Methylphenidate and amphetamine modulate differently the NMDA and AMPA glutamatergic transmission of dopaminergic neurons in the ventral tegmental area

Prieto-Gómez, B.; Vázquez-Alvarez, A. M.; Martínez-Peña, J. L.; Reyes-Vázquez, C.; Peng, Yang; Dafny, Nachum

doi:10.1016/j.lfs.2004.10.076

Cited by 26 publications

(17 citation statements)

References 37 publications

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“…In such behavioral sensitization animals, MPH indeed facilitates the postsynaptic NMDA-R mediated EPSC at PFC-ventral tegmental area (VTA) glutamatergic synapses [71]. In line with this, our results demonstrate for the first time that bath application of MPH enhances, via postsynaptic σ1 receptors, NMDA-R mediated excitatory synaptic transmission in pyramidal cells of the medial prefrontal cortex (mPFC) of rats.…”

Section: Discussionsupporting

confidence: 83%

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

et al. 2012

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Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca2+ increase, but does not require PKA and extracellular Ca2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

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Section: Discussionsupporting

confidence: 83%

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

et al. 2012

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“…Therefore, it has been postulated that when excitatory responses are observed, across all doses, that this is due to MPD binding and activation of D1 receptor activity; whereas, when attenuation responses was observed, it is probably due to MPD binding to D2 receptors. Using high impendence electrodes with a smaller electrode tip (1 to 5μ) and higher resistance, it is possible to determine if the recordings are from DA neurons or not, based on the neuronal firing rates (Prieto-Gomez et al, 2004; 2005). …”

Section: Discussionmentioning

confidence: 99%

Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

Claussen

Dafny

2015

Pharmacology Biochemistry and Behavior

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The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0 mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization were also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals was observed for the 2.5 and 10.0 mg/kg MPD exposed groups. For 2.5 mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0 mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0 mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and oppositely at ED10 MPD rechallenge. While the behaviorally sensitized animals in general increased in their percentage change of firing rats were observed following acute 10.0 mg/kg MPD and the behaviorally sensitized 10.0 mg/kg MPD animals and a robust increase in neuronal firing rates at ED1 and ED10 rechallenge. These results suggest the need to first individually analyze animal behavioral activity, and than to evaluate the neuronal responses to the drug based on the animals behavioral response to chronic MPD exposure.

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“…Chronic exposure to psychostimulants results in the initiation and alteration of biochemical, molecular, and morphological configuration as well as behavioral changes that lead to plasticity in the central nervous system (Chao and Nestler, 2004; Dafny and Yang, 2006; Dietz et al, 2009; Kim et al, 2009; Nestler 2004; Robison and Nestler, 2011). Previous electrophysiological studies investigating the mechanisms of MPD have been done primarily with the use of anesthesia (Lacroix and Ferron, 1988; Volz et al, 2009) or in vitro (Gronier, 2011; Prieto-Gomez et al, 2004, 2005). It has been shown that anesthesia modulates the central nervous system's activity, thus the use of anesthesia could potentially interact with MPD and modulate the drug effects on brain activity.…”

Section: Introductionmentioning

confidence: 99%

Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

Jones

Dafny²

2013

J Neural Transm

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Methylphenidate (MPD) is used to treat ADHD and as a cognitive enhancement and recreationally. MPD's effects are not fully understood. One of the sites of psychostimulant action is the ventral tegmental area (VTA). The VTA neuronal activity was recorded from freely behaving rats using a wireless system. 51 animals were divided into groups: saline, 0.6, 2.5, and 10.0 mg/kg MPD. The same repetitive MPD dose can elicit either behavioral sensitization or tolerance, thus the evaluation of the VTA neuronal activity was based on the animals’ behavioral response to chronic MPD exposure: animals exhibiting behavioral tolerance or sensitization. Acute MPD elicits dose related increases in behavioral activity. About half of the animals exhibited behavioral sensitization or tolerance to each of the MPD doses. 361 units were recorded from the VTA and exhibited similar spike shape on experimental day 1 (ED1) and on ED10. 71%, 84%, and 79% of VTA units responded to acute 0.6, 2.5, and 10.0 mg/kg MPD respectively. The neuronal baseline activity at ED10 was significantly modified in 94%, 95%, and 100% of VTA units following 0.6, 2.5 and 10.0 mg/kg MPD respectively. Following chronic MPD exposure, 91%, 98%, and 100% exhibit either electrophysiological tolerance or sensitization of 0.6, 2.6, or 10.0 mg/kg MPD respectively. In conclusion, the chronic administration of the same dose of MPD caused some animals to exhibit behavioral sensitization and other animals to exhibit tolerance. The VTA units recorded from animals exhibiting behavioral sensitization responded significantly differently to MPD from animals that exhibited behavioral tolerance.

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Methylphenidate and amphetamine modulate differently the NMDA and AMPA glutamatergic transmission of dopaminergic neurons in the ventral tegmental area

Cited by 26 publications

References 37 publications

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

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