Rat brain monoamines after acute and chronic myo-inositol treatment

Inositol was reported to have effects in depression, panic disorder and OCD, and in animal models of depression and anxiety. The present study tested whether inositol treatment alters monoamine systems. Brain areas of rats pre-treated with acute or chronic inositol were analysed by HPLC for monoamines and their metabolites and compared to control animals. Inositol treatment had no significant effect on levels of monoamines, their metabolites, or turnover rates compared to controls.     

Rat brain monoamines after acute and chronic myo-inositol treatment.

Inositol was reported to have effects in depression, panic disorder and OCD, and in animal models of depression and anxiety. The present study tested whether inositol treatment alters monoamine systems. Brain areas of rats pre-treated with acute or chronic inositol were analysed by HPLC for monoamines and their metabolites and compared to control animals. Inositol treatment had no significant effect on levels of monoamines, their metabolites, or turnover rates compared to controls.     

A comparison of the acute and chronic effects of four antidepressant drugs on the turnover of serotonin,dopamine and noradrenaline in the rat brain

The acute effects of imipramine, Org GB 94 and iprindol and the chronic effects of imipramine, desipramine, iprindol and Org GB 94 were studied on the turnover of dopamine, noradrenaline and serotonin in the whole rat brain. The effects of these drugs on amine turnover was assessed from the incorporation of tritiated tyrosine and tryptophan into the amines. Following acute administration, imipramine significantly reduced the turnover of serotonin whereas Org GB 94 increased that of noradrenaline. After chronic administration, imipramine and desipramine reduced the turnover of serotonin and dopamine, iprindol had no significant effect on brain amine turnover whereas Org GB 94 increased the turnover of noradrenaline. The effect of Org GB 94 on noradrenaline turnover was more marked after intraperitoneal than after oral administration.     

A combination of mirtazapine and milnacipran augments the extracellular levels of monoamines in the rat brain

Mirtazapine, an antidepressant, antagonizes α(2)-adrenergic autoreceptors and heteroreceptors, which leads to enhanced noradrenergic and serotonergic transmission without inhibiting monoamine transporters. Using a microdialysis technique, we investigated whether co-administration of mirtazapine and a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, augments the effects of each drug on the extracellular levels of monoamines by pharmacological synergy. Mirtazapine increased the extracellular levels of noradrenaline and serotonin in the dorsal hippocampus. In contrast, it increased the levels of noradrenaline and dopamine without changing serotonin levels in the prefrontal cortex. Milnacipran increased the levels of all monoamines evaluated in both areas, and the combined treatment with mirtazapine augmented these changes. The combined treatment with idazoxan, an α(2) adrenoceptor antagonist, and milnacipran also increased all monoamine levels in the prefrontal cortex. Ketanserin, a serotonin 5-HT(2A) receptor antagonist, showed no effect in combination with milnacipran, while SB242084, a 5-HT(2C) receptor antagonist, augmented the effects of milnacipran on the levels of serotonin and dopamine in the prefrontal cortex. These results suggest that combined treatment with mirtazapine and milnacipran augments the extracellular levels of noradrenaline, serotonin and dopamine through the blockade of α(2) adrenoceptors without regional specificity, whereas mirtazapine enhances serotonergic transmission in a region-specific manner. 5-HT(2C) receptor antagonism may also partly contribute to the amplification effects of mirtazapine on serotonin and dopamine levels. These neurochemical changes could play a role in reported advantageous clinical effects in patients treated with an SNRI and mirtazapine.     

Studies on possible mechanisms of action of electroconvulsive therapy; effects of repeated electrically induced seizures on rat brain receptors for monoamines and other neurotransmitters

There is evidence that repeated electroconvulsive shocks (ECS) in rats potentiate dopamine (DA)-, serotonin (5HT)- and -noradrenergic (-NA)-mediated drug-induced behaviour and reduce opiate-induced behaviours. These studies suggest changes at the level of the receptor or beyond. However, high affinity in vitro ³H-ligand binding studies in brain membranes from ECS-treated control rats failed to demonstrate generalized ECS-induced changes in 5HT, DA, -NA or opiate receptor binding. Binding of the -receptor ligand dihydroalprenolol (³H-DHA) was significantly reduced in ECS-treated rat brain membranes. This may be secondary to effects on NA neurones since ECS-induced reduction of ³H-DHA binding did not occur in animals with 6-hydroxydopamine-induced depletion of cortical noradrenaline. In conjunction with other studies, the results suggest that electroconvulsive therapy may have a noradrenergic mechanism of action.     

