Neural bases for addictive properties of benzodiazepines

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 (γ-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on α1-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 α1-containing GABA A receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing α1 may be devoid of addiction liability. Benzodiazepine addiction Psychoactive benzodiazepines are widely used clinically and recreationally and although considered safe and effective in the short term, they are addictive in some individuals. All addictive drugs studied so far act to increase dopamine levels in the mesolimbic area of the brain and to trigger adaptive synaptic plasticity in the ventral tegmental area. A new study shows that benzodiazepines, which act by binding to GABA A receptors, also increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of α1-containing GABA A receptors in nearby interneurons. This in turn triggers drug-evoked synaptic plasticity in dopamine neurons. The data also suggest that subunit-selective benzodiazepines that do not activate α1 receptors may lack addictive properties. Benzodiazepines, such as valium, are used both in clinics and for recreational purposes, but lead to addiction in some individuals. Addictive drugs increase the levels of dopamine and trigger synaptic adaptations in the mesolimbic reward system, but the neural basis for the addictive nature of benzodiazepines remains elusive. Here, they are shown to increase firing of dopamine neurons in the ventral tegmental area through GABA A receptor activation in nearby interneurons.