Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice

Fukui, Ryuichi; Svenningsson, Per; Matsuishi, Toyojiro; Higashi, Hideho; Nairn, Angus C.; Greengard, Paul; Nishi, Akinori

doi:10.1046/j.1471-4159.2003.02101.x

Cited by 54 publications

(33 citation statements)

References 53 publications

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“…Acute exposure to cocaine failed to increase the phosphorylation of DARPP-32 at the Thr 34 site in the dorsal striatum of postweanling mice, consistent with previous results in brain slices (Fukui et al, 2003). However, because we saw only a 32% increase in phosphoThr 34 -DARPP-32 after cocaine in simultaneously studied adult mice, it is difficult to make a firm conclusion as to whether these data are reflective of age and/or background strain (Sun et al, 2007).…”

Section: Discussionsupporting

confidence: 80%

“…Increased PKA activity results in phosphorylation of dopamine-and cAMP-regulated phosphoprotein of 32 kDa at the Thr 34 site (Hemmings et al, 1984), and DARPP-32 and its phosphorylation at the Thr 34 site are required for the development of cocaine place preference in adult mice (Zachariou et al, 2002(Zachariou et al, , 2006. Whereas cocaine induces phosphorylation of DARPP-32 in the adult, this does not occur in striatal slices from younger mice (Fukui et al, 2003). Levels of total DARPP-32 are unchanged after cocaine exposure in adults (Bibb et al, 2001;Ehrlich et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…This developmental window represents a period of increased plasticity of the brain (for review, see Laviola et al, 1999). Intrinsic alterations in modulators of neurotrophic and dopaminergic activity may contribute to the fact that younger animals are affected differentially by psychostimulants compared with their adult counterparts (Andersen, 2002;Ehrlich et al, 2002;Fukui et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Trk: A Neuromodulator of Age-Specific Behavioral and Neurochemical Responses to Cocaine in Mice

Niculescu¹,

Perrine²,

Miller³

et al. 2008

J. Neurosci.

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Responses to psychostimulants vary with age, but the molecular etiologies of these differences are largely unknown. The goal of the present research was to identify age-specific behavioral and molecular adaptations to cocaine and to elucidate the mechanisms involved therein. Postweanling, periadolescent, and adult male CD-1 mice were exposed to cocaine (20 mg/kg) for 7 d. The rewarding effects of cocaine were assessed, as were the response to a Trk antagonist and the regulation of dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32). Cocaine was rewarding in both periadolescent and adult mice using a conditioned place preference procedure. In contrast, postweanling mice failed to demonstrate significant cocaine-induced place preference. Because components of the neurotrophin system including brain-derived neurotrophic factor and TrkB are developmentally regulated, their role in the age-specific effects of cocaine was determined using the Trk receptor antagonist K252a. Postweanling mice that received K252a before daily cocaine showed a significant place preference to the cocaine-paired environment that was not seen in the absence of K252a. DARPP-32 protein levels were significantly upregulated in the lateral region of the caudate-putamen exclusively in postweanling mice after chronic cocaine. Daily pretreatment with K252a attenuated the induction of DARPP-32 in the postweanling striatum. These data indicate that Trk neurotransmission plays a role in age-specific behavioral and molecular responses to cocaine and concurrently modulates DARPP-32 levels.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Trk: A Neuromodulator of Age-Specific Behavioral and Neurochemical Responses to Cocaine in Mice

Niculescu¹,

Perrine²,

Miller³

et al. 2008

J. Neurosci.

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“…First, activation or inhibition of the cAMP pathway through D1 and D2 dopamine receptors leads to regulation of protein kinase A and modulation of the dopamine and cAMPregulated phosphoprotein, 32 kDa (DARPP-32), an inhibitor of protein phosphatase-1 (21). Phosphorylation of DARPP-32 on Thr-34 has been associated with locomotor activation and biochemical responses to multiple psychotropic drugs, including psychostimulants (14,16,17). Second, a distinct signaling pathway involves the serine/threonine kinase Akt that is negatively regulated by D2-class receptors through a signaling complex involving protein phosphatase-2A and ␤-arrestin 2 (14).…”

mentioning

confidence: 99%

Paradoxical Striatal Cellular Signaling Responses to Psychostimulants in Hyperactive Mice