Differential effects of adjunctive methylphenidate and citalopram on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain.

Several clinical studies have suggested that the combined treatment with methylphenidate and citalopram may accelerate the onset of antidepressant action and induce an improvement even in treatment-refractory patients. In the present study, in vivo microdialysis was used to monitor the extracellular levels of serotonin, noradrenaline and dopamine in the prefrontal cortex, hippocampus, nucleus accumbens and striatum of the rat. Administration of methylphenidate (2.5 mg/kg s.c.) with citalopram (5 mg/kg i.p.) compared to methylphenidate alone caused a marked enhancement of dopamine levels in the prefrontal cortex, n. accumbens and hippocampus, but not in the striatum. Citalopram-induced increase in serotonin levels was strongly enhanced by adjunctive methylphenidate in the hippocampus, but attenuated in the cortex. These findings suggest that the proposed augmentation effects of adjuvant methylphenidate to citalopram are most likely associated with enhanced dopamine transmission in the corticolimbic areas, whereas serotonin and noradrenaline levels show differential and region specific responses.     

Effect of acute tryptophan depletion on noradrenaline and dopamine in the rat brain

In human subjects, the acute tryptophan (TRP) depletion (ATD) paradigm has been shown to have effects on mood and cognition. It is assumed that these effects are mediated through the serotonin system. In this study, we have examined the effects of ATD on the central concentrations of the monoamine transmitters, noradrenaline (NA) and dopamine (DA) as well as on serotonin (5-HT). Effects on NA and DA could also affect mood and cognition. Following oral administration of TRP-containing (TRP+) and TRP-free (TRP-) amino acid mixtures, neurotransmitter concentrations and free plasma TRP concentrations were determined by High Performance Liquid Chromatography (HPLC) with electrochemical detection. Free plasma TRP was significantly and substantially reduced (79%) in rats given a TRP- amino acid mixture when compared with those given a TRP+ mixture. ATD also significantly decreased 5-HT and 5-hydroxyindolacetic acid in the frontal cortex, remaining cortex and hippocampus, but did not significantly reduce these in the striatum. Furthermore, ATD did not significantly alter the concentration of NA and DA in any brain region examined. This study demonstrates that the administration of a TRP- amino acid mixture in rats can reduce free plasma TRP to levels comparable to those reported in human studies. These results indicate that behavioural and cognitive changes produced by ATD in preclinical or clinical studies are likely to be due to specific effects on the serotonergic system.     

多塞平对急性脑缺血再灌注大鼠脑组织单胺类递质含量的影响

目的 :观察多塞平对急性脑缺血再灌注大鼠各脑区单胺类递质含量的影响。方法 :以阻断四血管方法造成急性脑缺血再灌注模型。动物随机分成假手术组 ,空白对照组 ,尼莫地平 3mg·kg- 1组和多塞平 15 ,10 ,5mg·kg- 1组共 6组。在缺血前及再灌注前分别腹腔给药 ,用荧光分光光度计测定大脑皮层、海马、纹状体、脑干中 5 羟色胺、去甲肾上腺素及多巴胺的含量。结果 :与空白对照组比较 ,多塞平 15 ,10 ,5mg·kg- 1剂量组及尼莫地平 3mg·kg- 1组大脑皮层、海马、纹状体各单胺类递质含量显著升高 (P <0 .0 5或P <0 .0 1) ,脑电活动亦显著恢复 (P<0 .0 5或P <0 .0 1)。结论 :多塞平对缺血再灌注脑损伤的保护作用与其改善单胺类递质的代谢紊乱有关     

Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat frontal cortex.

Reboxetine is a selective noradrenergic reuptake inhibitor that displays an antidepressant profile in both animal tests and in clinical trials. The present study examined the ability of reboxetine to alter stress-induced increases in norepinephrine, serotonin and dopamine efflux in the frontal cortex in awake behaving rats. Acute systemic administration of reboxetine (0.3-20.0 mg/kg) dose-dependently increased extracellular norepinephrine in the frontal cortex while having no effect on extracellular serotonin. At 20 mg/kg, reboxetine also increased extracellular dopamine. Application of a 20-min tailpinch stress increased extracellular norepinephrine. This effect was greatly potentiated in rats pretreated with reboxetine. Tailpinch did not elicit increases in dopamine in saline treated animals but this stimulus increased dopamine levels following reboxetine pretreatment. Furthermore, chronic administration of reboxetine for 14 days resulted in elevated basal concentrations of extracellular norepinephrine and dopamine and a greater net increase of extracellular norepinephrine and dopamine, but not serotonin, in response to tailpinch compared with vehicle control animals. Taken together, these data support the view that the noradrenergic and dopaminergic systems are modified by reboxetine treatment and may be important factors in the mechanism of action of antidepressant compounds.     

