Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new diestet research articles will be listed here shortly after becoming available to us.
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Medical research on diestet
Cerebellum. 2008 Apr 4;
Delis F, Mitsacos A, Giompres P
We studied the binding parameters, the pharmacological profile and the anatomical distribution of the dopamine transporter in the mouse cerebellum by using the specific dopamine uptake antagonist [(3)H]GBR12935 and an antidopamine transporter monoclonal antibody. Competition experiments in cerebellar and striatal membrane preparations showed that [(3)H]GBR12935 binds to a specific binding site, sensitive to dopamine and low concentrations of mazindol. The affinity of dopamine for the cerebellar binding site was one order of magnitude lower than the affinity for the striatal binding site. Saturation experiments in cerebellar membrane preparations and thin frozen sections showed that the affinity of [(3)H]GBR12935 for this binding site is similar to its affinity for the striatal dopamine transporter. Saturable binding was lobule specific and in general was higher in the molecular layer compared to the granule cell layer. The immunohistochemical signal was mostly concentrated in the Purkinje cell layer and the cerebellar nuclei. The results suggest that the cerebellar dopamine transporter is similar but not identical to the striatal dopamine transporter and that it is present in the mouse cerebellum in a lobule and lamina specific pattern.
Biol Pharm Bull. 2008 Mar; 31(3): 348-51
Niwa T, Okada K, Hiroi T, Imaoka S, Narimatsu S, Funae Y
We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the goal of clarifying whether neurosteroid levels are affected by psychotropic drugs in the brain. PROG or ALLO was incubated with rat CYP2D4 or human CYP2D6 in the presence of typical psychotropic drugs, fluoxetine, imipramine, desipramine, mazindol, and GBR12909, and the 21-hydroxylated metabolites of PROG and ALLO were determined by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. Fluoxetine competitively inhibited CYP2D4-mediated PROG 21-hydroxylation and increased both Km and Vmax values of CYP2D6-mediated PROG 21-hydroxylation. In addition, fluoxetine competitively inhibited ALLO 21-hydroxylation mediated by CYP2D4 and CYP2D6. Imipramine, desipramine, mazindol, and GBR12909 competitively inhibited PROG 21-hydroxylation mediated by CYP2D4 and/or CYP2D6, and all psychotropic drugs inhibited ALLO 21-hydroxylation mediated by CYP2D4 and/or CYP2D6. The inhibition constants (Ki values) of imipramine, desipramine, and mazindol against the 21-hydroxylation of PROG and ALLO by CYP2D6 were lower than those by CYP2D4. These results indicate that psychotropic drugs including fluoxetine affected the metabolism of neurosteroids, such as PROG and ALLO in the brain, suggesting that the regulation of the neurosteroid levels is modified by central nervous system-active drugs that inhibit brain CYP2D isoforms.
Systemic mazindol reduces food intake in rats via suppression of meal size and meal number.
J Psychopharmacol. 2008 Jan 30;
Wellman PJ
The aim of the present study was to determine the impact of theappetite suppressant mazindol on meal pattern in rats. Meal patternswere monitored in adult male rats after mazindol dosing during the firstthree hours of the dark cycle using automated feeding chambers(BioDAQ). Mazindol (0, 0.25, 1.25 and 2.5 mg/kg, IP) produced a dosedependenthypophagia and hypodipsia. Meal size and meal number weresignificantly suppressed by mazindol. The meal pattern findings indicatethat mazindol inhibits eating in the rat via a suppression of both mealsize and meal number.
The role of dopamine transporter in selective toxicity of manganese and rotenone.
