Increased Dopamine Transporter Binding Research Articles

Linking Striatal Dopaminergic Asymmetry with Personality Traits: Insights from Gambling Disorder.

The role of dopamine in the pathophysiology of gambling disorder (GD) remains incompletely understood, with disparate research findings concerning presynaptic and postsynaptic structures and dopaminergic synthesis. The aim of this study was to investigate potential correlations between striatal dopamine transporter (DAT) lateralization and asymmetry index, as assessed by 123I-FP-CIT SPECT, and temperamental traits, as measured by Cloninger's Temperament and Character Inventory (TCI), in GD subjects. Significant associations were found between DAT binding asymmetries in the caudate and putamen and the temperamental dimensions of harm avoidance and novelty seeking. Specifically, high noveltyseeking scores correlated with increased DAT binding in the left caudate relative to the right, whereas higher harm avoidance scores corresponded to increased DAT binding in the right putamen relative to the left. These observations potentially imply that the asymmetry in DAT expression in the basal ganglia could be an outcome of hemispheric asymmetry in emotional processing and behavioural guidance. In summary, our study provides evidence supporting the relationship between DAT asymmetries, temperamental dimensions and GD. Future investigations could be directed towards examining postsynaptic receptors to gain a more comprehensive understanding of dopamine's influence within the basal ganglia circuit in disordered gambling. If confirmed in larger cohorts, these findings could have substantial implications for the tailoring of individualized neuromodulation therapies in the treatment of behavioural addictions.

The 5-HT1A receptor agonist 8-OH-DPAT modulates motor/exploratory activity, recognition memory and dopamine transporter binding in the dorsal and ventral striatum

In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.

N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease.

This study assessed the biological and clinical effects in patients with Parkinson's disease (PD) of N-acetyl-cysteine (NAC), the prodrug to l-cysteine, a precursor to the natural biological antioxidant glutathione. Forty-two patients with PD were randomized to either weeklyintravenous infusions of NAC (50mg/kg) plus oral doses (500mg twice per day) for 3months or standard of care only. Participants received prebrain and postbrain imaging with ioflupane (DaTscan) to measure dopamine transporter (DAT) binding. In the NAC group, significantly increased DAT binding was found in the caudate and putamen (mean increase from 3.4% to 8.3%) compared with controls (P<0.05), along with significantly improved PD symptoms (P<0.0001). The results suggest NAC may positively affect the dopaminergic system in patients with PD, with corresponding positive clinical effects. Larger scale studies are warranted.

N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data.

BackgoundThe purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson’s disease (PD).MethodsThe overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD, using an in vitro and in vivo approach. In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine (mDA) neurons that were treated with rotenone as a model for PD. The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone. In the clinical study, patients continued their standard of care and were randomized to receive either daily NAC or were a waitlist control. Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter (DAT) binding and the Unified Parkinson’s Disease Rating Scale (UPDRS) to measure clinical symptoms.ResultsThe cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed. The clinical study showed significantly increased DAT binding in the caudate and putamen (mean increase ranging from 4.4% to 7.8%; p<0.05 for all values) in the PD group treated with NAC, and no measurable changes in the control group. UPDRS scores were also significantly improved in the NAC group (mean improvement of 12.9%, p = 0.01).ConclusionsThe results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients, and this observation may be associated with positive clinical effects. A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better elucidate the mechanism of action is warranted.Trial RegistrationClinicalTrials.gov NCT02445651

Functional Genomics of Attention-Deficit/Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine Transporter Binding in ADHD and Healthy Control Subjects

The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3'-untranslated region of the gene (3'-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene. Subjects consisted of 68 psychotropic (including stimulant)-naïve and smoking-naïve volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3'-UTR and intron8 VNTRs used standard protocols. The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p<.004) and 3'-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p<.008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3'-UTR genotype, and 3'-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3'-UTR-intron8 haplotype with DAT binding. The 3'-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3'-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3'-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans.

