Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane.

BACKGROUND: The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent studies of genetics, treatment, and imaging have highlighted the role of DAT in attention-deficit/hyperactivity disorder (ADHD). The findings of in vivo neuroimaging of DAT in ADHD have been somewhat discrepant, however. METHOD: Dopamine transporter binding was measured using a highly selective ligand (C-11 altropane) and positron emission tomography (PET). The sample consisted of 47 well-characterized, treatment-na?ve, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. RESULTS: Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. CONCLUSIONS: These results confirm abnormal DAT binding in the striatum of adults with ADHD and provide further support that dysregulation of DAT may be an important component of the pathophysiology of ADHD.     

Dopamine transporter dysfunction in Han Chinese people with chronic methamphetamine dependence after a short-term abstinence

Single-photon emission-computed tomography (SPECT) after the administration of ^99mTc-TRODAT-1 was performed on healthy subjects and subjects with methamphetamine (METH)dependence at time 1 (T1) after 24–48 h of abstinence, time 2 (T2) after 2 weeks of abstinence, and time 3 (T3) after 4 weeks of abstinence. In contrast to values in controls, the values of the striatal DAT specific uptake ratios (SURs) in subjects with METH dependence were significantly lower at T1 (n=25), T2 (n=9), and T3 (n=8); a mild increase in SURs was observed at T2 and T3, but values were still significantly lower than those in controls. In subjects with METH dependence, there was a trend for a negative correlation of striatal DAT SURs and craving for METH at T1. METH craving, anxiety and depression scores significantly decreased from T1 to T2 to T3. We conclude that Han Chinese people with METH dependence experience significant striatal DAT dysfunction, and that these changes may be mildly reversible after 4 weeks of abstinence, but that DAT levels still remain significantly lower than those in healthy subjects. The mild recovery of striatal DAT may parallel improvements in craving, anxiety and depression.     

褪黑素对锰致小鼠纹状体多巴胺能系统障碍的影响

目的研究锰对小鼠纹状体多巴胺系统的影响以及褪黑素(MLT)的干预作用,为锰中毒机制的研究提供理论依据。方法小鼠70只,随机均分为(1)对照组、(2)氯化锰组、(3)低MLT+氯化锰组、(4)中MLT+氯化锰组、(5)高MLT+氯化锰组。第1、2组皮下注射(sc)0.9%氯化钠,第3~5组sc给予1.25、2.5和5 mg/kg MLT;2 h后,第1组腹腔注射(ip)0.9%生理盐水,第2~5组ip给予50 mg/kg Mn Cl2。每天1次,连续2周。ELISA检测黑质内多巴胺(DA)含量,免疫组织化学及western blotting检测DAT和DRD1的蛋白水平。结果与对照组相比,氯化锰组上述指标均出现了不同程度的降低,纹状体DA含量显著降低69.97%(P0.01),免疫组织化学结果显示DAT和DRD1积分光密度分别下降62.54%和66.61%(P0.01),DAT和DRD1的蛋白水平均明显降低;与氯化锰组相比,随着MLT浓度的升高,DA含量、DAT和DRD1表达量逐渐上升,并呈剂量-效应关系。结论过量锰暴露可导致纹状体多巴胺系统的损伤,褪黑素可以拮抗锰所致的上述变化。     

Dravet syndrome with parkinsonian symptoms and intact dopaminergic neurons: A case report

IntroductionDravet syndrome (DS) is severe myoclonic epilepsy in infancy and associated with a heterozygous mutation of the gene for the sodium channel alpha 1 subunit (SCN1A). Recently, adult patients with DS have been reported to show parkinsonism, but no corresponding neuroimaging data are available. Here, we present neuroimaging data in 2 adult patients with DS showing parkinsonian symptoms.Case reportCase 1: A man who had intractable seizures from the age of 1 year and 2 months was diagnosed with DS at 7 with a mutation in the SCN1A gene. At 18, he had parkinsonian symptoms such as masked face and bradykinesia. At 20, he was admitted to our department. Dopamine transporter single-photon emission computed tomography (DAT SPECT) showed no decrease in striatal binding of ¹²³I–N–ω–fluoropropyl–2β–carbomethoxy–3β–(4–iodophenyl) nortropane (¹²³I-FP-CIT), and myocardial scintigraphy showed no decrease in cardiac uptake of ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG). Levodopa showed no significant improvement in his symptoms. Case 2: A woman who had febrile seizures at 4 months of age and myoclonic seizures at 1 year and 5 months was diagnosed with DS at 31. She had myoclonus, resting tremor, hypertonia, antecollis, crouch gait, and bradykinesia. DAT SPECT imaging showed no decrease in striatal FP-CIT binding, and levodopa did not improve her symptoms.DiscussionThe normal DAT SPECT and ¹²³I-MIBG results suggest that dopaminergic neurons projecting onto striatal neurons were not impaired in our patients, explaining the lack of response to levodopa. Thus, dopamine imaging can help to guide treatment decisions in patients with DS and parkinsonism.     

