共查询到20条相似文献,搜索用时 31 毫秒
1.
Julie M. Wilson Kathleen Shannak Stephen J. Kish Allan I. Levey Catherine Bergeron John Deck Kathryn Kalasinsky Lee Ang Frank Peretti Vernard I. Adams John Smialek William R. Anderson Hyman B. Niznik 《Annals of neurology》1996,40(3):428-439
Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic-precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users. Mean DA levels were normal in the putamen, the motor component of the striatum; however, 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, –33%; tail, –39%) with a trend for reduction in nucleus accumbens (–27%). Striatal DAT protein (–25 to –46%) and VMAT2 (–17 to –22%) were reduced, whereas DAT determined by [3H]WIN 35,428 binding was normal. In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug. 相似文献
2.
Jyoti C. Patel Melissa A. Stouffer Maria Mancini Charles Nicholson Kenneth D. Carr Margaret E. Rice 《The European journal of neuroscience》2019,49(6):794-804
Diet influences dopamine transmission in motor‐ and reward‐related basal ganglia circuitry. In part, this reflects diet‐dependent regulation of circulating and brain insulin levels. Activation of striatal insulin receptors amplifies axonal dopamine release in brain slices, and regulates food preference in vivo. The effect of insulin on dopamine release is indirect, and requires striatal cholinergic interneurons that express insulin receptors. However, insulin also acts directly on dopamine axons to increase dopamine uptake by promoting dopamine transporter (DAT) surface expression, counteracting enhanced dopamine release. Here, we determined the functional consequences of acute insulin exposure and chronic diet‐induced changes in insulin on DAT activity after evoked dopamine release in striatal slices from adult ad‐libitum fed (AL) rats and mice, and food‐restricted (FR) or high‐fat/high‐sugar obesogenic (OB) diet rats. Uptake kinetics were assessed by fitting evoked dopamine transients to the Michaelis‐Menten equation and extracting Cpeak and Vmax. Insulin (30 nm ) increased both parameters in the caudate putamen and nucleus accumbens core of AL rats in an insulin receptor‐ and PI3‐kinase‐dependent manner. A pure effect of insulin on uptake was unmasked using mice lacking striatal acetylcholine, in which increased Vmax caused a decrease in Cpeak. Diet also influenced Vmax, which was lower in FR vs. AL. The effects of insulin on Cpeak and Vmax were amplified by FR but blunted by OB, consistent with opposite consequences of these diets on insulin levels and insulin receptor sensitivity. Overall, these data reveal acute and chronic effects of insulin and diet on dopamine release and uptake that will influence brain reward pathways. 相似文献
3.
The specific binding of [3H]YM-09151-2 was used to investigate the possible differences in age-associated changes in striatal D2 dopamine (DA) receptor properties in genetically obese (fa/fa) Zucker rats and their lean3(Fa/?) littermates. The maximal binding sites (Bmax) of D2 DA receptors was found to decline with age in both obese and lean rats: the rate of decline in receptor Bmax was slightly higher in lean than obese rats. However. the Bmax of D2 DA receptor in 6-, 12- and 18-month-old obese rats was significantly lower compared to the age-matched lean rats. These data indicate that obesity decreases the number of striatal D2 DA receptors without affecting the rate at which receptor number decreases with age. 相似文献
4.
Lindsey P. Pattison Scot Mcintosh Tammy Sexton Steven R. Childers Scott E. Hemby 《Synapse (New York, N.Y.)》2014,68(10):437-444
Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate of dopamine. The present studies were undertaken to determine whether chronic self‐administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high‐ and low‐affinity DAT binding sites. Saturation binding of the cocaine analog [125I] 3β‐(4‐iodophenyl)tropan‐2β‐carboxylic acid methyl ester ([125I]RTI‐55) in rat NAc membranes resulted in binding curves that were best fit to two‐site binding models, allowing calculation of dissociation constant (Kd) and binding density (Bmax) values corresponding to high‐ and low‐affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high‐ and low‐ affinity binding sites in the NAc, with low‐affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self‐administration of cocaine and a cocaine:heroin combination increased the affinity of the low‐affinity site for the cocaine congener RTI‐55 compared to saline. These results indicate that the alterations observed following chronic speedball self‐administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. Synapse 68:437–444, 2014 . © 2014 Wiley Periodicals, Inc. 相似文献
5.