Toxicology. 2008 Feb 28; 244(2-3): 249-56
Hirata Y, Suzuno H, Tsuruta T, Oh-hashi K, Kiuchi K
The dopamine transporter has been shown to be the most relevant target site for the specificity of 1-methyl-4-phenylpyridinium ion (MPP+), a neurotoxin for dopaminergic neurons. In contrast, the mechanisms underlying the selective toxicity of manganese and rotenone, potentially toxic agents implicated in dopaminergic neuronal cell death, remain unknown. The aim of this study was to determine the cellular mechanisms of manganese or rotenone uptake in dopaminergic cells via the dopamine transporter. PC12 cells overexpressing the dopamine transporter, which were exposed to 10microM MPP+, showed extensive DNA fragmentation, a biochemical hallmark of apoptosis, whereas wild-type PC12 cells or vector-transfected PC12 cells, which were exposed to 5mM MPP+, did not show DNA fragmentation. In contrast, manganese and rotenone induced DNA fragmentation at slightly lower concentrations in PC12 cells overexpressing the dopamine transporter compared to control cells. Dopamine transporter inhibitors, such as mazindol, nomifensine, or GBR12909, inhibited MPP+-induced DNA fragmentation but did not affect manganese- and rotenone-induced DNA fragmentation in PC12 cells overexpressing the dopamine transporter. Finally, manganese accumulated to similar levels in PC12 cells overexpressing the dopamine transporter and control PC12 cells following incubation with manganese chloride. These results suggested that the dopamine transporter dose not confer cytotoxicity to manganese and rotenone.
Addiction. 2007 Dec; 102(12): 1871-87
Castells X, Casas M, Vidal X, Bosch R, Roncero C, Ramos-Quiroga JA, Capellà D
AIMS: To evaluate the efficacy of central nervous system (CNS) stimulants compared with placebo for the treatment of cocaine dependence. METHODS: A systematic review and meta-analysis was carried out. Bibliographic databases were searched, reference lists of retrieved studies were hand-searched and the first authors of each study were contacted. All randomized controlled clinical trials (RCCT) comparing the efficacy of any CNS stimulant with placebo in cocaine-dependent patients were included. Quantitative data synthesis was performed for each single CNS stimulant and for all CNS stimulants. RESULTS: Nine RCCT met the inclusion criteria. These RCCT included 640 patients and compared five CNS stimulants: mazindol, dextroamphetamine, methylphenidate, modafinil and bupropion with placebo. No CNS stimulant improved study retention [RR = 0.94 (0.81-1.09)] or cocaine use [RR = 0.90 (0.79-1.02)]. An exploratory analysis using indirect estimations of cocaine use showed that the proportion of cocaine-positive urine screens was lower with dexamphetamine than with placebo [RR = 0.73 (0.60-0.90)] and that all CNS stimulants pooled together also suggested a significant decrease of cocaine use [RR = 0.87 (0.77-0.99)]. Data on craving could not be meta-analysed due to heterogeneity, but no RCCT found differences in cocaine craving between active drug and placebo except one, whose outcome favoured dexamphetamine. No serious adverse event (AE) was reported. Average of AE-induced dropouts was low and was greater for CNS stimulants than placebo: 4.4% versus 1.3% (P = 0.03). CONCLUSION: The main outcomes of this study do not support the use of CNS stimulants for cocaine dependence. Nevertheless, secondary analyses provide some hopeful results that encourage further research with these drugs, mainly with dexamphetamine and modafinil.
Synapse. 2008 Jan; 62(1): 8-13
Yoo JH, Nam YS, Lee SY, Jang CG
We have previously shown that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT3 receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D1 receptor, D2 receptor, and dopamine transporter (DAT) binding labeled with [3H]SCH23390 for D1, [3H]raclopride for D2, and [3H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D1 receptor, D2 receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice.
J Pharmacol Exp Ther. 2007 Nov; 323(2): 720-9
Mason JN, Deecher DC, Richmond RL, Stack G, Mahaney PE, Trybulski E, Winneker RC, Blakely RD
Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS.
