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Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula

Nature Neuroscience volume 18, pages 376–378 (2015)Cite this article

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Abstract

Addictive substances mediate positive and negative states promoting persistent drug use. However, substrates for aversive effects of drugs remain elusive. We found that, in mouse lateral habenula (LHb) neurons targeting the rostromedial tegmental nucleus, cocaine enhanced glutamatergic transmission, reduced K+ currents and increased excitability. GluA1 trafficking in LHb was instrumental for these cocaine-evoked modifications and drug-driven aversive behaviors. Altogether, our results suggest that long-lasting adaptations in LHb shape negative symptoms after drug taking.

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Figure 1: Cocaine-evoked synaptic potentiation onto LHb→RMTg neurons requires GluA1 delivery.
Figure 2: Cocaine drives GluA1-mediated reduction of K+ conductance and hyperexcitability in LHb→RMTg neurons.
Figure 3: Cocaine-driven AMPAR trafficking in LHb serves for a cocaine-evoked depressive-like state in mice.

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Acknowledgements

We thank C. Bellone, M.T.C. Brown, C. Lüscher and J.C. Poncer for discussions and comments on the manuscript. This work was supported by funds from the INSERM Atip-Avenir, ERC StG SalienSy 335333 and the Paris School of Neuroscience Network (ENP) to M.M., and the Agence Nationale de la Recherche (ANR-12-bsv4-0022-01) to F. Georges. F.J.M. is supported by a postdoctoral fellowship from the Fyssen Foundation and K.V. is supported by a PhD fellowship from the French Ministry of Science (ESR).

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Author notes

  1. Frank J Meye, Kristina Valentinova and Salvatore Lecca: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut du Fer à Moulin, Paris, France

    Frank J Meye, Kristina Valentinova, Salvatore Lecca, Lucile Marion-Poll, Matthieu J Maroteaux, Imane Moutkine & Manuel Mameli

  2. Inserm, UMR-S 839, Paris, France

    Frank J Meye, Kristina Valentinova, Salvatore Lecca, Lucile Marion-Poll, Matthieu J Maroteaux, Imane Moutkine & Manuel Mameli

  3. Université Pierre et Marie Curie, Paris, France

    Frank J Meye, Kristina Valentinova, Salvatore Lecca, Lucile Marion-Poll, Matthieu J Maroteaux, Imane Moutkine & Manuel Mameli

  4. Dipartimento di Scienze Farmacologiche e Biomolecolari, DiSFeB, Università degli Studi di Milano, Milano, Italy

    Stefano Musardo & Fabrizio Gardoni

  5. Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Richard L Huganir

  6. Centre National de la Recherche Scientifique, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France

    François Georges

  7. Université de Bordeaux, Bordeaux, France

    François Georges

Authors
  1. Frank J Meye
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  2. Kristina Valentinova
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  11. Manuel Mameli
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Contributions

F.J.M., K.V., S.L. and M.M. performed and analyzed all of the in vitro electrophysiological recordings. K.V., L.M.-P., and M.M. designed and performed the behavioral experiments. I.M. and M.J.M., prepared and tested the viral construct. S.M. and F. Gardoni performed the immunoblots. R.L.H. provided the phospho-mutant mice. F. Georges performed the in vivo recordings. M.M. designed the study and wrote the manuscript with the help of F.J.M., S.L. and K.V.

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Correspondence to Manuel Mameli.

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Integrated supplementary information

Supplementary Figure 1 Cocaine-evoked plasticity onto LHb→RMTg neurons is long-lasting and is absent in LHb→VTA neurons.