Kimberley A. Pitman Ernest Puil Stephanie L. Borgland 《The European journal of neuroscience》2014,40(10):3472-3480
Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ‐Aminobutyric acid type B (GABAB) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABAB receptors, can decrease drug‐seeking behaviours. However, the mechanism by which GABAB receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast‐scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration‐dependently decreased single pulse‐evoked DA release. This effect was blocked by the GABAB antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D2 receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D2 receptors. Baclofen‐mediated suppression of DA release persisted after a locomotor‐sensitizing cocaine treatment, indicating that GABAB receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen‐mediated suppression of terminal DA release is due to GABAB activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment. 相似文献
6.
John R. Lever Emily A. Fergason‐Cantrell Lisa D. Watkinson Terry L. Carmack Sarah A. Lord Rong Xu Dennis K. Miller Susan Z. Lever 《Synapse (New York, N.Y.)》2016,70(3):98-111
Activation of sigma1 (σ1) receptors contributes to the behavioral and toxic effects of (?)‐cocaine. We studied a key step, the ability of (?)‐cocaine to occupy σ1 receptors in vivo, using CD‐1® mice and the novel radioligand [125I]E‐N?1‐(3′‐iodoallyl)‐N′‐4‐(3″,4″‐dimethoxyphenethyl)‐piperazine ([125I]E‐IA‐DM‐PE‐PIPZE). (?)‐Cocaine displayed an ED50 of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen. For comparison, an ED50 of 26 μmol/kg for (?)‐cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [125I]3β‐(4‐iodophenyl)tropan‐2β‐carboxylic acid isopropyl ester ([125I]RTI‐121) binding. A chief finding is the relatively small potency difference between (?)‐cocaine occupancy of σ1 receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (?)‐cocaine with σ1 receptors were assessed further using [125I]E‐IA‐DM‐PE‐PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (?)‐Cocaine binding to cerebral σ1 receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E‐IA‐DM‐PE‐PIPZE gave an ED50 of 0.23 μmol/kg for occupancy of cerebral σ1 receptors, and a 3.16 μmol/kg (i.p.) dose attenuated (?)‐cocaine‐induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E‐IA‐DM‐PE‐PIPZE is a probable σ1 receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ1 and σ2 receptors expressed in CD‐1® mouse brain. Synapse 70:98–111, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
7.
Scott C. Steffensen Seth R. Taylor Malia L. Horton Elise N. Barber Laura T. Lyle Sarah H. Stobbs David W. Allison 《The European journal of neuroscience》2008,28(10):2028-2040
The aim of this study was to evaluate the effects of cocaine on γ‐aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single‐unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage‐sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 μm ) current‐evoked spikes and TTX‐sensitive sodium currents in a use‐dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 μm ), increased IPSC paired‐pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity‐dependent GABA release on DA neurons in the VTA, and that cocaine’s use‐dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. 相似文献
8.
Mette Skinbjerg Nicholas Seneca Jeih‐San Liow Jinsoo Hong David Weinshenker Victor W. Pike Christer Halldin David R. Sibley Robert B. Innis 《Synapse (New York, N.Y.)》2010,64(9):699-703
In vitro, D2 dopamine receptors (DAR) can exist in low‐ and high‐affinity states for agonists and increases of D2 receptors in high‐affinity state have been proposed to underlie DA receptor supersensitivity in vivo. Deletion of the gene for dopamine β‐hydroxylase (DBH) causes mice to become hypersensitive to the effects of psychostimulants, and in vitro radioligand binding results suggest an increased percentage of D2 receptors in a high‐affinity state. To determine whether DBH knockout mice display an increase of high‐affinity state D2 receptors in vivo, we scanned DBH knockout and control mice with the agonist PET radioligand [11C]MNPA, which is thought to bind preferentially to the high‐affinity state of the D2 receptor. In addition, we performed in vitro binding experiments on striatal homogenates with [3H]methylspiperone to measure Bmax values and the percentages of high‐ and low‐affinity states of the D2 receptor. We found that the in vivo striatal binding of [11C]MNPA was similar in DBH knockout mice and heterozygous controls and the in vitro Bmax values and percentages of D2 receptors in the high‐affinity state, were not significantly different between these two groups. In summary, our results suggest that DBH knockout mice have normal levels of D2 receptors in the high‐affinity state and that additional mechanisms contribute to their behavioral sensitivity to psychostimulants. Synapse 64:699–703, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
9.