Clobenpropit,a histamine H3 receptor antagonist/inverse agonist,inhibits [3H]-dopamine uptake by human neuroblastoma SH-SY5Y cells and rat brain synaptosomes

Background

Clobenpropit, a potent antagonist/inverse agonist at the histamine H₃ receptor (H₃R), reduced the cytotoxic action of 6-hydroxydopamine (6-OHDA) in neuroblastoma SH-SY5Y cells transfected with the human H₃R. We therefore set out to study whether this effect involved a receptor-independent action on dopamine transport.

Severe IgA-mediated auto-immune haemolytic anaemia in a 48-yr-old woman

Auto-immune haemolytic anaemia (AIHA) is characterised by haemolysis associated with the presence of the immunoglobulins IgG, IgM or IgA, and/or components of the complement system on the red cell membrane. The immunoglobulins react as auto-antibodies against the red cell antigens of the patient. IgG antibodies and the complement component C3d can be detected by the direct antiglobulin test (DAT); however, IgM and particularly IgA antibodies may not necessarily be detected by the broad-spectrum anti-human-globulin serum. We present the case of a 48-yr-old woman with severe AIHA. The initial polyspecific direct antiglobulin test (DAT), using a broad-spectrum antiserum, was negative. Testing with monospecific antisera led to the diagnosis of AIHA due to warm-acting auto-antibodies solely of the IgA class, which is a very rare finding. As therapy with steroids alone did not lead to a lasting remission, splenectomy was performed 10 months after initial diagnosis. There has been no relapse of AIHA since, even after steroid medication was withdrawn and even though the monospecific IgA-DAT has remained positive. This case demonstrates the importance of performing a monospecific antiglobulin test if there is a strong suspicion of AIHA in apparently "Coombs-negative" haemolytic anaemia. In AIHA caused by solely IgA antibodies, the polyspecific direct antiglobulin test may be negative or only weakly positive because of a limited content of anti-IgA antibodies in the polyspecific anti-human-globulin serum. First-line treatment of warm-type AIHA is the administration of high-dose glucocorticosteroids; splenectomy is indicated in steroid-refractory patients.     

Own or dam’s genotype? Classical colony breeding may bias spontaneous and stress-challenged activity in DAT-mutant rats

There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post-traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT-HET) and homozygous mutant (DAT-KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT-HET males × DAT-HET females (breeding HET–HET), was used. A second WT colony was derived and maintained (breeding WT–WT). Additionally, a subgroup of rats was bred through mating DAT-KO males × WT females (atypical HET, breeding KO–WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET–HET breeding led to reduced activity in HET females compared to WT rats (from WT–WT breeding). However, HET females from KO–WT breeding did not differ so much from WT rats (WT–WT breeding). The maternal-care impact was then confirmed: HET mothers (breeding HET–HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT–WT). In their female offspring (HET, breeding HET–HET vs. WT, breeding WT–WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care.     

IgA-mediated autoimmune hemolytic anemia in an infant

Autoimmune Hemolytic anemia (AIHA) a relatively uncommon form of hemolytic anemia in children, occurs due to the premature destruction of red blood cells caused by presence of autoantibodies directed against antigens on RBCs. Warm reactive AIHA is the most common form due to IgG isotype of immunoglobulin class binding to autologous RBCs at 37⁰C and confirmed with a positive DAT screening. We present a case of DAT-negative primary warm AIHA in an infant due to IgA antibody. A 10 month old male infant presented with dark colored urine and irritability for past two months, with associated history of fever, diarrhea and vomiting. He had received one red cell transfusion 10 days prior. On physical examination he had pallor with tachycardia without splenomegaly. On investigation his hemoglobin was 5.8 g/dl, WBC 25.9 × 10³/mm³ and normal platelets counts. Peripheral blood smear had spherocytes and biochemical values showed high bilirubin and LDH. Immunohematological work up revelaed polyspecific DAT was negative but monospecific DAT screening showed strong (4+) positivity for IgA and a weak IgG positivity. The patient was diagnosed as IgA-mediated Warm AIHA and was started on prednisolone at 2 mg/kg/day following which hemoglobin improved over the next 2 months. After 2 weeks, prednisolone was tapered and stopped by the end of 3 months. Patients with clinical and laboratory evidence of acute hemolysis, an additional screening for IgA antibody may be done even in cases where poly-specific DAT is negative. Early detection helps in avoiding further investigations and provide efficient management.     

Polygenic inheritance of Tourette syndrome,stuttering, attention deficit hyperactivity,conduct, and oppositional defiant disorder: The additive and subtractive effect of the three dopaminergic genes—DRD2, DβH,and DAT1

Polymorphisms of three different dopaminergic genes, dopamine D₂ receptor (DRD2), dopamine β-hydroxylase (DβH), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse, and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique. © 1996 Wiley-Liss, Inc.