结果显示,与对照组相比,dKO小鼠皮层中单胺类神经递质在6月龄时显著降低,而随着年龄的增长,神经退行性病变加剧,递质浓度也均明显上升,在海马区,dKO小鼠单胺类递质则呈上升趋势,但仅6月龄时5-羟色胺和肾上腺素及12月龄时各递质的上升有统计学意义,前脑其他部位5-羟色胺和多巴胺递质在6、9月龄时与对照组相近,在12月龄时则显著降低,而去甲肾上腺素和肾上腺素在6月和12月龄时均呈降低趋势,且均有统计学差异(6月龄肾上腺素除外)．实验表明,单胺类神经递质在presenilins双基因敲除的小鼠前脑各区域中的水平均发生了随龄化的变化,且在前脑皮层、海马与前脑其他区域的变化趋势各有不同,而单胺类递质的变化是presenilins双基因敲除导致的直接结果还是间接结果,单胺类递质在AD样神经退性行病变中的作用如何,还有待于进一步的研究．     

通督调神针法联合丹参川芎嗪注射液对脑卒中后抑郁患者血清神经营养指标和单胺类神经递质的影响

摘要 目的：探讨丹参川芎嗪注射液联合通督调神针法对脑卒中后抑郁（PSD）患者血清神经营养指标和单胺类神经递质的影响。方法：病例选取自2020年3月-2021年9月期间东莞市中医院针灸科收治的98例PSD患者,入选的患者根据随机数字表法分为对照组（丹参川芎嗪注射液治疗,49例）和研究组（通督调神针法联合丹参川芎嗪注射液治疗,49例）,两组均治疗6周。观察两组治疗6周后的临床疗效,对比两组中医证候积分、汉密尔顿抑郁量表（HAMD）-17、巴氏指数（BI）、血清神经营养指标[胰岛素样生长因子-1（IGF-1）、脑源性神经营养因子（BDNF）]和单胺类神经递质[去甲肾上腺素（NE）、5-羟色胺（5-HT）和多巴胺（DA）]变化,记录两组不良反应发生率。结果：研究组的临床总有效率为91.84%（45/49）,优于对照组的67.35%（33/49）,差异有统计学意义（P<0.05）。研究组治疗6周后中医证候总积分、HAMD-17评分低于对照组,BI评分高于对照组（P<0.05）。研究组治疗6周后IGF-1低于对照组,BDNF高于对照组（P<0.05）。研究组治疗6周后NE、5-HT、DA高于对照组（P<0.05）。两组不良反应发生率对比无统计学差异（P>0.05）。结论：通督调神针法联合丹参川芎嗪注射液治疗PSD患者,可促进症状改善,调节神经营养指标,促进单胺类神经递质表达,是一种安全有效的治疗方案。     

Recent Advances in Antidepressant Drug Treatment

Psychiatric research has made remarkable advances in understanding the pathophysiology of depressive illnesses. Biologic depressions are now understood as neurotransmitter deficiency diseases. Certain forms of depression are treated with tricyclic antidepressant drugs, which increase the amount of available neurotransmitters. Complicating the clinical picture, however, is the problem of wide variability of levels of tricyclic drugs in the plasma of persons receiving the same dosage. Another problem is the apparent linear dose-response relationship of imipramine hydrochloride and its sister compound desipramine hydrochloride while amitriptyline and nortriptyline follow an inverted U-shaped dose-response curve. However, with newer, more sophisticated diagnostic methods, combined with monitoring of tricyclic drug levels in plasma, therapeutic efficacy can approach 90 percent.Available neurotransmitters also can be increased using monoamine oxidase (MAO) inhibitors. Although MAO inhibitors have been less popular than the tricyclic drugs, recent clinical research tends to support their efficacy. Distinct individual differences in the rate of metabolism of MAO inhibitors have been found. New methods are being devised to detect these differences and monitor directly the effects of these drugs. One of these methods, platelet MAO inhibition, shows some clinical promise.Tricyclic drugs and MAO inhibitors have recently been joined by lithium carbonate, which shows notable efficacy in removing acute manic-depressive symptoms as well as preventing their return during maintenance treatment. Its utility in treating cyclic depressions without mania is now being explored by researchers.     

Oxalic acid stabilizes dopamine, serotonin, and their metabolites in automated liquid chromatography with electrochemical detection

Use of antioxidative agents is required in automated LC assay of microdialysis samples, due to rapid degradation of the monoamine neurotransmitters and their metabolites. Addition of oxalic acid prevented degradation of dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid efficiently: after a 24-h incubation at room temperature the decreases in peak heights were less than 10%. The long-term stability of the analytes, however, was still enhanced when acetic acid and -cysteine were included in the solution. Using this antioxidative solution, the monoamine neurotransmitters and their metabolites could be determined with an automated LC assay even at room temperature.     