Barbara A. Bennett Charlotte K. Hollingsworth R. Shayn Martin Jill J. Harp 《Brain research》1998,782(1-2)
Repeated methamphetamine (METH) administration has been shown to produce differing neurochemical as well as behavioral effects in rats. This study was designed to examine the effects of acute and chronic METH exposure on uptake and release of [3H]dopamine (DA) in cultured midbrain dopamine neurons to determine if persistent neuronal adaptations ensue. In addition, we have assessed DA D2 receptor function to determine if chronic METH alters this receptor. Fetal midbrain cultures were exposed to METH (1, 10 μM) for 5 days and dopaminergic function examined 1 or 7 days after drug removal. The ability of METH to release [3H]DA was compared to other releasing agents as well as several potent uptake inhibitors. Chronic exposure to a release-promoting concentration of METH resulted in either no change or a reduction in [3H]DA release upon subsequent METH challenge. Pretreatment with METH was also found to cause a decrease in the Bmax for [3H]raclopride binding, suggesting that persistently elevated DA levels cause a downregulation of DA D2 receptors. Examination of transporter kinetics utilizing initial velocity of uptake revealed that METH treatment caused a significant decrease in affinity (Km) for the substrate (DA), while not altering the maximal velocity of uptake (Vmax). Binding studies with [125I]RTI-55 revealed that there was no alteration in either the Bmax or Kd for this ligand, suggesting that the changes induced by METH treatment are due to alterations in Km and not in the number of DA transport sites. The results from these studies indicate that METH treatment produces a modification in transporter function which may be associated with both the altered uptake and release of [3H]DA. These changes have broad implications for the regulation of transporter activity not only because of the relevance to pre-synaptic mechanisms controlling neurotransmission, but also to the importance of the neuronal adaptation that occurs in response to chronic METH exposure. 相似文献
10.
Alan J. Fischman Ali A. Bonab John W. Babich E. Prather Palmer Nathaniel M. Alpert David R. Elmaleh Ronald J. Callahan Sandra A. Barrow Wendy Graham Peter C. Meltzer Robert N. Hanson Bertha K. Madras 《Synapse (New York, N.Y.)》1998,29(2):128-141
Increasing evidence indicates that dopamine (DA) transporter density declines in Parkinson's disease (PD). 2β-Carbomethoxy-3β-(4-fluorophenyl)-n-(1-iodoprop-1-en-3-yl) nortropane (IACFT, Altropane™) is a cocaine analog with high affinity and selectivity for dopamine transporter (DAT) sites in the striatum. In this study, single photon emission computed tomography (SPECT) with [123I]altropane was used to measure DAT density in seven healthy volunteers (five males, age 37–75, and two females, ages 26 and 39) and eight male patients with Parkinson's disease (age 14–79, Hoehn and Yahr stage: 1.5–3 (n = 5) and 4–5 (n = 3)). Dynamic SPECT images and arterial blood samples were acquired over 1.5–2 hr and plasma radioactivity was analyzed chromatographically to obtain metabolite corrected arterial input functions. Binding potential (BP, B′max/KD) for striatal (Str) DAT sites was calculated by two methods using occipital cortex (Occ) as a reference. In the first method, tissue time–activity curves (TAC) and metabolite corrected arterial input functions were analyzed by a linear graphical method developed for reversible receptor ligands. In the second method, the expression (StrTAC − OccTAC) was fitted to a gamma variate function and the maximum divided by OccTAC at the same time was used to estimate BP. In five of the PD patients, the SPECT data were compared with the results of PET with [18F] 6-fluoro DOPA (FD-PET). Plasma analysis indicated that [123I]altropane is rapidly converted to polar metabolites. SPECT images in healthy volunteers showed that [123I]altropane accumulated rapidly and selectively in the striatum and yielded excellent quality images within 1 h after injection. Both methods of analysis revealed a 7.6%/decade reduction in BP and average striatal values (corrected to age 25) were 1.83 ± 0.22 and 2.09 ± 0.20 by methods 1 and 2. In all the PD patients, striatal accumulation was markedly reduced and the pattern of loss was similar to that reported for DA; most profound in the posterior putamen with relative sparing of the caudate nuclei. A comparable pattern was observed with FD-PET. For total striatum, age-corrected BP was significantly (P < 0.001) reduced; 0.83 ± 0.06 (method 1), 0.84 ± 0.07 (method 2). BPs measured by the two methods were remarkably similar and highly correlated r2 = 0.88, (P < 0.001). These results indicate that [123I]altropane is an excellent SPECT ligand for imaging the DAT/DA neurons in human brain. The high selectivity and rapid striatal accumulation of the ligand allows for accurate quantitation of DAT sites in less than 2 hr. The results further demonstrate that [123I]altropane is an effective marker for PD. Synapse 29:128–141, 1998. © 1998 Wiley-Liss, Inc. 相似文献
11.