Comparative study of the effects of desipramine and reboxetine on locus coeruleus neurons in rat brain slices

Several studies have suggested that the locus coeruleus may play an important role in the pathophysiology of depression. The aim of this study was to characterize, using single-unit extracellular recordings, the in vitro effects of the noradrenaline reuptake inhibitors desipramine and reboxetine, on locus coeruleus neurons from control rats and from those chronically treated with desipramine. Bath application of desipramine (1-100 microM) and reboxetine (0.1-10 microM) decreased the firing rate of locus coeruleus neurons in a concentration-dependent manner and the alpha(2)-adrenoceptor antagonist RX 821002 (10 microM) reversed these effects. In addition, reserpine (5 mg/kg, 3 h before the experiment) almost completely blocked the inhibitory effect of desipramine. Both drugs (1 microM desipramine and 0.1 microM reboxetine) potentiated the inhibitory effect of noradrenaline (10 microM). A 7-day treatment with desipramine (3 mg/kg/12 h, i.p.) caused a decrease in sensitivity to the alpha(2)-adrenoceptor agonist bromoxidine (EC(50) increased by 3.3-fold), but not to noradrenaline or reboxetine. In contrast, this treatment potentiated the inhibitory effect of desipramine with respect to control. Moreover, 14-day treatment with desipramine (3 mg/kg/12 h, i.p.) or reboxetine (10 mg/kg/12 h, i.p.) also potentiated the in vitro effect of desipramine without modifying the in vitro effect of reboxetine. These results show that desipramine and reboxetine modulate the activity of locus coeruleus neurons by noradrenaline acting on alpha(2)-adrenoceptors, and reveal that alpha(2)-adrenoceptor-independent mechanisms may also underlie the action of noradrenaline uptake inhibitors.     

Effect of chronic deuterated and non-deuterated phenelzine on rat brain monoamines and monoamine oxidase

Summary The effects of phenelzine and 1,1-dideuterophenelzine (0.5 or 2.5 mg/kg/day) administered s.c. via miniosmotic pumps for 13 days were compared. Striatal levels of p-tryrosine and tryptophan were unaffected by either treatment. The concentrations of DOPAC, HVA and 5-HIAA were dose-dependently decreased by phenelzine and deuterated phenelzine; furthermore, the deuterated compound decreased the amounts of these acids more than the same dose of phenelzine. Dopamine levels were increased by a rather small amount by all drug treatments; no effects of drug dose or drug type (deuterated or nondeuterated) were observed. With the exception of phenylethylamine, qualitatively similar effects were found with all other amines measured; their amounts were increased dose-dependently and the effects of deuterated phenelzine were greater than those of phenelzine. Rat cerebral MAO activity was inhibited dose-dependently by phenelzine and by deuterated phenelzine. Type A MAO was inhibited more than type B, and deuterated phenelzine inhibited both types more than did phenelzine. The present study shows that the efficacy of phenelzine was increased about 5-fold by deuteration, that deuterated phenelzine increased tryptamine, m-tyramine and p-tyramine levels much more than it did the other monoamines, that phenylethylamine levels were least affected by the drug treatments, and that deuterated phenelzine inhibited MAO more than did phenelzine.Abbreviations D deuterium - DOPAC 3,4-dihydroxyphenylacetic acid - 5HIAA 5-hydroxyindole acetic acid - HVA homovanillic acid - MAO monoamine oxidase - 3MT 3-methoxytyramine - 5-HT 5-hydroxytryptamine Send offprint requests to L. E. Dyck     

Effects of acute and chronic alcohol poisoning on the noradrenaline content in the rat hypothalamus

The content and distribution of norepinephrine in the hypothalamus following acute and chronic alcohol opisoning of animals (by introducing of a 20 degrees alcohol by mouth) was studied by applying biochemical and flurorscence histochemical methods. After poisoiing the content of neorpinephrine in the hypothalamus increased twice as compared with controls and continued to be high for 3 months. This was attended by a greater fluorescence intensity in the noradrenergic fibres, in the areas of the hypothalamic supra-optic nuclei and an inhibition of the transport and release of the neurosecretory material in the supra-optic neurohypophysial system was observed. And, conversely, 6--8 months after poisoning the content of neorpinephrine was halved in comparison with the controls.     

