Modulation of the activity of monoaminergic brain systems and emotional condition by dalargin in rats during development of emotional resonance response

Rats were divided in two groups by the reaction of emotional resonance (RER): with emotionally positive reactions (I, with fast RER acquisition, up to 100 s) and with emotionally negative reactions (II, with slow RER acquisition, more than 200 s). After the RER acquisition, the activity of 5-hydroxitryptophan (5-HT) system of the I group of animals was lower than in the II group. The activity of noradrenaline (NA) and dopamine (DA) systems of the I group of animals was higher than in the II group. The between-group differences were enhanced by subcutaneous injection of dalargin. In some brain structures dalargin reversed these relations. These findings point to a complicated interpenetrating character of emotionally positive and emotionally negative states. Emotionally positive states include components of emotionally positive states, and emotionally negative states include components of emotionally positive states. Increase in 5-HT activity and decrease in activity of NA, DA, and opioid (OP) systems induce formation of emotionally negative states. Decrease in 5-HT activity and increase in activity of NA, DA, and OP systems induce formation of the emotionally positive state. It is suggested that 5-HT, NA, and DA systems play the central role in the processes of reinforcement, acquire the evaluative function, and are included in realization of all types of behaviors. OP is a primary modulator system which accompanies the unconditioned pain stimulus and connects it with systems of evaluative function.     

Role of monoamine oxidase-B in medroxyprogesterone acetate (17-acetoxy-6 alpha-methyl-4-pregnene-3, 20-dione) induced changes in brain dopamine levels of rats

The effect of medroxyprogesterone acetate (MPA) on brain monoamine levels and monoamine oxidase (MAO) activity was studied in adult, healthy, non-pregnant female rats. MpA was injected in a single dose of 100 mg/kg i.m. Dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT) levels and MAO activity were estimated fluorometrically in rat brian. No change in DA, NA, 5-HT or MAO activity was observed after 7 days of MPA treatment while a significant decrease in DA levels along with a significant increase in MAO activity was observed after 21 days of MPA treatment. However, there was no change in NA and 5-HT levels after 21 days of MPA administration. The selective reduction of DA by MPA could be due to an increase in MAO-B activity. MPA does not appear to increase MAO-A activity because neither of the specific substrates (NA and 5-HT) of MAO-A was found to be decreased inspite of the increase in MAO activity as estimated by the kynuramine method. These findings suggest the importance of MAO-B also in DA metabolism in rat brain.     

Microdialysis Study of Modification of Hypothalamic Neurotransmitters in Streptozotocin-Diabetic Rats

Abstract: Neurochemical changes in the ventromedial hypothalamus (VMH) after a single intravenous injection of streptozotocin were examined, using in vivo brain microdialysis under free-moving conditions. Although streptozotocin-induced diabetes produced significant decreases in extracellular concentrations of noradrenaline (NA), serotonin (5-HT), and their metabolites in the VMH, the ratios of 3-methoxy-4-hydroxyphenylglycol/NA and 5-hydroxyindoleacetic acid (5-HIAA)/5-HT were increased. Experimental diabetes led to a pronounced increase in extracellular GABA, which correlated strongly with the decrease in dialysate levels of NA, and to a smaller extent with that of 5-HT. A modification of dopamine (DA) metabolism was induced in the VMH of diabetic rats, whereas there was no change in dialysate DA levels. Daily injections of insulin were able to restore their levels to normal in the areas tested in the microdialysis study. The equal increases in dialysate 5-HT and 5-HIAA and the better restoration of the 5-HIAA/5-HT ratio after insulin therapy indicate that serotonergic activity may depend on the levels of circulating insulin more than on noradrenergic activity. Circulating NA was reduced in streptozotocin-diabetic rats, suggesting that the diabetes-induced reduction in sympathetic activity is accompanied by decreases in NA, or 5-HT, or both, in the VMH.     

Inhibitory effects of cis- and trans-resveratrol on noradrenaline and 5-hydroxytryptamine uptake and on monoamine oxidase activity