Stress and drug dependence (animal studies)

This review describes a role of stress in formation of the primary drug-taking behaviour and the effects of stress on a drug-seeking behaviour after withdrawal of drugs. The psychophysiological and neurochemical mechanisms of the rewarding and aversive states during a drug taking and after its withdrawal are considered. A role of separate neurotransmitters and their interactions in formation of drug dependence and the effects of stress on neuroadaptive changes in these neurotransmitter systems are described. A review of the structures involved in mediation of the stress effects and a drug-seeking behaviour is also discussed.     

Adaptation of brain monoamine synthesis to hypoxia in the rat.

Oxygen is a substrate in the synthesis of the neurotransmitters, norepinephrine, dopamine, and serotonin. Changes in environmental oxygen appear to cause corresponding alterations in brain monoamine synthesis in vivo. The effect of chronic hypoxia was studied by exposing rats to 10% oxygen for up to 36 h. Brain monoamine synthesis, estimated in vivo, decreased initially and then returned to control levels, despite continued exposure to 10% oxygen. During this apparent adaptation to hypoxia, there were no changes in the concentration of brain serotonin, norepinephrine, dopamine, or tryptophan, while brain tryosine increased after 24 h of exposure. Tyrosine hydroxylase activity in vitro was not altered by the exposure to 10% oxygen. Evidence of hypoxic adaptation in these rats, a rightward shift of their hemoglobin dissociation curves, was found after 24 h of exposure. The adaptation of brain monoamine synthesis to hypoxia appeared to correlate with adaptive changes in brain tissue oxygen rather than any change in the intraneuronal regulation of amine synthesis.     

Monoamine oxidase and mitochondrial respiration

Mitochondrial defects encompassing complexes I-IV of the electron transport chain characterize a relatively large number of neurodegenerative diseases. The relationships between mitochondrial lesions and recently described genetic alterations have not yet been defined. We describe a general mechanism whereby the enzymatic metabolism of neurotransmitters by monoamine oxidase (MAO) damages mitochondria, altering their protein thiol status and suppressing respiration. In these experiments, incubation of rat brain mitochondria with tyramine (a mixed MAO-A/MAO-B substrate) for 15 min at 27 degrees C suppressed state 3 respiration by 32.8% and state 5 respiration by 40.1%. These changes were accompanied by a 10-fold rise in protein-glutathione mixed disulfides. Direct comparison of effects on respiration and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye reduction during electron flow gave similar results. It is suggested that certain mitochondrial lesions may derive from the natural turnover of monoamine neurotransmitters in susceptible individuals.     

难治性抑郁症治疗前后血浆单胺类神经递质代谢产物的变化

目的：探讨难治性抑郁症患者抗抑郁剂治疗前后的单胺类神经递质代谢产物的改变。方法：随机入组30例难治性抑郁症患者,进行汉密尔顿抑郁量表（HAMD）的临床评定。用酶联免疫吸附方法对这30例患者进行5-HIAA,MHPG检测,并与随机选取的经汉密尔顿抑郁量表（HAMD）临床评定的30名普通抑郁症患者进行比较。综合治疗8周后对难治性抑郁症患者进行治疗前后对比。结果：难治性抑郁症组治疗前血浆5-HIAA,MHPG浓度低于普通对照组（p〈0.05）,经5-羟色胺重摄取抑制剂治疗的难治性抑郁症患者,5-HIAA和MHPG含量与治疗前比较均有所升高,差异有显著性（p〈0.05）;结论：难治性抑郁症患者存在中枢5-羟色胺和去甲肾上腺素功能低下;个体化合理使用SSRIs类药物辅以心理治疗能有效地提高难治性抑郁症患者的外周单胺类递质水平,减轻患者的抑郁程度。     

