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Neural bases for addictive properties of benzodiazepines

Tan, K. R.
Yvon, Cedric
Fritschy, J. M.
Rudolph, Uwe
Published in Nature. 2010, vol. 463, no. 7282, p. 769-774
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 GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) 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 alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.
Keywords Action Potentials/drug effectsAdministration, OralAnimalsBehavior, Addictive/ chemically induced/pathology/ physiopathologyBenzodiazepines/administration & dosage/ adverse effects/ pharmacologyDopamine/metabolismElectric ConductivityGlutamic Acid/metabolismInhibitory Postsynaptic Potentials/drug effects/physiologyInterneurons/drug effects/metabolismMiceMice, Inbred C57BLMidazolam/administration & dosage/adverse effects/pharmacologyModels, BiologicalMorphine/pharmacologyNeuronal Plasticity/drug effectsNeurons/ drug effects/metabolismOrgan SpecificityReceptors, AMPA/metabolismReceptors, GABA-A/deficiency/genetics/metabolismSubstrate SpecificityVentral Tegmental Area/cytology/drug effects/metabolismGamma-Aminobutyric Acid/metabolism
PMID: 20148031
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Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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TAN, K. R. et al. Neural bases for addictive properties of benzodiazepines. In: Nature, 2010, vol. 463, n° 7282, p. 769-774. doi: 10.1038/nature08758 https://archive-ouverte.unige.ch/unige:10457

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Deposited on : 2010-08-06

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