Manning-Boğ AB Caudle WM Perez XA Reaney SH Paletzki R Isla MZ Chou VP McCormack AL Miller GW Langston JW Gerfen CR Dimonte DA 《Neurobiology of disease》2007,27(2):141-150
Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice. A subtle locomotor deficit was present in the absence of a change in striatal DA levels. However, increased [(3)H]-DA synaptosomal uptake and [(125)I]-RTI-121 binding were measured in null DJ-1 vs. wild-type mice. Western analyses of synaptosomes revealed significantly higher dopamine transporter (DAT) levels in pre-synaptic membrane fractions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure exacerbated striatal DA depletion in null DJ-1 mice with no difference in DAergic nigral cell loss. Furthermore, increased 1-methyl-4-phenylpyridinium (MPP(+)) synaptosomal uptake and enhanced MPP(+) accumulation were measured in DJ-1-deficient vs. control striatum. Thus, under null DJ-1 conditions, DAT changes likely contribute to altered DA neurotransmission and enhanced sensitivity to toxins that utilize DAT for nigrostriatal entry. 相似文献
12.
Auclair A Drouin C Cotecchia S Glowinski J Tassin JP 《The European journal of neuroscience》2004,20(11):3073-3084
Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of α1b‐adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an α1‐adrenergic antagonist. However, morphine‐induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the α1b‐adrenergic receptor (α1b‐AR KO) and in wild‐type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine‐evoked DA release was completely blocked in α1b‐AR KO mice by SR46349B (1 mg/kg), a 5‐HT2A antagonist. SR46349B also completely blocked, in α1b‐AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and d ‐amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5‐HT2A and α1b‐adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, d ‐amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or d ‐amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5‐HT2A receptors for the genetic deletion of α1b‐adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization. 相似文献
13.
Aracil-Fernández A Trigo JM García-Gutiérrez MS Ortega-álvaro A Ternianov A Navarro D Robledo P Berbel P Maldonado R Manzanares J 《Neuropsychopharmacology》2012,37(7):1749-1763
The potential involvement of the cannabinoid CB? receptors (CB?r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB?r (CB?xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB?r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB? receptors in the NAcc were also studied in both genotypes. CB?xP mice showed decreased motor response to acute administration of cocaine (10-20?mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB?xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB?r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB?xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB?xP than in cocaine-pretreated WT mice. These results revealed that CB?r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction. 相似文献
14.