Striatal Dopamine Transporter Binding in Adults With ADHD

Back to table of contents Previous article Next article Communications and UpdatesFull AccessStriatal Dopamine Transporter Binding in Adults With ADHDThomas J. Spencer, M.D., Bertha K. Madras, Ph.D., Alan J. Fischman, M.D., Ph.D., Johanna Krause, M.D., and Christian La Fougère, M.D.Thomas J. SpencerBostonSearch for more papers by this author, M.D., Bertha K. MadrasBostonSearch for more papers by this author, Ph.D., Alan J. FischmanBostonSearch for more papers by this author, M.D., Ph.D., Johanna KrauseMunichSearch for more papers by this author, M.D., and Christian La FougèreMunichSearch for more papers by this author, M.D.Published Online:1 Jun 2012https://doi.org/10.1176/appi.ajp.2012.12020232AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In the meta-analysis by Fusar-Poli et al. (1) appearing in the March 2012 issue, the authors contend that an overall 14% greater striatal dopamine transporter binding in the brains of adults with ADHD was caused by previous exposure to stimulant medications. Based on significant errors in the assignment of treatment status, this conclusion is unsupportable. In their Table 1, the ADHD treatment status of the studies defines “drug-free” as all subjects (100%) having previous exposure, and Figure 4 illustrates a metaregression analysis based on this critical variable—previous treatment status—as derived from the primary source manuscripts.There are some contradictions with the primary source materials. Two of the studies that were identified as drug free (i.e., from previous medication exposure) in Figure 4 were drug naive. The subjects in the la Fougère et al. study (2) were designated as “drug free” in Table 1, but ADHD subjects were drug naive. The second study is not explicitly identified in Figure 4 but can be inferred because 1) Figure 4 shows three studies in which all ADHD subjects had previous exposure, yet Table 1 lists only two studies in this category, and 2) Figure 4 shows four studies as drug naive, yet Table 1 lists five studies with drug-naive subjects. Table 1 lists the Dougherty et al. study (3) as 100% previous exposure when, as indicated in a clarification published in Lancet (4), there was 67% exposure. The Volkow et al. study (5) is listed and analyzed as if subjects were drug naive, but an earlier version of this Volkow et al. study (6) stated, “Subjects were excluded if they had a prior history of more than 1 month of medication treatment for ADHD.” The Jucaite et al. study (7) appears to fit the Figure 4 regression, as the three subjects with previous drug exposure appear to account for elevated mean dopamine transporter binding of ADHD subjects. Yet, the opposite conclusion can be drawn from the primary source manuscript, in which Figure 3 shows that ADHD subjects with previous medication exposure had lower average dopamine transporter binding (estimated 8 units) than drug-naive ADHD subjects (estimated 10 units). Thus, the Jucaite et al. data support the view that previous stimulant treatment is not associated with increased dopamine transporter binding but overall lower dopamine transporter binding.If two of the inaccurately designated studies are shifted from the drug-free (100% previous treatment) to drug-naive category, the analysis, the slope of Figure 4, and the conclusions of the paper will change.Finally, we noticed that Figure 1 shows typical positron emission tomography or single photon emission computed tomography probes for the dopamine transporter. It includes one probe (2β-carbomethoxy-3β-[4-fluorophenyl] tropane [CFT]) not used in the studies in this meta-analysis and excludes two (altropane and cocaine) that are used in the studies in this meta-analysis.BostonMunichDr. Spencer has received research support from Cephalon, the Department of Defense, Eli Lilly, Janssen, McNeil Pharmaceutical, NIMH, Novartis Pharmaceuticals, and Shire Laboratories; he has been a speaker for Shire Laboratories and Novartis Pharmaceuticals; he has been an adviser or on an advisory board for Alcobra, Shire Laboratories, and Eli Lilly; he receives research support from royalties and licensing fees on copyrighted ADHD scales through MGH Corporate Sponsored Research and Licensing; and he has a U.S. patent application pending (provisional number 61/233,686) through MGH corporate licensing on a method to prevent stimulant abuse. Dr. Madras is an inventor of and has a patent for [11C]altropane. Altropane has been licensed to Alseres, and Navidea has signed an option agreement to license altropane from Alseres. Dr. Krause receives speaking fees from Janssen, Novartis, Medice, and Shire and has served on the advisory board for Eli Lilly. Dr. Fischman and Dr. la Fougère report no financial relationships with commericial interests.Accepted for publication in April 2012.

