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Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum

Nature Neuroscience volume 17, pages 540–548 (2014)Cite this article

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Abstract

As prescription opioid analgesic abuse rates rise, so does the need to understand the long-term effects of opioid exposure on brain function. The dorsal striatum is an important site for drug-induced neuronal plasticity. We found that exogenously applied and endogenously released opioids induced long-term depression (OP-LTD) of excitatory inputs to the dorsal striatum in mice and rats. Mu and delta OP-LTD, although both being presynaptically expressed, were dissociable in that they summated, differentially occluded endocannabinoid-LTD and inhibited different striatal inputs. Kappa OP-LTD showed a unique subregional expression in striatum. A single in vivo exposure to the opioid analgesic oxycodone disrupted mu OP-LTD and endocannabinoid-LTD, but not delta or kappa OP-LTD. These data reveal previously unknown opioid-mediated forms of long-term striatal plasticity that are differentially affected by opioid analgesic exposure and are likely important mediators of striatum-dependent learning and behavior.

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Figure 1: Opioid receptor activation produces LTD of excitatory transmission in dorsal striatum.
Figure 2: Bath application of endogenous opioid peptides produces OP-LTD.
Figure 3: Endogenously released opioid peptides induce OP-LTD.
Figure 4: Endogenous opioids are released in an mGluR5 and activity-dependent manner.
Figure 5: mOP- and dOP-LTD operate independently.
Figure 6: MOPrs and DOPrs differentially inhibit specific striatal inputs.
Figure 7: A single in vivo exposure to oxycodone prevents induction of mOP- and eCB-LTD.

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Acknowledgements

We extend special thanks to W. Xiong for his efforts in performing preliminary experiments for this study. This research was supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health.

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Authors and Affiliations

  1. Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland, USA

    Brady K Atwood, David A Kupferschmidt & David M Lovinger

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Contributions

B.K.A. planned experiments, conducted whole-cell recordings, injections and stereotaxic surgeries, analyzed data, and wrote the manuscript. D.A.K. conducted extracellular field recordings and wrote the manuscript. D.M.L. supervised and assisted in experimental planning and wrote the manuscript.

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Correspondence to David M Lovinger.

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Integrated supplementary information

Supplementary Figure 1 Field recordings reveal OP-LTD of net striatal output.

(a) DAMGO (1 μM, 5 min) induced mOP-LTD of population spike amplitude in field recordings of the DLS (vs. control: P=0.0219, t(12)=2.631, n=14). (b) DPDPE (1 μM, 5 min) induced dOP-LTD of population spike amplitude in field recordings of the DLS (vs. control: P=0.0047, t(14)=3.360, n=16). (c) U69,593 (1 μM, 5 min) induced kOP-LTD of population spike amplitude in field recordings of the DLS (vs. control: P=0.0317, t(14)=2.386, n=16). Representative traces are the average of the first 5 min (first of each pair) and the final 5 min (second of each pair) of recording. Scale bars: 0.2 mV, 2 ms. Data analyzed with unpaired Student's t-test.

Source data

Supplementary Figure 2 OP-LTD is equivalent at –60 mV and –80 mV holding potentials in DLS, but only mOP- and dOP-LTD occur in DMS.

(a) DAMGO (1 μM, 5 min) induced comparable mOP-LTD in MSNs recorded at -60 mV (n=11) and -80 mV in DLS (n=4), and at -60 mV in DMS (n=6) (at 25 min: P=0.3741, F(2,18)=1.039). (b) DPDPE (1 μM, 5 min) induced comparable dOP-LTD in MSNs recorded at -60 mV (n=7) and -80 mV in DLS (n=5), and at -60 mV in DMS (n=4) (at 25 min: P=0.6461, F(2,13)=0.4518). (c) U69,593 (0.3 μM, 5 min) induced comparable kOP-LTD in MSNs recorded at -60 mV (n=5) and -80 mV in DLS (n=5). U69,593 failed to induce LTD in DMS (n=6) (at 25 min: P=0.0075, F(2,13)=7.308). Data analyzed with a one-way ANOVA with Dunnett's multiple comparisons post-test: vs. DLS, -60 mV. *: P<0.05.