Franklin R. Schneier M.D. Anissa Abi‐Dargham M.D. Diana Martinez M.D. Mark Slifstein Ph.D. Dah‐Ren Hwang Ph.D. Michael R. Liebowitz M.D. Marc Laruelle M.D. 《Depression and anxiety》2009,26(5):411-418
Background: Dopamine D2 receptor and dopamine transporter (DAT) availability in the striatum (STR) have each been reported abnormal in generalized social anxiety disorder (GSAD) in studies using single photon emission computerized tomography (SPECT). D2 receptors and DAT have not previously been studied within the same GSAD subjects, however, and prior GSAD studies have not assessed dopamine release or subdivided the STR into functional subregions. Methods: Unmedicated adults with GSAD (N=17) and matched healthy comparison (HC) subjects (N=13) participated in this study. Of these, 15 GSAD and 13 HC subjects completed baseline assessment of D2 receptor availability using positron emission tomography (PET) with the radiotracer [11C]raclopride. Twelve GSAD and 13 HC subjects completed a repeat scan after intravenous administration of d ‐amphetamine to study dopamine release. Twelve of the GSAD subjects and 10 of the HC subjects also completed SPECT with the radiotracer [123I] methyl 3β‐(4‐iodophenyl) tropane‐2β‐carboxylate ([123I]β‐CIT) to assess DAT availability. Results: GSAD and HC groups did not differ significantly in striatal DAT availability, the overall striatal or striatal subregion D2 receptor availability at baseline, or change in D2 receptor availability after d ‐amphetamine. Receptor availability and change after d ‐amphetamine were not significantly associated with severity of social anxiety or trait detachment. Conclusions: These findings do not replicate previous findings of altered striatal DAT and D2 receptor availability in GSAD subjects assessed with SPECT. The differences from results of prior studies may be due to differences in imaging methods or characteristics of samples. Depression and Anxiety, 2009. Published 2009 Wiley‐Liss, Inc. 相似文献
15.
Helen N. Panas Laurie J. Lynch Eric J. Vallender Zhihua Xie Guo‐lin Chen Spencer K. Lynn Thomas S. Scanlan Gregory M. Miller 《Journal of neuroscience research》2010,88(9):1962-1969
3‐Iodothyronamine (T1AM) is a metabolite of thyroid hormone. It is an agonist at trace amine‐associated receptor 1 (TAAR1), a recently identified receptor involved in monoaminergic regulation and a potential novel therapeutic target. Here, T1AM was studied using rhesus monkey TAAR1 and/or human dopamine transporter (DAT) co‐transfected cells, and wild‐type (WT) and TAAR1 knock‐out (KO) mice. The IC50 of T1AM competition for binding of the DAT‐specific radio‐ligand [3H]CFT was highly similar in DAT cells, WT striatal synaptosomes and KO striatal synaptosomes (0.72–0.81 μM). T1AM inhibition of 10 nM [3H]dopamine uptake (IC50: WT, 1.4 ± 0.5 μM; KO, 1.2 ± 0.4 μM) or 50 nM [3H]serotonin uptake (IC50: WT, 4.5 ± 0.6 μM; KO, 4.7 ± 1.1 μM) in WT and KO synaptosomes was also highly similar. Unlike other TAAR1 agonists that are DAT substrates, TAAR1 signaling in response to T1AM was not enhanced in the presence of DAT as determined by CRE‐luciferase assay. In vivo, T1AM induced robust hypothermia in WT and KO mice equivalently and dose dependently (maximum change degrees Celsius: 50 mg/kg at 60 min: WT ?6.0 ± 0.4, KO ?5.6 ± 1.0; and 25 mg/kg at 30 min: WT ?2.7 ± 0.4, KO ?3.0 ± 0.2). Other TAAR1 agonists including beta–phenylethylamine (β‐PEA), MDMA (3,4‐methylenedioxymethamphetamine) and methamphetamine also induced significant, time‐dependent thermoregulatory responses that were alike in WT and KO mice. Therefore, TAAR1 co‐expression does not alter T1AM binding to DAT in vitro nor T1AM inhibition of [3H]monoamine uptake ex vivo, and TAAR1 agonist‐induced thermoregulatory responses are TAAR1‐independent. Accordingly, TAAR1‐directed compounds will likely not affect thermoregulation nor are they likely to be cryogens. © 2010 Wiley‐Liss, Inc. 相似文献
16.
