Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration

Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1-3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1-3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1-1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse.     

Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤ 1, ≤ 10, ~ 25 and ~ 40 μg/dL, respectively, on PN10 and by PN30 all were ≤ 1 μg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity.     

应用脑电超慢涨落图技术对帕金森病患者脑内神经递质变化的研究

目的探讨帕金森病(PD)患者脑内神经递质的变化。方法应用脑电超慢涨落图技术(ET)检测51～60岁、61～70岁PD患者52例未用药时或停药48h后的脑内神经递质水平,其中已服用多巴丝肼治疗的34例患者再次检测服药1.5h后的变化。结果与正常值比较,2个年龄组PD患者去甲肾上腺素(NE)及多巴胺(DA)明显降低(P<0.05或P<0.01);5-羟色胺(5-HT)也有所降低,但无统计学意义(P>0.05);乙酰胆碱(Ach)增高,但仅61～70岁组有统计学意义(P<0.05)。2个年龄组比较,DA在61～70岁组实测值更低(P<0.05)。34例患者服用多巴丝肼后,NE、5-HT、DA较服药前明显升高(P<0.15)。结论PD患者脑内神经递质DA、NE、5-HT等都有不同程度的减少。年龄增加是PD发病的危险因素,不同年龄段其脑内神经递质变化有所不同。ET可测量脑内神经递质的水平,为PD的早期诊断、临床治疗和疗效评价提供参考。     

The effect of <Emphasis Type="Italic">l</Emphasis>-deprenyl on tissue mRNA expressions of NOS isoforms and NO levels in an experimental diabetes mellitus model

Summary Diabetes and aging share some common mechanisms in their pathogenesis and diabetics are more prone to diseases of the elderly. Seeking for therapies likely to be proposed in the synchronised treatment of aging and diabetes is of great interest and l-deprenyl, a selective monoamine oxidase (MAO-B) inhibitor, is a possible candidate with its antioxidant, antiapoptotic and neuroprotective properties. Tissue MAO, NO and mRNA expression of nitric oxide (NO) synthase (NOS) isoforms were assessed in streptozotocin (STZ)-induced diabetic rats to evaluate the effect of l-deprenyl treatment. Twelve weeks of treatment had no significant effect on NO levels. Four-weeks treatment decreased tissue MAO activities and caused a decrease in expression of NOS-2 and NOS-3 in heart tissue of both controls and diabetics, and a decrease of liver NOS-3 expression in controls (p < 0.05). l-Deprenyl, causing a decrease in tissue NOS expressions, might be of benefit by protecting the organism from the toxic radical effects of NO.     

Sex differences in antidepressant-like effect of chronic repetitive transcranial magnetic stimulation in rats

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurophysiological technique. Pre-clinical and clinical studies supported that rTMS might have antidepressant effects. However, whether antidepressant effect of chronic rTMS is gender-dependent is still unknown. In this study, male and female Wistar rats received 10-day rTMS (4 trains of 15 Hz; 200 stimuli/day; 1.0 T) or control condition, and then were subjected to the forced-swim test (FST). We found that female rats consistently showed higher activity levels than males in FST and revealed the significant effects of gender and rTMS as well as the interaction of gender and rTMS. The result suggested the antidepressant-like effects of chronic rTMS on behavioral components in FST are gender-dependent. The gender discrepancy related to rTMS should not be neglected in antidepressant treatment of rTMS.     

Cocaine,but not amphetamine,short term treatment elevates the density of rat brain vesicular monoamine transporter 2

Summary We compared the effect of 5 days D-amphetamine (5 mg/kg/day i.p.) and cocaine (15 mg/kg/day i.p.) administration on the vesicular monoamine transporter 2 (VMAT2) density in rat brain. VMAT2 expression was assessed by [³H]dihydrotetrabenazine high affinity binding. Cocaine administration led to significant increases in VMAT2 density in both prefrontal cortex (+40%, p < 0.01) and striatum (+23%, p < 0.05), while amphetamine did not affect VMAT2 expression. The upregulation of VMAT2 may serve as compensatory mechanism aimed to enhance the vesicular monoamine storage capacity.     

Modelling the roles of MAO and SSAO in glucose transport

Summary Amine oxidase substrates such as benzylamine and methylamine have been shown to stimulate glucose uptake by increasing the recruitment of the glucose transporter GLUT4 from vesicles within the cell to the cell surface. Inhibition of this effect by the presence of semicarbazide and catalase led to the suggestion that the process is mediated by the H₂O₂ produced in the oxidation of these amines. Tyramine, which is a substrate for both MAO and SSAO, can also stimulate this process and in that case both MAO and SSAO inhibitors attenuate the effect. Benzylamine does not occur physiologically and tyramine is normally present in only very low amounts. We have suggested that adrenaline, which also stimulates glucose metabolism through adrenoceptors, may act as the physiological substrate for GLUT4 recruitment. It is a substrate for MAO but not SSAO. However, oxidation of adrenaline by MAO releases both H₂O₂ and methylamine for further oxidation by SSAO. In order to gain a fuller understanding of this process we have performed simulation studies that may be used to assess the contributions of the amine oxidases to the process under a variety of conditions. The results are consistent with the experimentally observed behaviour. This approach not only helps to establish the feasibility of this process but also allows behaviour prediction and the identification of further experimental approaches.     

Acute dehydroepiandrosterone treatment exerts different effects on dopamine and serotonin turnover ratios in the rat corpus striatum and nucleus accumbens

It has been shown that the steroid dehydroepiandrosterone (DHEA) interacts with dopamine (DA) and serotonin (5-HT) neurotransmitter systems, which are involved in the pathophysiology of neurological and psychiatric diseases such as Parkinson's disease as well as mood and psychotic disorders. To explore if DHEA modulates DA and 5-HT metabolism we analyzed the content of both neurotransmitters and their metabolites in the rat corpus striatum (CS) and nucleus accumbens (NAc) 2 h after steroid administration (30, 60 and 120 mg/kg i.p.). DHEA treatment significantly reduced DA turnover (up to 33%) in the CS, but increased 5-HT turnover (up to 76%) in both regions. Those effects could be relevant to mood and neurodegenerative disorders.     

Acute effects of N-(2-propylpentanoyl)urea on hippocampal amino acid neurotransmitters in pilocarpine-induced seizure in rats

The present study aimed to investigate the anticonvulsant activity as well as the effects on the level of hippocampal amino acid neurotransmitters (glutamate, aspartate, glycine and GABA) of N-(2-propylpentanoyl)urea (VPU) in comparison to its parent compound, valproic acid (VPA). VPU was more potent than VPA, exhibiting the median effective dose (ED₅₀) of 49 mg/kg in protecting rats against pilocarpine-induced seizure whereas the corresponding value for VPA was 322 mg/kg. In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate whereas no significant change was observed on the level of glycine and GABA. Pretreatment with either VPU (50 and 100 mg/kg) or VPA (300 and 600 mg/kg) completely abolished pilocarpine-evoked increases in extracellular glutamate and aspartate. In addition, a statistically significant reduction was also observed on the level of GABA and glycine but less than a drastic reduction of glutamate and aspartate level. Based on the finding that VPU and VPA could protect the animals against pilocarpine-induced seizure it is suggested that the reduction of inhibitory amino acid neurotransmitters was comparatively minor and offset by a pronounced reduction of glutamate and aspartate. Therefore, like VPA, the finding that VPU could drastically reduce pilocarpine-induced increases in glutamate and aspartate should account, at least partly, for its anticonvulsant activity observed in pilocarpine-induced seizure in experimental animals. Some other mechanism than those being reported herein should be further investigated.