Med Hypotheses. 2008; 70(1): 12-6
Cortese S, Konofal E, Dalla Bernardina B, Mouren MC, Lecendreux M
Recent studies suggest a significant association between obesity and attention-deficit/hyperactivity disorder (ADHD). The factors underlying this newly described comorbidity are still unclear and unexplored. In the present article, we propose that excessive daytime sleepiness (EDS) contributes to explaining the association between ADHD and obesity. The background for this hypothesis comes from studies on the association between ADHD and EDS, as well as from investigations on EDS in obese individuals. Available studies suggest that ADHD behaviours are significantly associated with EDS. Moreover, increasing evidence indicates that obesity is significantly associated with EDS independently of sleep-disordered breathing (SDB) or any other sleep disorders. Given the relationship between EDS and ADHD behaviors, we hypothesize that the higher than expected rates of EDS in obese individuals contribute to explaining the association between obesity and ADHD behaviors. We further speculate on the role of the brain derived neurotrophic factor (BDNF) and other molecules such as the proinflammatory cytokines IL-6 and TNF-alpha. Our hypothesis generates potentially relevant clinical and therapeutic implications. From a clinical standpoint, it may suggest to systematically look for ADHD symptoms (including hyperactivity and impulsivity) in obese patients described as sleepy. With regard to the therapeutic implications, we suggest that wake-promoting agents with anorexigenic effect, such as mazindol, might be particularly indicated for the treatment of ADHD symptoms in obese patients, since they might address both ADHD symptoms and weight reduction. In conclusion, considering the burden that ADHD adds to obesity, we believe that further studies on the comorbidity between obesity and ADHD are necessary. Research on the role of EDS might allow advancements in this field, suggesting a more effective management and, ultimately, a better quality of life of patients with both obesity and ADHD.
Dopamine release is impaired in a mouse model of DYT1 dystonia.
J Neurochem. 2007 Aug; 102(3): 783-8
Balcioglu A, Kim MO, Sharma N, Cha JH, Breakefield XO, Standaert DG
Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non-transgenic littermates. Pre-synaptic DA transporters were studied using in vitro autoradiography with [(3)H]mazindol, a ligand for the membrane DA transporter, and [(3)H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post-synaptic receptors were studied using [(3)H]SCH-23390, a ligand for D(1) class receptors, [(3)H]YM-09151-2 and a ligand for D(2) class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine-stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non-transgenic littermates (253 +/- 71% vs. 561 +/- 132%, p < 0.05, two-way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre-synaptic transporters or post-synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.
J Neurochem. 2007 Apr; 101(2): 377-88
Chen N, Reith ME
The use of heterologous expression systems for studying dopamine (DA) transporter (DAT) function has provided important information corroborating and complementing in situ obtained knowledge. Preliminary experiments with human embryonic kidney cells (HEK293) heterologously expressing varying amounts of DAT suggested fluctuations in the potency of cocaine in inhibiting DA uptake and led to the present systematic assessment of the impact of the density of DAT on its function. Transiently expressing intact HEK293 cells, transfected with increasing amounts of DAT cDNA, displayed increasing levels of surface DAT, binding of the cocaine analog [(3)H]2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(3)H]CFT), and uptake of [(3)H]DA, [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)), [(3)H]norepinephrine, and [(3)H]serotonin. However, the amount of DAT cDNA and the DAT expression level required to produce 50% of maximal activity was threefold higher for CFT binding than for DA uptake. Increased DAT expression was accompanied by weakened potency in inhibiting [(3)H]DA uptake for cocaine, CFT, benztropine, and its analog JHW025, GBR 12909 and mazindol; their potency in inhibiting [(3)H]CFT binding was unaffected. Inhibition of uptake by the substrates DA, m-tyramine, d-amphetamine, or MPP(+) was also unaffected. Increasing DAT in stably expressing HEK293 cells by stimulation of gene expression with sodium butyrate also decreased the uptake inhibitory potency of a number of the above blockers without affecting the interaction between substrates and DAT. The present results prompt discussion of models explaining how factors regulating DAT expression at the plasma membrane can regulate DAT function and pharmacology.