Methylation of the dopamine transporter gene in blood is associated with striatal dopamine transporter availability in ADHD: A preliminary study
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Corinde E. Wiers Falk W. Lohoff Jisoo Lee Christine Muench Clara Freeman Amna Zehra Stefano Marenco Barbara K. Lipska Pavan K. Auluck Ningping Feng Hui Sun David Goldman James M. Swanson Gene‐Jack Wang Nora D. Volkow 《The European journal of neuroscience》2018,48(3):1884-1895
Dopamine transporters (DAT) are implicated in the pathogenesis and treatment of attention‐deficit hyperactivity disorder (ADHD) and are upregulated by chronic treatment with methylphenidate, commonly prescribed for ADHD. Methylation of the DAT1 gene in brain and blood has been associated with DAT expression in rodents' brains. Here we tested the association between methylation of the DAT1 promoter derived from blood and DAT availability in the striatum of unmedicated ADHD adult participants and in that of healthy age‐matched controls (HC) using Positron Emission Tomography (PET) and [11C]cocaine. Results showed no between‐group differences in DAT1 promoter methylation or striatal DAT availability. However, the degree of methylation in the promoter region of DAT1 correlated negatively with DAT availability in caudate in ADHD participants only. DAT availability in VS correlated with inattention scores in ADHD participants. We verified in a postmortem cohort with ADHD diagnosis and without, that DAT1 promoter methylation in peripheral blood correlated positively with DAT1 promoter methylation extracted from substantia nigra (SN) in both groups. In the cohort without ADHD diagnosis, DAT1 gene expression in SN further correlated positively with DAT protein expression in caudate; however, the sample size of the cohort with ADHD was insufficient to investigate DAT1 and DAT expression levels. Overall, these findings suggest that peripheral DAT1 promoter methylation may be predictive of striatal DAT availability in adults with ADHD. Due to the small sample size, more work is needed to validate whether DAT1 methylation in blood predicts DAT1 methylation in SN in ADHD and controls. 相似文献
17.
Mei-Ping Kung Ph.D. William D. Essman Dana Frederick Sanath Meegalla Mark Goodman Mu Mu Irwin Lucki Hank F. Kung 《Synapse (New York, N.Y.)》1995,20(4):316-324
An iodinated cocaine derivative, N-(3′-iodopropen-2′-yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane (IPT), was evaluated as a probe for in vitro and in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters in Sprague-Dawley rat brain. Saturation analysis of [125I]IPT in rat striatal homogenates, in two different buffer solutions, Tris-HCl and phosphate, demonstrated a one-site binding with affinities (Kd) of 0.25 ± 0.02 and 0.16 ± 0.02 nM and densities (Bmax) of 939 ± 161 and 1,982 ± 137 fmol/mg protein, respectively. Competition by known DA transporter ligands showed a rank order of RTI-55 > IPT > GBR12909 > mazindol > (−)cocaine. Binding to 5-HT transporter sites was evaluated in rat cortical homogenates. Saturation experiment results showed a single site with a Kd value of 1.2 ± 0.2 nM and a Bmax value of 100 ± 20 fmol/mg protein. The rank order of potency of several monoamine uptake inhibitors (paroxetine > fluoxetine > mazindol > R-nisoxetine > GBR12909) suggests that [l25I] IPT labels 5-HT transporters in rat cortical homogenates. Both ex vivo and in vitro autoradiographic studies revealed high densities of [125I]IPT binding sites in the caudate nucleus, putamen, olfactory tubercle and nucleus accumbens, areas known to be rich in dopaminergic innervation. Moderate accumulation of activity was also observed in the substantia nigra. The dorsal raphe, a region with a high density of 5-HT innervation, was labeled using in vitro autoradiography with [125I]IPT, but the labeling using ex vivo autoradiography was less prominent at 30 min postinjection and not noticeable at 60 min postinjection. Furthermore, systemic administration of IPT to rats increased the locomotor activity, a behavioral effect consistent with the in vitro and in vivo characteristics of compounds acting at dopaminergic sites. These results demonstrate that [125I]IPT is a useful ligand for in vitro labeling of DA and 5-HT transporters and a ligand selective for labeling of DA transport sites in vivo. When labeled with I-123,[123I]IPT holds promise as a SPECT imaging agent for studies of neuropsychiatric disorders that involve DA transporters. © 1995 Wiley-Liss, Inc. 相似文献
18.