Beaulieu

Sotnikova

Gainetdinov

et al. 2006

Journal of Biological Chemistry

101

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Recent investigations have shown that three major striatalsignaling pathways (protein kinase A/DARPP-32, Akt/glycogen synthase kinase 3, and ERK) are involved in the regulation of locomotor activity by the monoaminergic neurotransmitter dopamine. Here we used dopamine transporter knock-out mice to examine which particular changes in the regulation of these cell signaling mechanisms are associated with distinct behavioral responses to psychostimulants. In normal animals, amphetamine and methylphenidate increase extracellular levels of dopamine, leading to an enhancement of locomotor activity. However, in dopamine transporter knock-out mice that display a hyperactivity phenotype resulting from a persistent hyperdopaminergic state, these drugs antagonize hyperactivity. Under basal conditions, dopamine transporter knock-out mice show enhanced striatal DARPP-32 phosphorylation, activation of ERK, and inactivation of Akt as compared with wild-type littermates. However, administration of amphetamine or methylphenidate to these mice reveals that inhibition of ERK signaling is a common determinant for the ability of these drugs to antagonize hyperactivity. In contrast, psychostimulants activate ERK and induce hyperactivity in normal animals. In hyperactive mice psychostimulant-mediated behavioral inhibition and ERK regulation are also mimicked by the serotonergic drugs fluoxetine and 5-carboxamidotryptamine, thereby revealing the involvement of serotonin-dependent inhibition of striatal ERK signaling. Furthermore, direct inhibition of the ERK signaling cascade in vivo using the MEK inhibitor SL327 recapitulates the actions of psychostimulants in hyperactive mice and prevents the locomotor-enhancing effects of amphetamine in normal animals. These data suggest that the inhibitory action of psychostimulants on dopamine-dependent hyperactivity results from altered regulation of striatal ERK signaling. In addition, these results illustrate how altered homeostatic state of neurotransmission can influence in vivo signaling responses and biological actions of pharmacological agents used to manage psychiatric conditions such as Attention Deficit Hyperactivity Disorder (ADHD).Dopaminergic neurotransmission mediates a series of physiological functions ranging from the control of locomotion and cognition to attention, emotion, and reward (1-3). This neurotransmitter system is also the main target for the actions of psychostimulants. By interfering with dopamine transporter (DAT) 3 functions, compounds like methylphenidate and amphetamine normally increase extracellular levels of dopamine, leading to their well known locomotor-promoting/stimulant effect. However, under certain conditions psychostimulants can antagonize hyperactivity through a mechanism of action that is not well understood. Indeed, psychostimulants are used therapeutically to manage the symptoms of hyperactivity, impulsivity, and inattention associated with Attention Deficit Hyperactivity Disorder (ADHD), a common psychiatric condition affecting a significant portion...

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“…The interaction between PPP2R5D with A/C dimer, however, was not affected by phospho-Tyr 307 because pull down experiment for Flag-PPP2R5D using anti-Flag antibody from HEK293 cells treated without or with forskolin yielded same amount of A or C subunit co-immunoprecipitation. Forskolin treatment increased intracellular cAMP which triggers several biochemical signaling pathways, and interestingly, enhanced the PP2A activity via two separated targets (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation on the PPP2R5D B regulatory subunit modulates the biochemical properties of protein phosphatase 2A

Yu¹,

Ahn²

2010

BMB Reports

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To characterize the biochemical properties of the PP2A regulatory B subunit, PPP2R5D, we analyzed its phosphorylation sites, stoichiometry and effect on holoenzyme activity. PPP2R5D was phosphorylated on Ser-53, Ser-68, Ser-81, and Ser-566 by protein kinase A, and mutations at all four of these sites abolished any significant phosphorylation in vitro. In HEK293 cells, however, the Ser-566 was the major phosphorylation site after PKA activation by forskolin, with marginal phosphorylation on Ser-81. Inhibitory tyrosine phosphorylation on Tyr-307 of the PP2A catalytic C subunit was decreased after forskolin treatment. Kinetic analysis showed that overall PP2A activity was increased with phosphorylation by PPP2R5D phosphorylation. The apparent Km was reduced from 11.25 μM to 1.175 μM with PPP2R5D phosphorylation, resulting in an increase in catalytic activity. These data suggest that PKAmediated activation of PP2A is enabled by PPP2R5D phosphorylation, which modulates the affinity of the PP2A holoenzyme to its physiological substrates. [BMB reports 2010; 43(4): 263-267]

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Effect of methylphenidate on dopamine/DARPP signalling in adult, but not young, mice

Cited by 54 publications

References 53 publications

Trk: A Neuromodulator of Age-Specific Behavioral and Neurochemical Responses to Cocaine in Mice

Trk: A Neuromodulator of Age-Specific Behavioral and Neurochemical Responses to Cocaine in Mice

Paradoxical Striatal Cellular Signaling Responses to Psychostimulants in Hyperactive Mice

Phosphorylation on the PPP2R5D B regulatory subunit modulates the biochemical properties of protein phosphatase 2A

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