Long-term administration of citalopram reduces basal and stress-induced extracellular noradrenaline levels in rat brain

Rationale Panic disorders are commonly treated with selective serotonin reuptake inhibitors (SSRIs). However, the effect of SSRIs on noradrenaline systems in the brain has not been fully elucidated at the present time. Objectives The effects of long-term administration of citalopram, an SSRI, on basal as well as stress-induced extracellular noradrenaline levels in the basolateral nucleus of the amygdala (BLA) and the locus coeruleus (LC) were determined. In addition, the responsiveness of noradrenaline transporters and α₂-adrenoceptors were determined after long-term administration of citalopram. Materials and methods Brain microdialysis was used to assess the extracellular levels of noradrenaline in conscious rats. Desipramine and clonidine were used to functionally evaluate the noradrenaline transporter and α₂-adrenoreceptor, respectively. Results In rats treated daily for 14 days with citalopram (10 mg kg⁻¹ day⁻¹ s.c.), dialysate noradrenaline levels showed remarkable decreases in both the BLA and the LC to about 25 and 45% of controls, respectively. The stress-induced increase of noradrenaline was almost completely abolished in the BLA, but was relatively stable in the LC. The effect of local application of desipramine tended to be suppressed only in the LC. The effect of local application of clonidine was enhanced only in the BLA. Conclusion The present results indicate that chronic administration of citalopram strongly decreases the extracellular levels of noradrenaline in the brain. The anti-panic effect of citalopram might be due to sensitization of the α₂-adrenoceptors leading to suppression of the stress response through noradrenergic activity. This mechanism is specific for the BLA.     

Testosterone manipulations: effects on ranacide aggression and brain monoamines in the adult female rat.

The effect of testosterone propionate on ranacide (frog-killing) behavior and brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) levels was determined in 40 female Wistar rats. Adult rats were screened for frog killing behavior on the basis of a single 30 min testing session. Aggressors were defined as animals which attacked or killed during this session while nonaggressors failed to do so. Using either aggressors or nonaggressors, testosterone and sesame oil equally increased aggresive behavior as measured in a second 30 min testing session. Biochemical analyses indicated that testosterone treated animals had significantly higher brain NE and NE/5-HT levels. Aggressors, testosterone or sesame treated had higher NE/5-HT ratios. Whole-brain levels of DA and 5-HT and the DA/5-HT ratios were unaffected. It is concluded that the elicitation of ranacide in the adult female rat is not androgen dependent nor is this behavior functionally related to the observed differences in brain noradrenergic/serotonergic levels. This study provides additional evidence that ranacide is a type of predatory aggression and yet presents data which may be at variance with the classic monoaminergic theory of aggressive behaviors.     

Comparative actions of diazepam and other phosphodiesterase inhibitors on the effects of noradrenaline in rat myocardium

Diazepam inhibits different isoforms of the enzyme cyclic nucleotide phosphodiesterase and also potentiates the inotropic effect of endogenous catecholamines in rat heart. In the present study we have examined whether this late effect is the consequence of inhibition of a phosphodiesterase subtype or whether inhibition of several phosphodiesterase subtypes is involved. We compared the effect of diazepam with that of the selective inhibitors of phosphodiesterase1 (MIMX), phosphodiesterase2 (EHNA), phosphodiesterase3 (milrinone) and phosphodiesterase4 (rolipram) on the inotropic effect of noradrenaline in rat ventricle. Both rolipram or diazepam were equipotent and more effective than milrinone in potentiating the inotropic effect of noradrenaline whereas EHNA and MIMX had no effect. The results suggest that the diazepam induced potentiation of the contractile effect of noradrenaline is due principally to inhibition of phosphodiesterase4 isoenzyme activity.     

Influence of chronic administration of nicotine on the turnover and metabolism of noradrenaline in the rat brain

Chronic administration of nicotine (0.5 mg/kg, subcutaneously, 3 to 5 times a day for 6 weeks) accelerated the rate of disappearance of intraventricularly administered ³H-noradrenaline from rat brain. This was associated with normal levels of ³H-normetanephrine suggesting an increase in intraneuronal deamination.The rate constant of amine decline (k) in animals chronically treated with nicotine was significantly greater than that of controls, while the steady state level of brain noradrenaline was about equal in both groups of rats. Amphetamine, reserpine, acetylcholine, histamine, pheniprazine, pargyline, and nicotine affected the catecholamine levels in the rat brain treated with nicotine to the same degree as they did in the controls. It is concluded that chronic administration of nicotine may increase noradrenaline turnover in the brain and possibly increase the deamination of this amine.