Dopamine transporter binding in social anxiety disorder: the effect of treatment with escitalopram

Social anxiety disorder (SAD) is characterised by fear of social or performance situations where the individual is exposed to unfamiliar people or to possible scrutiny by others. The literature on dopamine ligands and dopamine genotypes in SAD is however inconsistent. In this study we measured the effects of SSRI pharmacotherapy on dopamine transporter (DAT) binding in patients with SAD, also addressing variability in DAT genotype. Adult subjects meeting DSM-IV criteria for generalised SAD were studied before and after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor (SSRI) escitalopram. DAT single photon emission computed tomography (SPECT) using (123)I-FP-CIT was performed at baseline, and repeated at 12 weeks. Striatal DAT binding was analysed for changes following therapy, and for correlations with clinical efficacy, in the whole group as well as for a subgroup with the A10/A10 DAT genotype. The study included 14 subjects (9 male, 5 female) with a mean (SD) age of 41 (±13) years. The subjects' Liebowitz Social Anxiety Scale (LSAS) score was significantly decreased following pharmacotherapy. In the combined group the left caudate and left putamen showed clusters of increased DAT binding after therapy. The left caudate changes were also observed in the subgroup of 9 A10/A10 homozygotes. However no correlation was found between improved symptoms and DAT binding. The changes found in DAT binding in the caudate and putamen may be due to serotonergic activation of dopamine function by SSRI therapy. This is consistent with previous work indicating decreased DAT binding in SAD, and increased DAT binding after SSRI administration.

Further Evidence of Dopamine Transporter Dysregulation in ADHD: A Controlled PET Imaging Study Using Altropane

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. 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-naïve, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. 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.

Dopaminergic function in a family with the PARK6 form of autosomal recessive Parkinson’s syndrome

A G309D mutation in the PINK1 gene in a consanguineous Spanish kindred with seven siblings, three of whom are clinically affected, has recently been shown to be a cause of the PARK6 form of autosomal-recessive Parkinson's syndrome. In this family, we studied pre- and postsynaptic dopaminergic function using 123I-FP-CIT- and 123I-iodobenzamide-SPECT to determine binding to the presynaptic dopamine transporter (DAT) and postsynaptic D2 receptors respectively. All three PARK6 patients showed reduced striatal DAT binding with posterior preponderance similar to sporadic idiopathic PD, but only one patient showed significant striatal asymmetry. In two of the siblings, DAT binding was markedly increased. IBZM-SPECT was normal in both patients and sibs. Our findings indicate that 123I-FP-CIT-SPECT shows similar DAT binding in PARK6 patients compared to idiopathic Parkinson's disease. The increased DAT binding in heterozygous PARK6 carriers may be a new very early preclinical finding, but its significance is still unclear.

Effect of 1,2,3,4,-tetrahydroisoquinoline administration under conditions of CYP2D inhibition on dopamine metabolism, level of tyrosine hydroxylase protein and the binding of [ 3H]GBR 12,935 to dopamine transporter in the rat nigrostriatal, dopaminergic system

Current concepts of Parkinson's disease (PD) postulate that interaction between neurotoxins and specific genetic background may play an important role in pathogenesis of PD. Therefore, the effect of multiple administration of 1,2,3,4-tetrahydroisoquinoline (TIQ) under conditions of CYP2D blockade on the expression of key markers of PD was studied in the rat striatum (STR) and substantia nigra (SN). TIQ administered alone (50 mg/kg i.p. twice daily for 14 days) markedly decreased the level of tyrosine hydroxylase protein (TH) in the STR; however, this effect was not accompanied by reduction of dopamine (DA) concentration and [ 3H]GBR 12,935 binding to dopamine transporter (DAT). Administration of CYP2D inhibitor, quinine, jointly with TIQ lowered the levels of TH and DA in that structure, but slightly increased DAT binding. In the SN, treatment with TIQ alone did not change TH level although it enhanced DA content and decreased [ 3H]GBR 12,935 binding to DAT in the substantia nigra pars compacta (SNc). Neither the TH level nor DA concentration was affected by the combined treatment, although DAT binding was still reduced in the SN. TIQ did not change the total DA catabolism in the STR, but caused its inhibition in the SN. It strongly depressed the levels of intraneuronal DA metabolite DOPAC and enhanced that of extraneuronal 3-MT in either structure. TIQ more weakly affected the levels of both DA metabolites in the presence of quinine. Our results suggest that endogenous TIQ may act rather as neuromodulator but not as parkinsonism-inducing neurotoxin in the rat brain.

