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Dual action of ketamine confines addiction liability

Nature volume 608, pages 368–373 (2022)Cite this article

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Abstract

Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion1,2,3,4. The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N-methyl-d-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability.

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Fig. 1: Ketamine causes hyperlocomotion, reinforcement and increased dopamine in the NAc.
Fig. 2: Accumbal dopamine transients are mediated by disinhibition of VTA dopamine neurons.
Fig. 3: D2R-mediated fast off-kinetics of dopamine transients and lack of early adaptive synaptic plasticity.
Fig. 4: Absence of accumbal drug-evoked synaptic plasticity, locomotor sensitization and uncontrolled self-administration.

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Data availability

The datasets generated during and/or analysed during the current study are available in the Zenodo repository (https://doi.org/10.5281/zenodo.5772449)51.

Code availability

The MATLAB code used for analysing the fibre photometry raw data is available in the Zenodo repository (https://doi.org/10.5281/zenodo.5772449).

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Acknowledgements

We thank J. Cand for laboratory assistance and L. Zweifel for providing the conditional NR1-KO and control viruses. We thank A. Kwan, C. Bellone and M. Mameli for their comments on an earlier version of the manuscript. This study was supported by the Swiss National Science Foundation (L.D.S., grant number PZ00P3_174178; C.L., 310030_189188) and the European Research Council (AdG F-Addict).

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  1. These authors contributed equally: Linda D. Simmler, Yue Li

Authors and Affiliations

  1. Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland

    Linda D. Simmler, Yue Li, Lotfi C. Hadjas, Agnès Hiver, Ruud van Zessen & Christian Lüscher

  2. Service de Neurologie, Department of Clinical Neurosciences, Geneva University Hospital, Geneva, Switzerland

    Christian Lüscher

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Contributions

L.D.S. conceived the experiments and performed patch recordings, fibre photometry and behavioural experiments. Y.L. performed fibre photometry, patch recordings and behavioural experiments. L.C.H. performed immunohistochemistry, fibre photometry and behavioural experiments. A.H. performed mice surgeries and behavioural experiments. R.v.Z. performed fibre photometry experiments. L.D.S., Y.L., L.C.H. and R.v.Z. performed analyses. C.L., L.D.S. and Y.L. wrote the manuscript with the help of all authors. C.L. supervised the study.

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Correspondence to Christian Lüscher.

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Extended data figures and tables

Extended Data Fig. 1 Lever presses and infusion intervals of self-administration.

a, Lever presses on active and inactive lever during self-administration for each session. n (mice) = 8 (saline), 10 (ketamine), 8 (cocaine). b, Median inter-infusion interval per mouse in session 6 to estimate rate of infusion during non-contingent self-administration (Fig. 3k). n (mice) = 10 (ketamine), 7 (cocaine). Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

Extended Data Fig. 2 Dose-dependence of accumbal dopamine transients.

a, Schematic of virus injection and fibre implantation targeting the medial shell of the nucleus accumbens. b, Mean dLight response to i.p. injections of different doses of ketamine. n = 5 mice. c, AUC from 0–10 min after i.p. injection of different doses of ketamine. n = 5 mice. Data are represented as mean ± SEM.

Extended Data Fig. 3 Validation of NR1 ablation.

a, Schematic of experimental details with virus injections and location of patch-clamp recordings. b, Representative traces of NMDA/AMPA recordings of NR1-KO (KO; sgGrin1) and control (CT; sgRosa26). Scale bar, 10 ms, 200 pA. c, NMDA/AMPA ratios (amplitudes measured for NMDA component 20 ms after the peak at +40 mV and AMPA component at −70 mV) of VTA GABA neurons from KO and CT mice. n (cells) = 6 (KO) and 6 (CT). Data are represented as mean ± SEM. *P < 0.05.

Extended Data Fig. 4 Fentanyl- and ketamine-induced GABA inhibition and dopamine transients.

a,c,e, Schematic of virus injection and fibre implantation. b, Mean Ca2+ signal of VTA GABA neurons from NR1-control (CT) and KO mice with i.p. injections of saline or fentanyl. n (mice) = 3 (CT) and 3 (KO). d, Average dopamine transients induced by ketamine (30 mg/kg) and fentanyl (0.3 mg/kg). n = 8 mice. f, Average dopamine transients induced by ketamine (30 mg/kg) and cocaine (15 mg/kg) in NR1-CT mice. n = 11 mice. g, Average dopamine transients induced by ketamine and cocaine in NR1-KO mice. n = 11 mice. Data are represented as mean ± SEM.

Extended Data Fig. 5 In vitro NMDAR inhibition in acute brain slices of the NAc.

a, Example traces of NMDAR EPSCs induced by electrical stimulation in the NAc, recorded in Mg2+-free aCSF. Top: before bath-application of ketamine; bottom: with 50 µM ketamine. Stimulation artefact was removed. Scale bar is 50 ms, 50 pA. b, NMDAR EPSCs before and with ketamine. n = 5 cells. Data are presented as mean ± SEM. **P < 0.01.

Extended Data Fig. 6 Compulsive ketamine self-administration and pain perception affected by ketamine infusions.

a. Number of ketamine infusions in baseline and punishment sessions. n = 17 mice. b. Latency to hotplate before and after mocked saline and ketamine i.v. infusions (1 mg/kg/infusion, 30 infusions). n (mice) = 16 (saline) and 17 (ketamine). Data are presented as mean ± SEM. ***P < 0.001.

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Simmler, L.D., Li, Y., Hadjas, L.C. et al. Dual action of ketamine confines addiction liability. Nature 608, 368–373 (2022). https://doi.org/10.1038/s41586-022-04993-7

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