Inhibition of vesicular uptake of monoamines by hyperforin

Hyperforin is the major active ingredient of Hypericum perforatum (St John's Wort), a traditional antidepressant medication. This study evaluated its inhibitory effects on the synaptic uptake of monoamines in rat forebrain homogenates, comparing the nature of the inhibition at synaptic and vesicular monoamine transporters. A hyperforin-rich extract inhibited with equal potencies the sodium-dependent uptake of the monoamine neurotransmitters serotonin [5-HT], dopamine [DA] and norepinephrine [NE] into rat brain synaptosomes. Hyperforin inhibited the uptake of all three monoamines noncompetitively, in marked contrast with the competitive inhibition exerted by fluoxetine, GBR12909 or desipramine on the uptake of these monoamines. Hyperforin had no inhibitory effect on the binding of [3H]paroxetine, [3H]GBR12935 and [3H]nisoxetine to membrane presynaptic transporters for 5-HT, DA and NE, respectively. The apparent presynaptic inhibition of monoamine uptake could reflect a "reserpine-like mechanism" by which hyperforin induced release of neurotransmitters from synaptic vesicles into the cytoplasm. Thus, we assessed the effects of hyperforin on the vesicular monoamine transporter. Hyperforin inhibited with equal potencies the uptake of the three tritiated monoamines to rat brain synaptic vesicles. Similarly to the synaptosomal uptake, the vesicular uptake was also noncompetitively inhibited by hyperforin. Notably, hyperforin did not affect the direct binding on [3H]dihydrotetrabenazine, a selective vesicular monoamine transporter ligand, to rat forebrain membranes. Our results support the notion that hyperforin interferes with the storage of monoamines in synaptic vesicles, rather than being a selective inhibitor of either synaptic membrane or vesicular monoamine transporters.     

Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers

OBJECTIVE: Monoamine oxidase (MAO), the enzyme responsible for metabolism of monoamine neurotransmitters, has an important role in the brain development and function, and MAO inhibitors have a range of potential therapeutic uses. We investigated systematically in vitro effects of pharmacologically different antidepressants and mood stabilizers on MAO activity. Methods: Effects of drugs on the activity of MAO were measured in crude mitochondrial fraction isolated from cortex of pig brain, when radiolabeled serotonin (for MAO-A) or phenylethylamine (for MAO-B) was used as substrate. The several antidepressants and mood stabilizers were compared with effects of well known MAO inhibitors such as moclobemide, iproniazid, pargyline, and clorgyline. Results: In general, the effect of tested drugs was found to be inhibitory. The half maximal inhibitory concentration, parameters of enzyme kinetic, and mechanism of inhibition were determined. MAO-A was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > desipramine > amitriptyline > imipramine > citalopram > venlafaxine > reboxetine > olanzapine > mirtazapine > tianeptine > moclobemide, cocaine > lithium, valproate. MAO-B was inhibited by the following drugs: pargyline > clorgyline > iproniazid > fluoxetine > venlafaxine > amitriptyline > olanzapine > citalopram > desipramine > reboxetine > imipramine > tianeptine > mirtazapine, cocaine > moclobemide, lithium, valproate. The mechanism of inhibition of MAOs by several antidepressants was found various. Conclusions: It was concluded that MAO activity is acutely affected by pharmacologically different antidepressants at relatively high drug concentrations; this effect is inhibitory. There are differences both in inhibitory potency and in mechanism of inhibition between both several drugs and the two MAO isoforms. While MAO inhibition is not primary biochemical effect related to their therapeutic action, it can be supposed that decrease of MAO activity may be concerned in some effects of these drugs on serotonergic, noradrenergic, and dopaminergic neurotransmission.     

Effects of natural and synthetic neuroactive substances on the growth and feeding of cabbage looper, Trichoplusia ni

In this study we investigated the effects of two naturally occurring beta-carboline alkaloids and two synthetic tricyclic antidepressants on the growth and food consumption of fifth instar larvae of the cabbage looper, Trichoplusia ni Hübner (Lepidoptera: Noctuidae). In artificial diets at high concentrations (3,000 ppm), harmane, amitriptyline, and imipramine reduce growth and feeding; harmane reduced feeding consistently at a lower concentration (200 ppm). In animals other than insects, beta-carboline alkaloids inhibit monoamine oxidase (MAO) activity and thus affect rates of disposition of serotonin and other monoamine neurotransmitters. Because brain serotonin levels are associated with variation in rates of carbohydrate and protein intake in insects, the effects of beta-carboline alkaloid ingestion on dietary self-selection behavior were examined. Choosing between diets lacking carbohydrate but containing protein and diets lacking protein but containing carbohydrate, larvae consumed a greater proportion of diet containing protein but lacking carbohydrate in the presence of harmane than in its absence. These results are consistent with beta-carboline alkaloid-mediated persistence of serotonin in the brain due to MAO inhibition. Alternatively, these results could reflect alkaloid-mediated peripheral inhibition of sucrose taste receptors influencing ingestive behaviors. That beta-carboline alkaloid ingestion is associated with changes in feeding behavior is consistent with a possible defensive role for these compounds in plant foliage.     

Neurochemical and neuropharmacological properties of 4-Fluorotranylcypromine

1. The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and B in vitro and ex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine. 2. 4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and B in vitro in rat brain homogenates. 3. After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount. 4. At the dose employed, the ex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other. 5. Although the drugs had similar effects on inhibition of brain MAO ex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain. 6. In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAO in vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.     

