Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomes

Iwata, Shin; Hewlett, Guy; Gnegy, Margaret E.

doi:10.1002/(sici)1098-2396(199707)26:3<281::aid-syn9>3.0.co;2-3

Cited by 54 publications

(19 citation statements)

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“…Several independent laboratories have demonstrated that both acute and chronic amphetamine treatment alter PKC activity, PKC’s relative cytosol to membrane distribution, and phosphorylation of GAP-43, which has been implicated in long-term alterations of presynaptic neurotransmitter release (Giambalvo, 1992a, b; Gnegy, 1993; Iwata et al, 1997). Sleep deprivation is another animal model of mania, and its effects can be prevented by lithium (Gessa et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of Mania

et al. 2009

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SummaryConsiderable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in maniaassociated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site NR1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro-and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.

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Section: Discussionmentioning

confidence: 99%

Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of Mania

et al. 2009

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“…Both acute AMPH and repeated AMPH increase the phosphorylation of neuromodulin (GAP‐43, F1) in rat striatum in vivo and rat striatal synaptosomes in vitro at serine‐41, the PKC‐substrate site (Gnegy et al . 1993; Iwata et al . 1996, 1997a,b).…”

Section: Discussionmentioning

confidence: 99%

Repeated amphetamine treatment induces neurite outgrowth and enhanced amphetamine‐stimulated dopamine release in rat pheochromocytoma cells (PC12 cells) via a protein kinase C‐ and mitogen activated protein kinase‐dependent mechanism

Park

Kantor

Guptaroy

et al. 2003

Journal of Neurochemistry

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Repeated intermittent treatment with amphetamine (AMPH) induces both neurite outgrowth and enhanced AMPH-stimulated dopamine (DA) release in PC12 cells. We investigated the role of protein kinases in the induction of these AMPHmediated events by using inhibitors of protein kinase C (PKC), mitogen activated protein kinase (MAP kinase) or protein kinase A (PKA). PKC inhibitors chelerythrine (100 nM and 300 nM), Ro31-8220 (300 nM) and the MAP kinase kinase inhibitor, PD98059 (30 lM) inhibited the ability of AMPH to elicit both neurite outgrowth and the enhanced AMPH-stimulated DA release. The direct-acting PKC activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA, 250 nM) mimicked the ability of AMPH to elicit neurite outgrowth and enhanced DA release. On the contrary, a selective PKA inhibitor, 100 lM Rp-8-Br-cAMPS, blocked only the development of AMPH-stimulated DA release but not the neurite outgrowth. Treatment of the cells with acute AMPH elicited an increase in the activity of PKC and MAP kinase but not PKA. These results demonstrated that AMPH-induced increases in MAP kinase and PKC are important for induction of both the enhancement in transporter-mediated DA release and neurite outgrowth but PKA was only required for the enhancement in AMPH-stimulated DA release. Therefore the mechanisms by which AMPH induces neurite outgrowth and the enhancement in AMPH-stimulated DA release can be differentiated.

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“…Moreover, the β I and β II isoforms of PKC co-immunoprecipitate with DAT and overexpressing PKCβ II enhances AMPH-stimulated DA efflux again from DAT expressing HEK-293 cells [13]. In addition, AMPH increases particulate PKC activity [7,8] and leads to increased PKC phosphorylation of (S41) neuromodulin, the calmodulin-binding protein thought to modulate transmitter release [10,11]. Although AMPH activates PKC and results in PKC-dependent phosphorylation, it is not known whether PKC produces its effects by directly phosphorylating DAT or other DAT-associated proteins [6].…”

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The PKC inhibitor Ro31-8220 blocks acute amphetamine-induced dopamine overflow in the nucleus accumbens

Loweth

Svoboda

Austin

et al. 2009

Neuroscience Letters

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Acute administration of the psychostimulant amphetamine increases extracellular levels of dopamine (DA) by reversing the DA transporter on ascending midbrain DA neurons. In vitro studies using striatal synaptosomal, slice and nucleus accumbens (NAcc) tissue preparations have implicated protein kinase C (PKC) in this effect. The present study further examined this effect in vivo by assessing the ability of the PKC inhibitor, Ro31-8220 (10 μM), to inhibit acute amphetamine-induced DA overflow when applied with this drug to the NAcc via reverse dialysis. Amphetamine was applied at a concentration of 30 μM and the core and shell subregions of the NAcc were assayed separately in freely moving rats. These brain regions play a role in the acute locomotor-activating and motivational effects of amphetamine. Consistent with the findings of previous in vitro experiments, reverse dialysis of Ro31-8220 with amphetamine robustly attenuated the ability of this drug to increase extracellular levels of dopamine in both the core and shell subregions of the NAcc. These results confirm that amphetamine stimulates dopamine overflow via a PKC-dependent mechanism.Keywords dopamine overflow; nucleus accumbens; PKC; amphetamine; microdialysis Psychomotor stimulant drugs like amphetamine (AMPH) increase locomotion and support self-administration [29,30,31]. There is wide-spread acceptance that AMPH produces these effects through an action-potential independent mechanism by interacting with the dopamine transporter (DAT) to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcc), the major subcortical projection field of midbrain DA neurons [18,21,26]. The outward-facing, membrane-bound form of DAT can bind AMPH, transport the drug into the nerve terminal, release the AMPH in exchange for DA, and transport the neurotransmitter out of the neuron, releasing it into the extracellular space [5,15,26]. In addition to this exchange diffusion mechanism, a number of studies have demonstrated that additional intracellular signal transduction mechanisms may also play a role in AMPH-induced DA release.There is evidence that the cytoplasmic serine/threonine protein kinase C (PKC) contributes importantly to AMPH-stimulated DA release. The PKC activator phorbol ester 12-0-*, Correspondence: Jessica Loweth, 5841 South Maryland Avenue, MC 3077, Chicago, IL 60637, TEL: (773) 702-2891, FAX: (773) 702-0857, E-MAIL: E-mail: jloweth@uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Together, the above findings indicate that PKC activity contributes to AMPH-stimulated DA re...

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Amphetamine increases the phosphorylation of neuromodulin and synapsin I in rat striatal synaptosomes

Cited by 54 publications

References 48 publications

Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of Mania

Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of Mania

Repeated amphetamine treatment induces neurite outgrowth and enhanced amphetamine‐stimulated dopamine release in rat pheochromocytoma cells (PC12 cells) via a protein kinase C‐ and mitogen activated protein kinase‐dependent mechanism

The PKC inhibitor Ro31-8220 blocks acute amphetamine-induced dopamine overflow in the nucleus accumbens

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