This study investigated for the first time the potential effects of cis- and trans-resveratrol (c-RESV and t-RESV) on noradrenaline (NA) and 5-hydroxytryptamine (5-HT) uptake by synaptosomes from rat brain, on 5-HT uptake by human platelets, and on monoamine oxidase (MAO) isoform activity. Both c-RESV and t-RESV (5-200 microM) concentration-dependently inhibited the uptake of [3H]NA and [3H]5-HT by synaptosomes from rat brain and the uptake of [3H]5-HT by human platelets. In both experimental models, t-RESV was slightly more efficient than c-RESV. Furthermore, in synaptosomes from rat brain, the RESV isomers were less selective against [3H]5-HT uptake than the reference drug fluoxetine (0.1-30 microM). On the other hand, both c-RESV and t-RESV (5-200 microM) concentration-dependently inhibited the enzymatic activity of commercial (human recombinant) MAO isoform (MAO-A and MAO-B) activity, c-RESV being slightly less effective than t-RESV. In addition, both RESV isomers were slight but significantly more selective against MAO-A than against MAO-B. Since the principal groups of drugs used in the treatment of depressive disorders are NA/5-HT uptake or MAO inhibitors, under the assumption that the RESV isomers exhibit a similar behaviour in humans in vivo, our results suggest that these natural polyphenols may be of value as structural templates for the design and development of new antidepressant drugs with two important biochemical activities combined in the same chemical structure: NA/5-HT uptake and MAO inhibitory activity.     

Stress by forced swimming in the rat: effects of mianserin and moclobemide on GABAergic-monoaminergic systems in the brain

The stress caused by forced swimming in male rats provoked a decrease in brain NA levels without changes in DA and 5-HT content, MAO and GABAergic activity. Acute or chronic treatment with mianserin did not modify the decrease in NA concentration in the brain of stressed rats. Acute treatment with moclobemide (IMAO) did not modify the decrease in NA content caused by stress; chronic treatment blocked the decrease in NA content in stressed rats.     

Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome

The serotonin (5-HT) syndrome is the most serious toxic interaction of antidepressants, but no pharmacotherapy has yet been established. In the present study, we created an animal model of the 5-HT syndrome by intraperitoneally injecting rats with clorgyline (2 mg/kg) and 5-hydroxy-L-tryptophan (5-HTP) (100 mg/kg) and evaluated the effectiveness of potent 5-HT(2A) receptor antagonists and GABA-enhancing drugs, including diazepam and chlormethiazole. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured by microdialysis. In the group pre-treated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min after administration. Pre-treatment with potent 5-HT(2A) receptor antagonists prevented the development of hyperthermia and death in the rats. Pre-treatment with diazepam, 10 and 20mg/kg, and chlormethiazole, 50 and 100mg/kg, attenuated the development of hyperthermia. Although neither of these drugs completely prevented the rats from dying, they prolonged their survival time. Regardless of the type of therapeutic agents, the concentration of 5-HT increased to about 1100-fold the pre-administration level. The NA levels in the saline group increased to about 16-fold the pre-administration levels, but the increase was significantly lower in the rats that survived as a result of drug therapy. These results suggest that GABA-mimetic drugs may be effective against the 5-HT syndrome, although they have a somewhat weaker effect than the potent 5-HT(2A) receptor blockers, and that not only is 5-HT activity increased in the brain in the 5-HT syndrome, but the NA system is also enhanced.     

THE EFFECTS OF OUABAIN AND THE ACTIVATION OF NEURAL MEMBRANE ATPase BY BIOGENIC AMINES

Abstract— The effects of 10⁻⁵ m -noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) on the activities of Na⁺-K⁺ ATPase (EC 3.6.1.3) were studied in synaptic membranes from 6 regions of the rabbit brain. NA and 5-HT stimulated the synaptic membrane Na⁺-K⁺ ATPase from the cerebrum, but none of the amines influenced the activity of this enzyme in the other brain regions. The Na⁺-K⁺ ATPase activity of the cerebral synaptic membrane isolated at the 0.8/0.9 m & 0.9/1.0 m interphase of a sucrose density gradient was increased two-fold by 10⁻⁵ m -NA and 5-HT. The Na⁺-K ⁺ ATPase recovered at the 1.0/1.2 m interphase was not influenced by NA, DA or 5-HT. NA, DA and 5-HT did not activate the Mg ATPase of synaptic membranes from any of the 6 brain regions or whole brain synaptic vesicles. The cortex synaptic membrane (Na⁺-K⁺) ATPase is postulated to have a direct role in the uptake of the biogenic amines. An indirect role is proposed for this enzyme in amine uptake into brain stem.     

