Cocaine up-regulates norepinephrine transporter binding in the rat placenta

Shearman, Lauren P.; Meyer, Jerrold S.

doi:10.1016/s0014-2999(99)00624-x

Cited by 18 publications

(7 citation statements)

References 28 publications

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“…Studies examining the effect of repeated treatment of rats with cocaine have revealed conflicting findings. Prenatal exposure to cocaine has been reported to increase radioligand binding to the NET in the placenta (Shearman and Meyer 1999), to decrease radioligand binding to the NET in postnatal rat cardiac tissue (Zhao and Sun 2004), and to have no effect on NET protein in postnatal rat brain (Shearman and Meyer 1999). Benmansour et al .…”

Section: Regulation By Substrates and Inhibitors Acting At The Netmentioning

confidence: 99%

The norepinephrine transporter and its regulation

Mandela¹,

Ordway²

2006

Journal of Neurochemistry

129

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For many years, the norepinephrine transporter (NET) was considered a 'static' protein that contributed to the termination of the action of norepinephrine in the synapse of noradrenergic neurons. The concept that the NET is dynamically regulated, adjusting noradrenergic transmission by changing its function and/or expression, was considered initially in the mid 1980s. Since that time, a plethora of studies demonstrate that the NET is regulated by several intracellular and extracellular signaling molecules, and that phosphorylation of the NET is a major pathway regulating its cell surface expression and thereby its function. The NET is a target of action of a number of drugs that are used long-term therapeutically or abused chronically. This has driven numerous investigations of how the NET and its function are regulated by long-term exposure to drugs. While repeated exposure to many drugs has been shown to affect NET function and expression, the intracellular mechanisms for these effects remains elusive.

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Section: Regulation By Substrates and Inhibitors Acting At The Netmentioning

confidence: 99%

The norepinephrine transporter and its regulation

Mandela¹,

Ordway²

2006

Journal of Neurochemistry

129

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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%

“…In addition to its abuse potential resulting from monoaminergic dysregulation, the use of cocaine during pregnancy has been associated with an increased risk for adverse intrauterine effects including growth restriction and placental abruption. NET binding sites are also increased in the placenta of pregnant dams following chronic cocaine exposure (12). Placental NET is thought to shield the fetus from maternal catecholamines (13,14), and fetomaternal complications associated with cocaine addiction have been attributed to alterations in placental NET function (15).…”

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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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“…57 Another study showed increased levels of NET binding sites in the placentas of rats treated with cocaine refl ecting increased NET mRNA levels. 58 NET binding sites are also increased in stria terminalis of cocaine self-administered monkeys. 59 Although the actual cellular signaling pathways responsible for such regulation at the genetic level are yet to be identifi ed, these studies suggest a signifi cant functional role for the monoamine transporters not only in the monoaminergic neurotransmission, but also in the fetal development.…”

Section: Regulation At the Gene Levelmentioning

confidence: 90%

Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants

Jayanthi

Ramamoorthy

2005

AAPS J

108

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A BSTRACT Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specifi c molecular targets. At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre-and postsynaptic receptors and transporters. Monoamines, 5-hydroxytryptamine or serotonin (5-HT), norepinephrine (NE), and dopamine (DA) play an important modulatory role in the CNS and are involved in numerous physiological functions and pathological conditions. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine. Monoamine transporters are the sites of action for widely used antidepressants and are high affi nity molecular targets for drugs of abuse including cocaine, amphetamine, and 3,4-methylenedioxymetamphetamine (MDMA) " Ecstasy. " Monoamine transporters also serve as molecular gateways for neurotoxins. Emerging evidence indicates that regulation of transporter function and surface expression can be rapidly modulated by " intrinsic " transporter activity itself, and antidepressant and psychostimulant drugs that block monoamine transport have a profound effect on transporter regulation. Therefore, disregulations in the functioning of monoamine transporters may underlie many disorders of transmitter imbalance such as depression, attention defi cit hyperactivity disorder, and schizophrenia. This review integrates recent progress in understanding the molecular mechanisms of monoamine transporter regulation, in particular, posttranscriptional regulation by phosphorylation and traffi cking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in infl uencing monoamine transport regulation.K EYWORDS: phosphorylation , traffi cking , interacting proteins , substrates , and ligands NEUROBIOLOGY OF MONOAMINE TRANSPORTERSThe catecholamines dopamine (DA) and norepinephrine (NE) derived from tyrosine and the indolamine 5-hydroxytryptamine or serotonin (5-HT) derived from tryptophan, packaged into synaptic vesicles and released into synapse in response to depolarizing stimuli, activate pre-and postsynaptic receptors and elicit synaptic responses. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine, thereby dictating the kinetics of postsynaptic responses and receptor desensitization. Drugs that modulate the activity of biogenic monoamine transporters produce profound behavioral effects, leading to their therapeutic use in depression, obsessive-compulsive disorder, and other mental diseases and also to their abuse as stimulants. SERTAltered serotonergic neurotransmission and s...

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Cocaine up-regulates norepinephrine transporter binding in the rat placenta

Cited by 18 publications

References 28 publications

The norepinephrine transporter and its regulation

The norepinephrine transporter and its regulation

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

Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants

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