Neural bases for addictive properties of benzodiazepines

Abstract

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABAA (γ-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on α1-containing GABAA receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of α1-containing GABAA receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing α1 may be devoid of addiction liability.

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Figure 1: BDZ-evoked synaptic plasticity is abolished in α1(H101R) mutant mice.
Figure 2: Synaptic plasticity evoked by α1-subunit-selective compounds.
Figure 3: α1 is selectively expressed in GABA neurons of the VTA.
Figure 4: The total current generated by sIPSCs in DA neurons is decreased by MDZ.
Figure 5: Opposing effects of MDZ on in vivo firing rates of DA and GABA neurons.
Figure 6: Oral self-administration of MDZ.

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Acknowledgements

We thank members of the Lüscher laboratory as well as M. Frerking, M. Serafin and H. Möhler for critical reading of the manuscript. Y. Yanagawa provided the GAD67–GFP Δneo mouse line, and we thank K. A. Miczek and H. U. Zeilhofer for help with the GABAA mutant mouse lines. This work is supported by the National Institute on Drug Abuse (NIDA; DA019022; C.L., P. Slesinger), the Swiss National Science Foundation, the Swiss Initiative in Systems Biology (Neurochoice) and the European Commission Coordination Action ENINET (LSHM-CT-2005-19063). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDA or the National Institutes of Health.

Author Contributions K.R.T. carried out all in vitro electrophysiology experiments. M.B., G.L. and C.Y. contributed equally to the in vivo recordings. K.R.T. and C.C. performed the behavioural experiments. J.-M.F. carried out the immunohistochemistry. U.R. generated the mutant mice. C.L. designed the study and wrote the manuscript with the help of all authors.

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Correspondence to Christian Lüscher.

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Tan, K., Brown, M., Labouèbe, G. et al. Neural bases for addictive properties of benzodiazepines. Nature 463, 769–774 (2010). https://doi.org/10.1038/nature08758

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