Maria Hadjiconstantinou Anne‐Marie Duchemin Hailing Zhang Norton H. Neff 《Synapse (New York, N.Y.)》2011,65(2):91-98
Spontaneous and antagonist‐precipitated withdrawal from nicotine is characterized by marked deficits in extracellular dopamine (DA) in striatum, especially in nucleus accumbens, that have been thought to underlie the affective state associated with drug discontinuation. Uptake via the dopamine transporter (DAT) is a key mechanism for regulating the concentrations of extracellular DA. Accordingly, we questioned whether DAT expression and function are altered in striatum in nicotine withdrawal. Male mice, 30–35 g, were injected with nicotine free base 2 mg/kg, s.c., or saline four times daily for 14 days and euthanized 4–72 h after drug discontinuation. DA uptake into striatal synaptosomes was increased 12–24 h into nicotine withdrawal, and accompanied by elevated DAT mRNA in the substantia nigra pars compacta and ventral tegmental area, evaluated by in situ hybridization. The overflow of endogenous DA, measured under basal conditions in striatal slices ex vivo, was decreased during nicotine withdrawal in a time pattern paralleling to that of uptake. Added to striatal slices, the DAT inhibitor nomifensine reduced the observed difference in DA overflow between saline and nicotine withdrawn mice implying a role for the transporter. The presented data suggest that DAT is transiently upregulated in the striatum early during nicotine withdrawal, and enhanced transporter function contributes to the decreased extracellular DA levels. Synapse, 2011. © 2010 Wiley‐Liss, Inc. 相似文献
19.
Summary The present study examined whether exposure to 5 days of continuous cocaine in rats would produce any persisting alterations
of the decrease in striatal dopamine (DA) overflow produced by local infusion of a D1 receptor agonist. Using a microdialysis
probe in striatum, changes in DA, DA metabolites, and GABA were assessed 14 to 21 days following a 5-day continuous cocaine
treatment. There were no differences in baseline levels of DA and it's metabolites. SKF 38393 (10−6) infusion into the striatum decreased striatal DA levels in the controls and this effect was attenuated in cocaine-pretreated
rats. This result, together with other observations, supports the hypothesis of a persistently altered D1-mediated negative
feedback produced by previous exposure to continuous cocaine. 相似文献
20.
A variable number of tandem repeats in the 3′‐untranslated region of the dopamine transporter modulates striatal function during working memory updating across the adult age span
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Fabio Sambataro Jamie E. Podell Vishnu P. Murty Saumitra Das Bhaskar Kolachana Terry E. Goldberg Daniel R. Weinberger Venkata S. Mattay 《The European journal of neuroscience》2015,42(3):1912-1918
Dopamine modulation of striatal function is critical for executive functions such as working memory (WM) updating. The dopamine transporter (DAT) regulates striatal dopamine signaling via synaptic reuptake. A variable number of tandem repeats in the 3′‐untranslated region of SLC6A3 (DAT1‐3′‐UTR‐VNTR) is associated with DAT expression, such that 9‐repeat allele carriers tend to express lower levels (associated with higher extracellular dopamine concentrations) than 10‐repeat homozygotes. Aging is also associated with decline of the dopamine system. The goal of the present study was to investigate the effects of aging and DAT1‐3′‐UTR‐VNTR on the neural activity and functional connectivity of the striatum during WM updating. Our results showed both an age‐related decrease in striatal activity and an effect of DAT1‐3′‐UTR‐VNTR. Ten‐repeat homozygotes showed reduced striatal activity and increased striatal–hippocampal connectivity during WM updating relative to the 9‐repeat carriers. There was no age by DAT1‐3′‐UTR‐VNTR interaction. These results suggest that, whereas striatal function during WM updating is modulated by both age and genetically determined DAT levels, the rate of the age‐related decline in striatal function is similar across both DAT1‐3′‐UTR‐VNTR genotype groups. They further suggest that, because of the baseline difference in striatal function based on DAT1‐3′‐UTR‐VNTR polymorphism, 10‐repeat homozygotes, who have lower levels of striatal function throughout the adult life span, may reach a threshold of decreased striatal function and manifest impairments in cognitive processes mediated by the striatum earlier in life than the 9‐repeat carriers. Our data suggest that age and DAT1‐3′‐UTR‐VNTR polymorphism independently modulate striatal function. 相似文献