Selective reduction by isolation rearing of 5-HT1A receptor-mediated dopamine release in vivo in the frontal cortex of mice

Serotonin (5-HT)1A receptors modulate in vivo release of brain monoaminergic neurotransmitters which may be involved in isolation-induced aggressive behavior. The present study examined the effect of isolation rearing on the 5-HT1A receptor-mediated modulation of dopamine (DA), 5-HT and noradrenaline (NA) release in the frontal cortex of mice. The selective 5-HT1A receptor agonist (S)-5-[-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) increased the release of DA and NA and decreased the release of 5-HT in the frontal cortex of mice. The effect of MKC-242 on DA release was significantly less in isolation-reared mice than in group-reared mice, while effects of the drug on NA and 5-HT release did not differ between both groups. The effect of the other 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin on cortical DA release was also less in isolation-reared mice than in group-reared mice, and that of the drug on cortical 5-HT release did not differ between both groups. In contrast to MKC-242-induced DA release, amphetamine-induced increase in cortical DA release in vivo was greater in isolation-reared mice. The present findings suggest that isolation rearing enhances the activity of cortical dopaminergic neurons and reduces selectively the 5-HT1A receptor-mediated release of DA in the cortex.     

Distribution of 5-hydroxytryptamine and indolealkylamine metabolites in the American cockroach, Periplaneta americana L

A procedure is described for simultaneous estimation of tryptophan (TP), 5-hydroxytryptophan (5-OHTP), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), N-acetyl 5-hydroxytryptamine (NA5-HT) and N-acetyldopamine (NADA) using high performance liquid chromatography with coulometric electrochemical detection. The procedure has been used to determine the distribution of these compounds in the central nervous system of the American cockroach, Periplaneta americana. The ratio of TP:5-HT is greatest in the cerebral ganglia (6.5) with lesser ratios evident in the thoracic ganglia (15.5-18.9) and abdominal ganglia (9.6-11.2). Relatively low concentrations of 5-OHTP and NA5-HT were observed in the cerebral ganglia whereas 5-HIAA was not detected. Incubation of ganglia resulted in increased concentrations of NA5-HT. Reserpine reduced levels of 5-HT and NADA whereas probenecid caused a marked reduction in TP and slight elevation of NADA levels. No MAO activity was detected in the central nervous system.     

Learning of animals during adaptation to altitude and its relations with serotonin metabolism in the brain

The influence of high altitude (3 200 m) on learning was studied on 104 non-linear male rats weighing 120 to 140 g, along with biochemical analysis of serotonin content (5-HT) and noradrenaline (NA) in brain structures. A drastic deterioration in the animals' learning has been established in conditions of high altitude, both with alimentary and pain reinforcement attended with a considerable suppression of the 5-HT and NA brain systems activity. Systematic administration of 5-HTP resulting in an enhanced serotonin level in the cortex and the caudal part of the brainstem, improved the learning process, regardless of the emotional sign of the reinforcing stimulus. The prospect, is being substantiated, of evolving methods preventing pathological implications of external influences of high altitudes on the organism by means of pharmacological actions on monoamines' metabolism.     

Influence of hypo- and hyperthyroidism on the turnover rate of noradrenaline, dopamine and serotonin in various rat cerebral structures]

The effect of chronic treatment with tyroxine (T4) or propylthiouracile (PTU) on the turnover of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) has been studied in various areas of the rat brain (brain stem, hypothalamus, striatum and "rest of the brain"). The turnover of NE and DA was determined by the decay in endogenous levels after inhibition of tyrosine hydroxylase by alpha-methylparatyrosine and the turnover of 5-HT was evaluated by the initial accumulation of endogenous 5-HT after inhibition of monoamine oxydase by pargyline. T4 treatment accelerated the release of DA from the striatum but had no significant effects on NA release in the various cerebral areas : nevertheless the NE endogenous level was significantly reduced in the brain stem. PTU treatment delayed the release of DA and NA only from the "rest of the brain". Concerning 5-HT, the only significant variation was observed in the hypothalamus of PTU-treated rats and implied increased turnover. The possible relations between the changes in cerebral monoamines turnover and the behavioural alterations which are observed in thyroid disfunction are discussed.     

Development of tolerance to benzodiazepines. I. Changes in the systems of central nervous system neurotransmitters during long-term administration of nitrazepam

A purpose of the study was determination of the relationships between the brain levels of neuro-mediators: noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) and the development of tolerance to the sedative and anticonvulsive action of Nitrazepam. It was found that during tolerance development the GABA level increased in the cerebral tissue and changes appeared in the activity state of the serotoninergic system.     

Serotonin, dopamine, noradrenaline and their metabolites: levels in the brain of the house cricket (Acheta domesticus L.) during a 24-hour period and after administration of quipazine--a 5-HT2 receptor agonist.

1. The levels of 5-HT, DA, NA and DA metabolites (NADA, DOPAC) measured by HPLC (with electrochemical detection) in the brain of the house cricket did not change over a 24-hr period. The level of 5-HIAA, a 5-HT metabolite, was below the limit of detection. 2. The 5-HT and DOPAC levels decreased and NADA increased after quipazine injection but DA and NA levels did not change after it. 3. [3H]Ketanserin was used to identify serotonin receptors bound to sites in the house cricket brain with a KD of 5 nM and a concentration of Bmax 180 fmol/mg protein.     