Deep brain stimulation of the accumbens increases dopamine,serotonin, and noradrenaline in the prefrontal cortex

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is effective in treatment‐refractory obsessive‐compulsive disorder and major depressive disorder. However, little is known about the neurobiological mechanisms underlying the rapid and effective changes of DBS. One of the hypotheses is that DBS modulates activity of monoamine neurotransmitters. In this study, we evaluated the effects of DBS in the NAc core on the extracellular concentration of monoaminergic neurotransmitters in the medial (mPFC) and orbital prefrontal cortex (OFC). Freely moving rats were bilaterally stimulated in the NAc core for 2 h while dopamine, serotonin, and noradrenaline were measured using in vivo microdialysis in the mPFC and the OFC. We report rapid increases in the release of dopamine and serotonin to a maximum of 177% and 127% in the mPFC and an increase up to 171% and 166% for dopamine and noradrenaline in the OFC after onset of stimulation in the NAc core. These results provide further evidence for the distal effects of DBS and corroborate previous clinical and pre‐clinical findings of altered neuronal activity in prefrontal areas.     

合欢花对慢性应激大鼠生长和脑单胺类神经递质含量的影响

为探讨合欢花对慢性应激大鼠生长和脑单胺类神经递质的影响,采用15只大鼠,设置了对照组、应激组和合欢花组3组实验。应激组和合欢花组均接受7天的应激刺激,之后合欢花组再灌胃合欢花10天。实验结束后,取3组大鼠的脑组织,用高效液相色谱法测定高香草酸(HVA)、去甲肾上腺素(NE)、多巴胺(DA)和5-羟色胺(5-HT)的含量。结果表明,应激组大鼠日增重显著低于对照组(P=0.011);而合欢花组大鼠的日增重极显著高于应激组(P=0.002)。应激组大鼠海马、纹状体和前额叶中的HVA含量与对照组相比,虽有升高的趋势,但无显著差异;两组间的NE、DA和5-HT也无显著差异。合欢花组大鼠海马中的HVA、DA含量明显高于应激组,而前额叶中的多巴胺和5-羟色胺,以及纹状体中的5-羟色胺均明显低于应激组。这表明合欢花对慢性应激引起的大鼠生长受抑有缓解作用,对其脑内单胺类神经递质有调节作用。     

Brain neurotransmitter deficits in mice transgenic for the Huntington's disease mutation

Huntington's disease (HD) is associated with an expansion in the CAG repeat sequence of a gene on chromosome 4, resulting in a neurodegenerative process particularly affecting the striatum and with profound but selective changes in content of various neurotransmitters. Recently, transgenic mice expressing a fragment of the human HD gene containing a large CAG expansion have been generated; these mice exhibit a progressive neurological phenotype that includes motor disturbances, as well as neuronal deficits. To investigate their underlying neurotransmitter pathology, we have determined concentrations of GABA, glutamate, and the monoamine neurotransmitters in several brain regions in these mice and control animals at times before and after the emergence of the behavioural phenotype. In contrast to the findings in HD, striatal GABA was unaffected, although a deficit was observed in the cerebellum, consistent with a dysfunction of Purkinje cells. Losses of the monoamine transmitters were observed, some of which are not seen in HD. Thus, 5-hydroxytryptamine and, to a greater extent, 5-hydroxyindoleacetic acid levels were diminished in all brain regions studied, and noradrenaline was particularly affected in the hippocampus. Dopamine was decreased in the striatum in older animals, parallelling evidence for diminished dopaminergic activity in HD.     

贯叶连翘对应激大鼠生长和脑单胺类神经递质含量的影响

为探讨贯叶连翘对慢性应激大鼠生长和脑单胺类神经递质的影响,用15只大鼠设置对照组、应激组和贯叶连翘组3组实验。应激组和贯叶连翘组均进行7天的应激刺激后,贯叶连翘组灌胃贯叶连翘10d。实验结束后,取3组大鼠的脑组织,用高效液相色谱法测定高香草酸(HVA)、去甲肾上腺素(NE)、多巴胺(DA)和5-羟色胺(5-HT)的含量。结果表明,应激组大鼠日增重明显低于对照组;而贯叶连翘组大鼠的日增重明显高于应激组。应激组大鼠海马、纹状体和前额叶中的HVA、NE、DA和5-HT与对照组间均无显著差异。贯叶连翘组大鼠纹状体中的DA含量明显高于应激组;而前额叶中的DA则明显低于应激组。因此,贯叶连翘对慢性应激引起的大鼠生长受抑有缓解作用,对其脑内单胺类神经递质有部分调节作用。