Dopamine transporter binding in the rat striatum is increased by gestational, perinatal, and adolescent exposure to heptachlor.

Heptachlor is a persistent cyclodiene pesticide that affects GABAergic function. Recent reports indicate that heptachlor exposure also alters dopamine transporter (DAT) expression and function in adult mice. The aim of this study was to determine whether gestational, perinatal, and/or adolescent heptachlor exposure in rats altered dopamine-receptor and DAT binding. Adolescent exposure to dieldrin was included to evaluate the generality of the findings. Sprague-Dawley rats received doses (po) ranging from 0 to 8.4 mg/kg/day of heptachlor, or dieldrin, 3 mg/kg/day, during different developmental periods. There were dose-related decreases in maternal weight gain and pup survival, as well as delayed righting reflex, at heptachlor doses > or =3 mg/kg/day. There were no changes in striatal dopamine receptor-D1 ([(3)H]SCH-23390) and -D2 ([(3)H]spiperone) binding in preweanling pups exposed perinatally to heptachlor, and no differences in the response of adult rats to the motor activity-increasing effects of d-amphetamine. However, there were significant (27-64%) increases in striatal DAT binding of [(3)H]mazindol in preweanling rats exposed only gestationally. In rats exposed perinatally and/or during adolescence, there were also increases (34-65%) in striatal DAT binding at postnatal days (PND) 22, 43, and 128. Adolescent exposure to dieldrin also increased DAT binding. In other rats exposed perinatally and throughout adolescence, even the lowest dose of heptachlor 0.3 mg/kg/d increased DAT binding on PND 130. The DAT affinity for mazindol was unchanged in heptachlor-exposed striata. In vitro binding studies indicated that heptachlor (> or =10 microM) displaced mazindol binding. Thus, gestational, perinatal, and/or adolescent exposure to heptachlor produced an increase in DAT binding as early as PND 10, and this change persisted into adulthood.

Expression and regulation of the human dopamine transporter in a neuronal cell line

Human cocaine users exhibit increased striatal [ 3 H ]WIN35428 binding to the dopamine transporter (DAT). However, the nature of the changes induced in the DAT are complex and may not result from a simple increase in number of DAT molecules. To better understand the regulation of DAT inhibitor binding sites and their relationship to the overall process of dopamine uptake, a neuronal model system expressing the human DAT has been developed. Initial experiments were attempted with native dopaminergic neurons so as to allow examination of DAT interactions with vesicular release and storage mechanisms. Dissociated fetal rat mesencephalic neurons, of various ages and mixtures with target cells, were grown to confluence. However, [ 3 H ]WIN35428 binding was of low affinity at all levels of maturity. Following this, a simpler model was assessed, using DAT cDNA transfected into neuroblastoma-derived Neuro2A cells. Initially, no specific and little non-specific [ 3 H ]WIN35428 or [ 3 H ]paroxetine binding was found in non-transfected cells. After transfection with the human DAT inserted in the pcDNA vector, both DAT binding and dopamine uptake were significantly and stably present. Treatment with (−)cocaine, 10 −6 M for 24 h, increased DAT binding and uptake, which did not occur in parallel COS-7 experiments. Other experiments with Neuro2A cells also found that dopamine uptake was down-regulated by treatment with a PKC activator. These results suggest that the transfected Neuro2A neurons should be useful for ongoing experiments examining the regulation of the DAT by assorted treatments.