Chronic Stress Increases Serotonin and Noradrenaline in Rat Brain and Sensitizes Their Responses to a Further Acute Stress

The effects of 1 h/day restraint in plastic tubes for 24 days on the levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP), and noradrenaline (NA) in six regions of rat brain 20 h after the last restraint period were investigated. The levels of 5-HT, 5-HIAA, and NA but not TP increased in several regions. The effects of 1 h of immobilization on both control and chronically restrained rats were also studied. Immobilization per se did not alter brain 5-HT, 5-HIAA, and TP levels, but decreased NA in the pons plus medulla oblongata and hypothalamus. However, immobilization after chronic restraint decreased 5-HT, increased 5-HIAA, and decreased NA in most brain regions in comparison with values for the chronically restrained rats. We suggest that chronic restraint leads to compensatory increases of brain 5-HT and NA synthesis and sensitizes both monoaminergic systems to an additional acute stress. These changes may affect coping with stress demands.     

Influence of circadian disruption on neurotransmitter levels,physiological indexes,and behaviour in rats

Brain monoamines – such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) – regulate several important physiological functions, including the circadian rhythm. The purpose of this study was to examine changes in NA, DA and 5-HT levels in various brain regions and their effect on core body temperature (T_c), heart rate (HR) and locomotor activity (Act) in rats following exposure to an artificial light/dark (LD) cycle. For this, male Wistar rats were housed at an ambient temperature (T_a) of 23?°C and 50% relative humidity with free access to food and water. Rats were exposed to either natural (12?h:12?h) or artificial (6?h:6?h) LD cycles for 1 month, after which each brain region was immediately extracted and homogenized to quantify the amounts of NA, DA and 5-HT by high-performance liquid chromatography. Behavioural changes were also monitored by the ambulatory activity test (AAT). Notably, we found that artificial LD cycles disrupted the physiological circadian rhythms of T_c, HR and Act. Although the 5-HT levels of rats with a disrupted circadian rhythm decreased in cell bodies (dorsal and median raphe nuclei) and projection areas (frontal cortex, caudate putamen, preoptic area and suprachiasmatic nucleus) relative to the control group, NA levels increased both in the cell body (locus coeruleus) and projection area (paraventricular hypothalamus). No significant changes were found with respect to DA. Moreover, circadian rhythm-disrupted rats also showed anxious behaviours in AAT. Collectively, the results of this study suggest that the serotonergic and noradrenergic systems, but not the dopaminergic system, are affected by artificial LD cycles in brain regions that control several neural and physiological functions, including the regulation of physiological circadian rhythms, stress responses and behaviour.     

Neurotransmitter Changes in Guinea-Pig Brain Regions Following Soman Intoxication

The effects of the organophosphate acetylcholinesterase (AChE) inhibitor soman (31.2 micrograms/kg s.c.) on guinea-pig brain AChE, transmitter, and metabolite levels were investigated. Concentrations of acetylcholine (ACh) and choline (Ch), noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), and their metabolites, and six putative amino acid transmitters were determined concurrently in six brain regions. The brain AChE activity was maximally inhibited by 90%. The ACh content was elevated in most brain areas by 15 min, remaining at this level throughout the study. This increase reached statistical significance in the cortex, hippocampus, and striatum. The Ch level was significantly elevated in most areas by 60-120 min. In all regions, levels of NA were reduced, and levels of DA were maintained, but those of its metabolites increased. 5-HT levels were unchanged, but those of its metabolites showed a small increase. Changes in levels of amino acids were restricted to those areas where ACh levels were significantly raised: Aspartate levels fell, whereas gamma-aminobutyric acid levels rose. These findings are consistent with an initial increase in ACh content, resulting in secondary changes in DA and 5-HT turnover and release of NA and excitatory and inhibitory amino acid transmitters. This study can be used as a basis to investigate the effect of toxic agents and their treatments on the different transmitter systems.     