(a) Schematic indicating the injections of the HSV-eGFP in the RMTg. (b) Grouped data for recordings obtained from LHb neurons after HSV infusion or in naïve mice (n = 10-19; 8 mice of ~6 weeks; Frequency, HSV 1.8 ± 2.4 Hz; Naive 3.1 ± 1.8 Hz; p > 0.05 t27 = 1.3; Amplitude, HSV 22.8 ± 0.8 pA; Naive 27.6 ± 2.4 pA; p > 0.05 t27 = 1.3) (c) Grouped data for recordings obtained 7 days after the last injection of saline/cocaine (n = 9-12; 4 mice of 6 weeks; Frequency, Saline 2.9 ± 0.8 Hz; Cocaine 1.7 ± 0.7 Hz; p > 0.05 t19 = 1.1; Amplitude, Saline 21.5 ± 1.4 pA; Cocaine 25.8 ± 1.3 pA; *p < 0.05 t19 = 2.1). (d) Same as b but for recordings obtained 14 days after 5 cocaine injections (n = 22-26; 4 mice of 6-7 weeks; Frequency, Saline 2.6 ± 0.8 Hz; Cocaine 3.8 ± 0.9 Hz; p > 0.05 t46 = 1; Amplitude, Saline 15.7 ± 0.9 pA; Cocaine 20.3 ± 1.3 pA; **p < 0.01 t46 = 2.8). (e) Same as c but for recordings obtained in LHb→VTA neurons (n = 15-17; 3 mice of 6-7 weeks; Frequency, Saline 5.8 ± 3.1 Hz; Cocaine 3.4 ± 1.1 Hz; t30 = 0.7 p > 0.05; Amplitude, Saline 19.1 ± 2.1 pA; Cocaine 17.7 ± 1.3 pA; t30 = 0.5 p > 0.05). (f) Schematic describing the AAV-GluA1ct injections in the LHb and parallel HSV-eGFP injections in the RMTg (g) Timeline for experimental procedures. Representative images obtained from mice injected with the AAV-GluA1ct in LHb, and treated (or not) with doxycycline (2 X 5 mg/day) intragastrically for three consecutive days. (h, i) Scatter plot representing the AMPA (h) and NMDA-EPSCs (i) from consecutively patched neighboring neurons (AAV-GluA1ct infected and uninfected) in saline and cocaine treated groups (n = 9-11; 4 mice of 7-9 weeks; NMDA EPSCs, Saline uninfected, 25.6 ± 6.5; Saline infected, 22.1 ± 0.7; Cocaine uninfected, 19.8 ± 1.9; Cocaine infected, 19 ± 2.4; Interaction factor F(1,36) = 0.09, p > 0.05 two way ANOVA). (j) Pooled data indicating the rectification index (RI = EPSC-70/EPSC+50) in AAV-GluA1ct infected and uninfected LHb-RMTg neurons in saline and cocaine treated groups (n = 9-11; 4 mice of 7-9 weeks; Saline uninfected, 9.5 ± 1.5; Cocaine uninfected, 12.8 ± 2.3; p > 0.05 t18 = 1.1; Saline infected, 9.9 ± 1.1; Cocaine infected, 9.1 ± 1.1; t18 = 0.4 p > 0.05).

Supplementary Figure 2 Cellular mechanisms underlying cocaine-evoked plasticity in the LHb.

