Neural bases for addictive properties of benzodiazepines

Kelly R. Tan, Matthew Brown, Gwenaël Labouèbe, Cédric Yvon, Cyril Creton, Jean-Marc Fritschy, Uwe Rudolph and Christian Lüscher ()
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Kelly R. Tan: Medical Faculty, University of Geneva
Matthew Brown: Medical Faculty, University of Geneva
Gwenaël Labouèbe: Medical Faculty, University of Geneva
Cédric Yvon: Medical Faculty, University of Geneva
Cyril Creton: Medical Faculty, University of Geneva
Jean-Marc Fritschy: Institute of Pharmacology and Toxicology, University of Zurich
Uwe Rudolph: Laboratory of Genetic Neuropharmacology, Harvard Medical School, Belmont, Massachusetts 02478, USA
Christian Lüscher: Medical Faculty, University of Geneva

Nature, 2010, vol. 463, issue 7282, 769-774

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature08758

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