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Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses

Nature Neuroscience volume 19, pages 915–925 (2016)Cite this article

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Abstract

Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. In an effort to explain this paradox, we found that both drugs induced NMDA receptor–containing, AMPA receptor-silent excitatory synapses, albeit in distinct cell types through opposing cellular mechanisms. Cocaine selectively induced silent synapses in D1-type neurons, likely via a synaptogenesis process, whereas morphine induced silent synapses in D2-type neurons via internalization of AMPA receptors from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses became 'unsilenced' by recruiting AMPA receptors to strengthen excitatory inputs to D1-type neurons, whereas morphine-generated silent synapses were likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell type–specific, opposing mechanisms produced the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.

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Figure 1: Exposure to morphine generates silent synapses in NAc MSNs.
Figure 2: Morphine-induced generation of silent synapses is mediated by AMPAR internalization.
Figure 3: Alterations in spine morphology of rat NAc MSNs 1 d after morphine or cocaine administration.
Figure 4: Alterations in spine morphology of rat NAc MSNs 21 d after morphine or cocaine administration.
Figure 5: Drug-induced alterations in spine morphology of mouse NAc MSNs.
Figure 6: Cell type–specific generation of silent synapses after exposure to cocaine or morphine remodels excitatory circuits in the NAc.
Figure 7: Intra-NAc infusion of GluA23Y peptide selectively impairs the retention of morphine-induced CPP.

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Acknowledgements

We thank L. Cai, K. Chua, Y. Li, K. Tang, A. Kim and S. Singh for technical support. The study was supported by NIH NIDA DA035805 (Y.H.H.), MH101147 (Y.H.H.), DA008227 (E.J.N.), DA014133 (E.J.N.) DA023206 (Y.D.), DA034856 (Y.D.), DA040620 (E.J.N., Y.D.), and the Pennsylvania Department of Health (Y.H.H.). Cocaine and morphine were provided by the Drug Supply Program of NIDA NIH.

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  1. Shichao Sun and William J Wright: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Nicholas M Graziane, Shichao Sun, William J Wright, Daniel Jang, Oliver M Schlüter & Yan Dong

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Nicholas M Graziane, Zheng Liu, Yanhua H Huang & Yan Dong

  3. Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Eric J Nestler

  4. Brain Research Centre and Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia Vancouver, British Columbia, Canada

    Yu Tian Wang

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Contributions

N.M.G., S.S., W.J.W., Y.H.H., E.J.N., Y.T.W., O.M.S. and Y.D. designed the experiments and analyses. N.M.G., S.S., W.J.W., D.J. and Z.L. conducted the experiments and data analyses. N.M.G., Y.H.H., E.J.N., O.M.S. and Y.D. wrote the manuscript.

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Correspondence to Yan Dong.

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Integrated supplementary information

Supplementary Figure 1 Co-administration of GluA23Y peptide does not affect cocaine-induced locomotor responses and cocaine-induced CPP.

a Summary showing that co-administration of GluA23Y with cocaine did not affect cocaine-induced locomotor responses over the 5d procedure compared to mice with cocaine injection alone (F8,120=0.9436, p=0.4836, two-way ANOVA). Time line of the experimental procedure is diagramed in Figure 7A. Briefly, mice received saline injections and locomotor activity was assayed on d-1 and d0. On d1-5, locomotor activity was measured following administration of scrambled peptide or GluA23Y (1.5 nm/g, iv) with saline or cocaine (15 mg/kg, ip). On d21, saline- or cocaine-treated mice were challenged with saline then cocaine (15 mg/kg), while saline- or morphine-treated mice were challenged with cocaine (15 mg/kg). b Summary showing that co-administration of GluA23Y during the 5d cocaine procedure did not affect cocaine challenge-induced locomotor responses 21d after the 5d procedure (distance in meters: saline 21.9±1.2, n=10, saline-scrambled 19.8±3.6, n=5, saline-GluA23Y 23.0±3.2, n=4, cocaine 22.9±3.0, n=8, cocaine-scrambled 29.9±2.2, n=10, cocaine-GluA23Y 27.1±2.2, n=9; F5,40=2.422, p=0.05, one-way ANOVA). c Time line of the experimental procedure for drug challenge-induced locomotor responses 21d after the 5d drug procedure. d Summary showing cocaine-induced locomotor responses in two groups of mice with the 5d cocaine procedure (F6,126=0.1425, p=0.99, two-way ANOVA). During the procedure, these mice did not receive co-administration of peptides. e Summary showing that 21d after the 5d cocaine procedure, a cocaine challenge induced similar locomotor responses in mice with GluA23Y or scrambled peptides co-administered with cocaine challenge (distance in meters: scrambled 33.4±2.5, n=10, GluA23Y 30.6±1.7, n=10, t18=0.92, p=0.37; t-test). f Summary showing morphine-induced locomotor responses in two groups of mice with the 5d procedure (F6,102=0.3672, p=0.8981, two-way ANOVA). During the procedure, these mice did not receive co-administration of peptides. g Summary showing that 21d after the 5d cocaine procedure, a morphine challenge induced similar locomotor responses in mice with GluA23Y or scrambled peptides co-administered with morphine challenge (distance in meters: scrambled 54.5±2.9, n=10, GluA23Y 61.3±4.0, n=10, t18=1.38, p=0.18; t-test). h Diagrams showing the cannulation sites where GluA2 peptides were delivered in CPP experiments (open circles, scrambled peptide; filled circles, GluA23Y).

Supplementary Figure 2 Determination of successes and failures of synaptic responses in minimal stimulation assay.

a Trials of the amplitudes of synaptic responses evoked by minimal stimulations. Black dots indicate amplitudes of success and gray dots indicate amplitudes of failures (n=20 rats). Inset: Example traces at -70 or +50 mV containing both successes and failures over continuous trials are stacked. b Stacked traces in a are individually presented. Responses that are deemed failures (in gray) are presented in the upper panel, and responses that are deemed successes (in black) are presented in the lower panel (n=20 mice). Vertical dash lines in black trace #2 in the upper panel indicate the time window during which the averaged amplitudes (mean) of EPSCs were obtained for graphing the trial course in a. c Trials of amplitudes of synaptic responses in an example NAcSh MSN evoked by minimal stimulations at -70 mV, at +50 mV, and at +50 mV with perfusion of the AMPAR-selective antagonist NBQX (5 µM) (n=6 cells). d Example EPSCs taken from the cell in c (n=6 cells). Black traces indicate successful responses and gray traces indicate failed responses (n=6 mice). e Averaged successful traces in three recording conditions as indicated. f Summary showing that the mean amplitudes of EPSCs at +50 mV exhibited a trend to decrease by perfusion of NBQX (n=6 cells; t5=1.97, p=0.10, paired t-test). g Summary showing that % silent synapses was not statistically different when EPSCs were recorded at +50 mV in the presence or absence of NBQX (t5=0.95, p=0.39, paired t-test).

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Graziane, N., Sun, S., Wright, W. et al. Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci 19, 915–925 (2016). https://doi.org/10.1038/nn.4313

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