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Articles, Neurobiology of Disease

Extrasynaptic Targeting of NMDA Receptors Following D1 Dopamine Receptor Activation and Cocaine Self-Administration

Pavel I. Ortinski, Jill R. Turner and R. Christopher Pierce
Journal of Neuroscience 29 May 2013, 33 (22) 9451-9461; DOI: https://doi.org/10.1523/JNEUROSCI.5730-12.2013
Pavel I. Ortinski
1Department of Psychiatry and
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Jill R. Turner
2Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
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R. Christopher Pierce
1Department of Psychiatry and
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Abstract

We previously showed that after repeated exposure to cocaine, D1-like dopamine receptor (D1DR) stimulation reverses plastic changes of AMPA receptor-mediated signaling in the nucleus accumbens shell. However, there is little information on the impact of cocaine self-administration on D1–NMDA receptor interactions in this brain region. Here, using whole-cell patch-clamp recordings, we assessed whether cocaine self-administration alters the effects of D1DR stimulation on synaptic and extrasynaptic NMDA receptors (NMDARs). In slices from cocaine-naive rats, pretreatment with a D1DR agonist decreased synaptic NMDAR-mediated currents and increased the contribution of extrasynaptic NMDARs. In contrast, neither cocaine self-administration alone nor cocaine experience followed by D1DR stimulation had an effect on synaptic or extrasynaptic NMDAR signaling. Activation of extrasynaptic NMDARs relies on the availability of extracellular glutamate, which is regulated primarily by glutamate transporters. In cocaine-experienced animals, relative to cocaine-naive rats, administration of a glutamate reuptake blocker, dl-threo-β-benzyloxyaspartic acid, revealed increased extrasynaptic NMDAR activity and stronger baseline activity of glutamate uptake transporters. In cocaine-naive rats, the D1DR-mediated increase in extrasynaptic NMDAR signaling was independent of the activity of glutamate reuptake transporters. Together, these results indicate that cocaine experience blunts the influence of D1DRs on synaptic and extrasynaptic NMDAR signaling. Additionally, prior cocaine self-administration limits activation of the extrasynaptic NMDAR pool by increasing glutamate reuptake. These findings outline a pattern of adaptive interactions between D1DRs and NMDARs in the nucleus accumbens shell and demonstrate upregulation of extrasynaptic NMDAR signaling as a novel consequence of cocaine self-administration.

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The Journal of Neuroscience: 33 (22)
Journal of Neuroscience
Vol. 33, Issue 22
29 May 2013
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Extrasynaptic Targeting of NMDA Receptors Following D1 Dopamine Receptor Activation and Cocaine Self-Administration
Pavel I. Ortinski, Jill R. Turner, R. Christopher Pierce
Journal of Neuroscience 29 May 2013, 33 (22) 9451-9461; DOI: 10.1523/JNEUROSCI.5730-12.2013

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Extrasynaptic Targeting of NMDA Receptors Following D1 Dopamine Receptor Activation and Cocaine Self-Administration
Pavel I. Ortinski, Jill R. Turner, R. Christopher Pierce
Journal of Neuroscience 29 May 2013, 33 (22) 9451-9461; DOI: 10.1523/JNEUROSCI.5730-12.2013
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JNeurosci   Print ISSN: 0270-6474   Online ISSN: 1529-2401