Source data

Supplementary Figure 3 mOP- and dOP-LTD are expressed presynaptically, whereas kOP-LTD has an unclear site of expression.

(a) Representative traces of sEPSCs recorded from a DLS MSN before, immediately after, and 20-25 min following DAMGO (0.3 μM, 5 min). DAMGO (0.3 μM, 5 min) induced a long-lasting increase in sEPSC inter-event interval (IEI) (b,c; P=0.0063, Friedman statistic=9.800, n=9) with no change in sEPSC amplitude (d; P=0.2223, Friedman statistic=3.200). (e) Representative sEPSC traces for DPDPE (0.3 μM, 5 min). DPDPE (0.3 μM, 5 min) produced a long-lasting increase in sEPSC IEI (f,g; P=0.0207, Friedman statistic=7.714, n=7) with no change in sEPSC amplitude (h; P=0.0854, Friedman statistic=5.429). (i) Representative sEPSC traces for U69,593 (0.3 μM, 5 min). U69,593 (0.3 μM, 5 min) produced no change in sEPSC IEI (j,k; P=0.0570, Friedman statistic=6.000, n=9), but produced a delayed decrease in sEPSC amplitude (l; P=0.0307, Friedman statistic=6.889). Scale bars: 20 pA, 2 s. Data in c-d, g-h, and k-l analyzed with Friedman test with Dunn's multiple comparisons post-test. *: P<0.05.

Source data

Supplementary Figure 4 The lack of an additive effect of a MOPr and a CB1 agonist suggests a presynaptically localized occlusiveness of mOP-LTD and CB1-LTD.

DAMGO (0.3 μM; n=5), WIN55,212-2 (1 μM, n=5), or their combination (n=6), each applied for 10 min, induced comparable magnitudes of depression (P=0.7797, F(2,13)=0.2537). Representative traces are the average of the first 10 min (first of pair) and the final 10 min (second of pair) of recording. Scale bars: 50 pA, 50 ms. Data analyzed with one-way ANOVA with Tukey's post-test.

Source data

Supplementary Figure 5 eCB-LTD is not blocked by opioid receptor antagonists, and OP-LTD is not blocked by a CB1 antagonist.

(a) Pre-application of the CB1 receptor antagonist, AM251 (3 μM), did not alter mOP-LTD induced by DAMGO (0.3 μM to 1 μM, 5 min; at 30 min:P=0.9836, t(8)=0.02127, n=5 each). (b) Pre-application of AM251 (3 μM) did not alter dOP-LTD induced by DPDPE (0.3 μM to 1 μM, 5 min; at 30 min: P=0.5996; t(9)=0.5441, n=5 control, n=6 AM251). (c) Pre-application of the opioid receptor antagonist, naloxone (2 μM), did not alter eCB-LTD induced by HFS paired with postsynaptic depolarization (at 30 min: P=0.6162, t(10)=0.5173, n=6 each). Data analyzed with unpaired Student's t-test.

Source data

Supplementary Figure 6 Expression of ChR2-Venus in hippocampus does not result in striatal ChR2-Venus expression.

(a) Lack of striatal expression of ChR2-Venus in striatum following an injection of AAV vector in hippocampus. Injection coordinates: A/P: -2.0, M/L: ± 0.35, D/V: -1.45. (b) AAV vector injection in hippocampus produces substantial ChR2-Venus expression at the injection site. Images are representative of 1 injected mouse. Scale bars: 1 mm.

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Atwood, B., Kupferschmidt, D. & Lovinger, D. Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum. Nat Neurosci 17, 540–548 (2014). https://doi.org/10.1038/nn.3652

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