(a) Representative immunoblots for p845, and p831 and total GluA1 obtained from microdissected LHb in saline and cocaine groups. (b) Grouped data for immunoblots (n = 30 animals; n = 5 observations; p845, cocaine 152.8 ± 7.5%, t8 = 4.3 **p < 0.01; p831, cocaine 112.1 ± 2.6%, t8 = 1.7 p > 0.05; GluA1-total, cocaine 119.8 ± 22.8%; p > 0.05 t8 = 1.3). (c) Sample traces of mEPSCs obtained in LHb→RMTg neurons in S845A knock-in mice. (d) Scatter plot and grouped data for mEPSC frequency and amplitude from S845A knock-in mice (n = 10-11; 4 mice of 4-6 weeks; Frequency; Saline 1.5 ± 0.5 Hz; Cocaine 1.9 ± 0.4 Hz; t19 = 0.6 p > 0.05; Amplitude; Saline 21.9 ± 1.1 pA; Cocaine 23.2 ± 1 pA; t19 = 0.8 p > 0.05). (e) Sample traces of mEPSCs obtained in LHb→RMTg neurons in S831A knock-in mice. (f) Scatter plot and grouped data for mEPSC frequency and amplitude in the saline and cocaine groups of S831A knock-in mice (n = 18; 4 mice of 4-6 weeks; Frequency; Saline 3.2 ± 1.2 Hz; Cocaine 4 ± 1.4 Hz; t34 = 0.4 p > 0.05; Amplitude; Saline 16.6 ± 0.9 pA; Cocaine 24.8 ± 2.6 pA; t34 = 2.9 p < 0.01). (g) Representative LHb neuron spike recorded in vivo, and sample antidromic collision test (*, erasure of antidromic spike; arrow, stimulus artifact). (h) Current-clamp sample traces (100 pA injection) and action potentials as function of current steps, for LHb→RMTg neurons recorded 2 weeks after chronic treatment (n = 9–10; 4 mice of 8–9 weeks; saline versus cocaine, F5, 85 = 6.05, *P < 0.05 repeated-measures ANOVA). (i) Current-clamp sample traces (100 pA injection) and action potentials as function of current steps, for LHb→RMTg neurons recorded 24 hrs after 2 days of saline/cocaine treatment in the presence of NBQX (20 µM) in the ACSF (n = 12-16; 8 mice of 7-9 weeks Saline vs Cocaine, F(5, 135)= 3.5, **p < 0.01 repeated measures ANOVA). (j) Same as g but for for LHb→RMTg neurons recorded at 14 days of withdrawal after 5 days of cocaine treatment in the presence of NBQX (20 µM) in the ACSF (n = 5; 2 mice of 7-8 weeks Saline vs Cocaine, F(5, 37)= 11.3, **p < 0.01 repeated measures ANOVA).

Supplementary Figure 3 Precluding cocaine-evoked GluA1 trafficking in LHb prevents a depressive-like behavior elicited by drug exposure.

(a,b) Injection sites in the LHb for AAV-GluA1ct for animals included in the behavioral analysis (c) Tail suspension test analysis after AAV-GluA1ct and AAV-control injection in LHb (n = 9-10 mice; 8-9 weeks; AAV-Venus; total immobility, Interaction factor F(1,35) = 4.6, *p < 0.05). (d) Scatter plot of cocaine-induced preference indicating no statistical differences between control and AAV-GluA1ct infused mice (See Figure 3) (n = 6-8 for saline CPP and n = 10 for cocaine CPP; mice of 8-9 weeks. Unpaired t-test, Pre-test vs Test, Saline-Saline, AAV-control t7 = 1.7 p > 0.05; AAV-GluA1ct t5 = 1.3 p > 0.05; Saline-Cocaine, AAV-control t9 = 1.9 *p < 0.05; AAV-GluA1ct t9 = 1.9 p < 0.05). (e) Same as (d) but indicating the total time spent by mice in the compartments for saline CPP and cocaine CPP (Saline CPP; Compartment #1 AAV-control t14 = 0.05 p > 0.05, AAV-GluA1ct t14 = 0.3 p > 0.05; Compartment #2 AAV-control t12 = 1.48 p > 0.05, AAV-GluA1ct t12 = 0.8 p > 0.05. Cocaine CPP; Compartment #1 AAV-control t18 = 3.1 p < 0.01, AAV-GluA1ct t18 = 2.7 p < 0.05; Compartment #2 AAV-control t18 = 2.7 p < 0.05, AAV-GluA1ct t18 = 3.4 p < 0.01).

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Meye, F., Valentinova, K., Lecca, S. et al. Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula. Nat Neurosci 18, 376–378 (2015). https://doi.org/10.1038/nn.3923

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