Norepinephrine transporter immunoblotting and radioligand binding in cocaine abusers

Mash, Deborah C.; Ouyang, Qinjie; Qin, Yujing; Pablo, John

doi:10.1016/j.jneumeth.2004.09.013

Cited by 32 publications

(24 citation statements)

References 39 publications

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“…Studies in postmortem tissue have identified multiple structural and neurochemical changes in the human brain following extended cocaine abuse [10][11][12][13][14][15][16][17][18][19]. These include changes in gene expression, which indicate involvement of similar pathways for addiction [20].…”

Section: Introductionmentioning

confidence: 99%

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

2008

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Chronic abuse of cocaine is known to cause neuroadaptive changes in the nucleus accumbens (NAc) and ventral tegmental area (VTA). In addition, altered expression of the myelin-related genes MBP, MOBP, PLP1 as well as of MAL2 in NAc was recently reported by gene array analysis in brains from cocaine abusers. In the present study we used in situ hybridization to quantify transcript expression of these four genes, as well as for the myelin-related transcripts encoding quaking, EDG2, claudin-11, transferrin, CNP, and MAG in caudate, putamen, internal capsule, and NAc in postmortem brain from cocaine abusers and matched comparison subjects. Most transcripts were not different between these groups in these striatal regions, and contrary to previous reports, we did not detect any changes in the NAc. However, expression of the transcript encoding PLP1 was significantly decreased in ventral and dorsal regions of the caudate, putamen, and in the internal capsule. Additionally, expression of claudin-11 and transferrin was decreased in the caudate and internal capsule, respectively. PLP1 is expressed at very high levels in oligodendrocytes and is essential in maintaining stability of myelin sheets. Based on these findings, altered expression of PLP1 in most areas of the striatum suggests that widespread changes to the myelin structure could be associated with the adaptive changes following chronic cocaine abuse.

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Section: Introductionmentioning

confidence: 99%

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

2008

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“…In addition, a functional coupling exists between DA and NE transmission, and DA-related behavior at the transport level is linked to NET function (46). Cocaine up-regulates both dopamine transporter and NET (10,12,29,47,48). However, the underlying cellular and molecular mechanisms are unknown.…”

Section: Discussionmentioning

confidence: 99%

Cocaine Up-regulation of the Norepinephrine Transporter Requires Threonine 30 Phosphorylation by p38 Mitogen-activated Protein Kinase

Padmanabhan

Arapulisamy

Shippenberg

et al. 2011

Journal of Biological Chemistry

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The norepinephrine (NE) transporter (NET) regulates NE signaling by rapidly clearing synaptic NE. Cocaine binds NET and modulates NE transport. These actions contribute to rewarding effects and abuse liability of cocaine. Activation of mitogen-activated protein kinase (MAPK) cascades is implicated in cocaine-induced neuroadaptations. However, the role of MAPK and the mechanisms involved in cocaine modulation of NET are not clear. Acute intra-peritoneal injections of cocaine (20 mg/kg body weight) to rats resulted in increased NE uptake by prefrontal cortex (PFC) synaptosomes with a parallel increase in the surface expression of endogenous NET. Cocaine also enhanced the immunoreactivity of phospho-p38 MAPK in the PFC synaptosomes without affecting the total p38 MAPK. In vitro cocaine (30 -50 M) treatment of rat PFC synaptosomes increased native NET function, surface expression, and phosphorylation in a manner sensitive to p38 MAPK inhibition by PD169316. We next examined cocaine-elicited effects on wild-type human NET (hNET) expressed heterologously in human placental trophoblast cells to gain more insights into the mechanisms involved. Cocaine treatment of hNET expressing human placental trophoblast cells up-regulated the function, surface expression, and phosphorylation of hNET in a PD169316-sensitive manner. In addition, cocaine inhibited constitutive endocytosis of hNET. Mutational analysis of serine and threonine residues revealed that substitution of threonine 30, located at the amino terminus of hNET with alanine (T30A-hNET), abolished cocaine-induced up-regulation of NET function, surface expression, and phosphorylation. Furthermore, cocaine did not alter T30A-hNET endocytosis. These studies identify a novel molecular mechanism that cocaine-activated p38 MAPK-mediated phosphorylation of NET-T30 dictates surface NET availability, and hence, NE transport.

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“…(17). Yield: 61%, brown resin, THF: 25 mL, purification: silica gel 60, petroleum ether/ethyl acetate 9:1, (18). Yield: 69%, brown resin, THF: 20 mL, purification: silica gel 60, petroleum ether/ethyl acetate 9:1, …”

Section: General Procedures For the Synthesis Of 16-18mentioning

confidence: 99%

“…Thus, the NET, responsible for NE equilibrium in the synaptic cleft, is representing the reuptake site and considered to be involved in a variety of neurological/psychiatric disorders [1,2], but also plays a pivotal role in cardiovascular [1][2][3] and metabolic diseases [3][4][5]. Reduced NET levels go along with neurological disorders like major depression [6,7], Parkinson's disease (PD), Alzheimer's disease (AD) [8][9][10][11][12][13][14][15][16][17][18], and cardiovascular diseases such as hypertension, cardiomyopathy, and heart failure [5,13]. Furthermore, a dysfunction of the NE system was reported in Attention Deficit Hyperactivity Disorder (ADHD) [9,17,19], suicide [1,12,20], substance abuse (cocaine dependence) [16], and schizophrenia [10].…”

Section: Introductionmentioning

confidence: 99%

“…All methylamine-derived benzimidazolone derivatives 4-6 will be subjected to affinity, selectivity, and lipophilicity studies towards the NET as well as blood brain barrier penetration experiments at the Medical University of Vienna. The most promising NET ligands will then be selected for the development of new, selective PET tracers for the NET and after radiolabeling with both 11 C and 18 F, they will be the subject of further experiments. …”

Section: Introductionmentioning

confidence: 99%

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Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter

et al. 2015

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Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz-ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylaminebased analogs of this compound. The newly synthesized compounds were computationally

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Norepinephrine transporter immunoblotting and radioligand binding in cocaine abusers

Cited by 32 publications

References 39 publications

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

Cocaine Up-regulation of the Norepinephrine Transporter Requires Threonine 30 Phosphorylation by p38 Mitogen-activated Protein Kinase

Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter

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