Courtney Sakas’s research while affiliated with Rosalind Franklin University of Medicine and Science and other places

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Publications (2)


Ionotropic and metabotropic glutamate receptors regulate protein translation in co-cultured nucleus accumbens and prefrontal cortex neurons
  • Article

May 2018

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27 Reads

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7 Citations

Neuropharmacology

Michael T. Stefanik

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Courtney Sakas

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Dennis Lee

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Marina E. Wolf

The regulation of protein translation by glutamate receptors and its role in plasticity have been extensively studied in the hippocampus. In contrast, very little is known about glutamatergic regulation of translation in nucleus accumbens (NAc) medium spiny neurons (MSN), despite their critical role in addiction-related plasticity and recent evidence that protein translation contributes to this plasticity. We used a co-culture system, containing NAc MSNs and prefrontal cortex (PFC) neurons, and fluorescent non-canonical amino acid tagging (FUNCAT) to visualize newly synthesized proteins in neuronal processes of NAc MSNs and PFC pyramidal neurons. First, we verified that the FUNCAT signal reflects new protein translation. Next, we examined the regulation of translation by group I metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors by incubating co-cultures with agonists or antagonists during the 2-h period of non-canonical amino acid labeling. In NAc MSNs, basal translation was modestly reduced by blocking Ca2+-permeable AMPARs whereas blocking all AMPARs or suppressing constitutive mGluR5 signaling enhanced translation. Activating group I mGluRs with dihydroxyphenylglycine increased translation in an mGluR1-dependent manner in NAc MSNs and PFC pyramidal neurons. Disinhibiting excitatory transmission with bicuculline also increased translation. In MSNs, this was reversed by antagonists of mGluR1, mGluR5, AMPARs or NMDARs. In PFC neurons, AMPAR or NMDAR antagonists blocked bicuculline-stimulated translation. Our study, the first to examine glutamatergic regulation of translation in MSNs, demonstrates regulatory mechanisms specific to MSNs that depend on the level of neuronal activation. This sets the stage for understanding how translation may be altered in addiction.


AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

April 2016

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59 Reads

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83 Citations

Biological Psychiatry

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Marina E. Wolf

Background: The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. Methods: Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-naphthyl acetyl spermine followed by a seeking test, or 3) systemic administration of a mGluR1 positive allosteric modulator followed by a seeking test. Results: Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc core 1-naphthyl acetyl spermine injection or systemic mGluR1 positive allosteric modulator administration. Conclusions: These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine compared with cocaine. However, a common mGluR1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts.

Citations (2)


... We have previously validated FUNCAT as a measure of protein translation in processes of NAc MSNs in the same co-culture system utilized here [35]. Briefly, we showed that AHA incorporation was abolished by the protein translation inhibitor cycloheximide and colocalizes with the ribosomal protein S6, a marker of translation. ...

Reference:

Dopamine D1 and NMDA receptor co-regulation of protein translation in cultured nucleus accumbens neurons
Ionotropic and metabotropic glutamate receptors regulate protein translation in co-cultured nucleus accumbens and prefrontal cortex neurons
  • Citing Article
  • May 2018

Neuropharmacology

... These genes were divided into four classes. The first class includes glutamate receptors because previous work in rodents implicated glutamate signaling across multiple brain areas in incubation of Meth craving (e.g., Li et al., 2015;Scheyer et al., 2016;Murray et al., 2019;Pena-Bravo et al., 2019). The second includes GABAergic receptors, based on previous work demonstrating the critical roles of GABAergic signaling in DS in context-induced reinstatement of Meth seeking (Rubio et al., 2015) and Meth-induced conditioned place preference (Jiao et al., 2016) in rats. ...

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving
  • Citing Article
  • April 2016

Biological Psychiatry