家兔若干与下行抑制有关的中枢部位中去甲肾上腺素、5-羟色胺和脑啡肽在针刺镇痛中的变化

应用推挽灌流技术、去甲肾上腺素(NA)放射酶学法和亮-脑啡肽放射免疫法观察不同脑区 NA 和脊髓背角亮-脑啡肽的释放。应用分子筛柱层析分离家兔不同脑区的5-羟色胺(5-HT)和5-羟吲哚乙酸(5-HIAA),并对它们进行荧光微量测定。以此来阐明针刺镇痛时 NA、5-HT 和亮-脑啡肽在下行抑制中的作用。1.家兔电针20 min,痛阈显著提高,此时中脑导水管周围灰质(PAG)和中缝大核(NRM)的 NA 释放显著减少,而 Al 核团和脊髓背角的 NA释放显著增加。2.电针镇痛时,PAG、延脑中缝核区和脊髓的5-HT 和5-HIAA 含量均有显著增加,除 PAG 外,这种增加的出现较 NA 为晚。提示可能在针刺镇痛的下行抑制中,NA 的参予较5-HT 为早。3.针刺镇痛时脊髓背角亮-脑啡肽的释放也明显增加。     

Inhibition of Monoamine Oxidase Within Monoaminergic Neurons in the Rat Brain by (E)-β-Fluoromethylene-m-Tyrosine (MDL 72394)

The irreversible inhibition of the monoamine oxidase (MAO) activity within monoaminergic neurons in the rat brain 24 h after single or repeated administration of (E)-beta-fluoromethylene-m-tyrosine (FMMT, MDL 72394) was examined. The enzyme activity was determined by incubating synaptosome-rich homogenates of hypothalamus or striatum with low concentrations of 5-[14C]hydroxytryptamine (5-HT), [14C]noradrenaline (NA), or [14C]dopamine (DA) in the absence and presence of the selective amine uptake inhibitors citalopram (5-HT), maprotiline (NA), and GBR 12909 (DA). After a single subcutaneous injection of FMMT, the inhibition of MAO within the noradrenergic and dopaminergic neurons was significant but only slightly greater than that outside these neurons. The opposite relationship was observed for the serotonergic neurons. After 7 days' treatment of rats with carbidopa, 20 mg/kg p.o., + FMMT once daily, the preference for the inhibition of MAO within the noradrenergic and dopaminergic neurons was accentuated further. The inhibition outside the serotonergic neurons was still greater than within these neurons. The NA uptake inhibitor CPP 199 antagonized the selective inhibition of MAO within the noradrenergic neurons, which indicates that this preference is due to the accumulation of the active metabolite (E)-beta-fluoromethylene-m-tyramine by the NA transporter.     

Inhibition of tryptophan hydroxylase: Neurochemical action of a catecholamide seizure-inducing agent

H13/04, an audiogenic seizure-inducing catecholamide, has previously been demonstrated to decrease the accumulation of 5-hydroxytryptophan (5-HTP), while increasing the accumulation of dihydroxyphenylalanine (DOPA) after aromatic acid decarboxylase inhibition in vivo. The present study examined the effect of H13/04 on intracellular storage, release, and metabolism of serotonin (5-HT) and noradrenaline (NA) in vitro in order to differentiate between the primary effects of the drug and possible secondary effects due to neurotransmitter interaction. H13/04 had no effect on NA synthesis by brain minces from C57BL/6 mice, but did have a marked effect on [³H]5HT synthesis from [³H]tryptophan in mouse brain minces. H13/04 was subsequently shown to competitively inhibit tryptophan hydroxylase. The data presented in this study indicate that the primary action of H13/04 on biogenic amines is to decrease the synthesis rate of 5-HT by competitive inhibition of tryptophan hydroxylase. The lack of any effect on NA in vitro is consistent with the hypothesis that the primary biochemical action of the drug is on the 5-HT system and that the action on NA in vivo is an indirect effect possibly secondary to the inhibition of 5-HT synthesis.     

Functional recuperation of the serotoninergic innervation in the rat locus coeruleus

1. 5,6-dihydroxytryptamine (5,6-DHT) or a lesion of the raphe centralis superior (RCS) cause significant decreases in the serotonin (5-HT) content and significant increases in the tyrosine hydroxylase activity in the locus coeruleus (LC) of the rat. This suggests that noradrenaline (NA) synthesis is controlled by serotonin-containing neurons in the raphe system via their terminals in the LC. 2. Radioautography after intraventricular infusion of tritiated serotonin (3H-5-HT) and biochemical determinations of endogenous 5-HT content showed an almost complete disappearance of serotoninergic axonal varicosities and content in the LC region 10-15 days after intraventricular administration of 75 micrograms of 5,6-DHT. Two to 4 months after neurotoxin administration, 5-HT fibers had regrown in the LC but, contrary to the normal innervation pattern, the majority of them invaded the medial most portion of the nucleus and the adjacent subependymal region. The LC region regained almost all of its endogenous 5-HT content in the same time period. 3. Functional recuperation of these 5-HT fibers was demonstrated by the fact that the RCS had, after regeneration, the same functional control on NA synthesis as in the normal animal.