Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

Cheng, Jia; Xiong, Zhe; Duffney, Lara J.; Wei, Jing; Liu, Aiyi; Liu, Sihang; Chen, Guojun; Yan, Zhen

doi:10.1016/j.biopsych.2014.04.003

Cited by 64 publications

(68 citation statements)

References 56 publications

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“…All these events could be related to detriment of synaptogenesis and maturation of functional synaptic connectivity in the hippocampus of juvenile rats treated with MPH. In agreement with our result, Cheng et al [60] showed that SNAP-25 has important role on behavioral, electrophysiological, and biochemical changes promoted by MPH. However, we cannot rule out the hypothesis that the reduction of SNAP-25 immunocontent in the hippocampus of juvenile rats exposed to chronic treatment with MPH may be a way that the body found to protect themselves from the toxic effects of increased release of neurotransmitters (glutamate, dopamine, noradrenaline, and others) in the synaptic cleft and/or a consequence of the reduction of neurons.…”

Section: Discussionsupporting

confidence: 95%

Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats

et al. 2016

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Although the use, and misuse, of methylphenidate is increasing in childhood and adolescence, there is little information about the consequences of this psychostimulant chronic use on brain and behavior during development. The aim of the present study was to investigate hippocampus biochemical, histochemical, and behavioral effects of chronic methylphenidate treatment to juvenile rats. Wistar rats received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9 % saline solution (controls), once a day, from the 15th to the 45th day of age. Results showed that chronic methylphenidate administration caused loss of astrocytes and neurons in the hippocampus of juvenile rats. BDNF and pTrkB immunocontents and NGF levels were decreased, while TNF-α and IL-6 levels, Iba-1 and caspase 3 cleaved immunocontents (microglia marker and active apoptosis marker, respectively) were increased. ERK and PKCaMII signaling pathways, but not Akt and GSK-3β, were decreased. SNAP-25 was decreased after methylphenidate treatment, while GAP-43 and synaptophysin were not altered. Both exploratory activity and object recognition memory were impaired by methylphenidate. These findings provide additional evidence that early-life exposure to methylphenidate can have complex effects, as well as provide new basis for understanding of the biochemical and behavioral consequences associated with chronic use of methylphenidate during central nervous system development.

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Section: Discussionsupporting

confidence: 95%

Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats

et al. 2016

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“…Thus, catecholamines exert receptor-dependent modulation of excitatory and inhibitory amino acid signaling in a variety of brain regions (87–89), including the PFC (90,91). In the PFC, NMDA-receptor mediated excitatory postsynaptic currents (EPSCs) are potentiated by a cognition-enhancing dose of MPH, an action that involves D1 receptors (89–91). Moreover, at least a subset of catecholamine actions in the PFC is linked to the modulation of hyperpolarizationactivated cyclic nucleotide (HCN) channels (92).…”

Section: Receptor Mechanisms In the Pfc: Ne α2 And Da D1 Receptorsmentioning

confidence: 99%

“…In contrast, suppressive effects of high dose psychostimulant on evoked discharge of PFC neurons (reduced by ~80%; Figure S2; 6) involve D1-mediated activation of HCN channels and/or α1-mediated activation of SK channels (92). Additionally, psychostimulant-driven reductions in evoked discharge may involve suppression of glutamatergic signaling, as high doses of MPH (8.0 mg/kg) suppress both NMDA and AMPA-receptor mediated EPSCs (89). …”

Section: Receptor Mechanisms In the Pfc: Ne α2 And Da D1 Receptorsmentioning

confidence: 99%

The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex

Spencer

Devilbiss

Berridge

2015

Biological Psychiatry

140

111

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Psychostimulants are highly effective in the treatment of attention deficit hyperactivity disorder (ADHD). The clinical efficacy of these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) and extended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2- and dopamine D1 receptors. In contrast, while the striatum is a critical participant in ‘PFC-dependent’ cognition, where examined, psychostimulant action within the striatum is not sufficient to enhance cognition. At doses that moderately exceed the clinical range, psychostimulants appear to improve PFC-dependent attentional processes at the expense of other PFC-dependent processes (e.g. working memory, response inhibition). This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 vs. α1 receptors. Collectively, this evidence indicates that at low, clinically-relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation.

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“…Our previous studies in rodents have found that D4R activation modulates NMDAR trafficking and function (Wang et al, 2003), and this modulation goes awry in a schizophrenia model (Wang et al, 2006). Administration of methylphenidate (MPH), a dopamine and norepinephrine reuptake inhibitor approved for ADHD treatment, facilitates attention by potentiating PFC NMDAR function (Cheng et al, 2014). These animal studies prompt us to speculate that the ADHD-linked human D4R variants may induce ADHD-like behaviors via dampening NMDAR function through the aberrant interaction with NMDAR/PSD-95 complex.…”

Section: Introductionmentioning

confidence: 99%

The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex

Qin

Liu

et al. 2016

Neurobiology of Disease

Self Cite

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The human dopamine D4 receptor (hD4R) variants with long tandem repeats in the third intracellular loop have been strongly associated with attention deficit hyperactivity disorder (ADHD) and risk taking behaviors. To understand the potential molecular mechanism underlying the connection, we have investigated the synaptic function of human D4R polymorphism by virally expressing the ADHD-linked 7-repeat allele, hD4.7, or its normal counterpart, hD4.4, in the prefrontal cortex (PFC) of D4R knockout mice. We found that hD4R bound to the SH3 domain of PSD-95 in a state-dependent manner. Activation of hD4.7 caused more reduction of NR1/PSD-95 binding and NR1 surface expression than hD4.4 in PFC slices. Moreover, the NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSC) in PFC pyramidal neurons were suppressed to a larger extent by hD4.7 than hD4.4 activation. Direct stimulation of NMDARs with the partial agonist D-cycloserine prevented the NMDAR hypofunction induced by hD4.7 activation. Moreover, hD4.7-expressing mice exhibited the increased exploratory and novelty seeking behaviors, mimicking the phenotypic hallmark of human ADHD. D-cycloserine administration ameliorated the ADHD-like behaviors in hD4.7-expressing mice. Our results suggest that over-suppression of NMDAR function may underlie the role of hD4.7 in ADHD, and enhancing NMDAR signaling may be a viable therapeutic strategy to ADHD humans carrying the D4.7 allele.

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Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

Cited by 64 publications

References 56 publications

Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats

Methylphenidate Causes Behavioral Impairments and Neuron and Astrocyte Loss in the Hippocampus of Juvenile Rats

The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex

The ADHD-linked human dopamine D4 receptor variant D4.7 induces over-suppression of NMDA receptor function in prefrontal cortex

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