Hooked on benzodiazepines: GABAA receptor subtypes and addiction

Abstract

Benzodiazepines are widely used clinically to treat anxiety and insomnia. They also induce muscle relaxation, control epileptic seizures, and can produce amnesia. Moreover, benzodiazepines are often abused after chronic clinical treatment and also for recreational purposes. Within weeks, tolerance to the pharmacological effects can develop as a sign of dependence. In vulnerable individuals with compulsive drug use, addiction will be diagnosed. Here we review recent observations from animal models regarding the cellular and molecular basis that might underlie the addictive properties of benzodiazepines. These data reveal how benzodiazepines, acting through specific GABA(A) receptor subtypes, activate midbrain dopamine neurons, and how this could hijack the mesolimbic reward system. Such findings have important implications for the future design of benzodiazepines with reduced or even absent addiction liability.

Fig. 1. Schematic representation of the mechanism of action of BDZs in the VTA

(a) The VTA is composed of two major cell types, DA neurons and GABA interneurons. DA neurons receive local inhibitory inputs from the GABA interneurons, and send projections to the ventral striatum (NAc). While interneurons express α1-containing GABA_ARs, the DA neurons express GABA_ARs that contain other subunits, such as the α3 isoform. (b) BDZs such as diazepam bind to GABA_ARs on both cell types. In the presence of BDZs, inhibitory GABA_AR currents are potentiated in both sets of neurons; however, the overall impact is much stronger in the interneurons, since GABA_ARs in interneurons cause larger unitary currents than in DA neurons. Such potentiation of the inhibitory currents in the interneurons leads to an overall hyperpolarization and a decrease in their activity (as depicted by the slower rate of neuronal excitability, seen in the single unit reading of neuronal activity in green). These results imply a decrease in the release of GABA from these neurons, and as a consequence, DA neurons are disinhibited and their firing rate increases (see example single unit recording in red). This results in more DA being released in the striatum and other target regions of the VTA [9].

Box 1. Figure I. GABA_AR BDZ-specific pharmacology

Over the past decade, an emerging understanding of the specific GABA_AR subtypes that are responsible for mediating the diverse spectrum of BDZ pharmacological effects. For example, the sedative actions are known to be mediated by α1-containing GABA_ARs, whereas the anxiolytic actions are mediated by α2-containing GABA_ARs.

Box 2. Figure I. Schematic cartoon depicting the circuitry of the mesolimbic DA system

The reward system originates in the VTA, which is composed of two major cell types, the DA neurons and the GABA neurons. The DA neurons (blue) project to the ventral striatum, the NAc, the PFC and the hippocampus. The VTA receives inhibitory projections (red) back from the NAc and from the pedunculopontine nucleus (PPT) and excitatory projections (green) from the PFC, the PPT, the amygdala, the lateral hypothalamus (LH), the laterodorsal tegmental nucleus (LDTg) and the bed nucleus of the stria terminalis (BNST), as well as receiving local inhibitory feedback from the GABA interneurons in the VTA.