Review
Hooked on benzodiazepines: GABAA receptor subtypes and addiction

https://doi.org/10.1016/j.tins.2011.01.004Get rights and content

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 GABAA 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.

Introduction

Four benzodiazepines (BDZs), alprazolam (Xanax®), clonazepam (Klonopin®), diazepam (Valium®), and lorazepam (Ativan®) are listed among the 200 most commonly prescribed drugs in the US 1, 2. Since the discovery in 1955 of the first BDZ, chlordiazepoxide (Librium®) [3], about 30 other BDZs have been introduced for clinical use. They are typically categorized according to their pharmacokinetic properties as either short-, intermediate- or long-acting, and are prescribed to obtain one of the following major effects: decrease of sleep latency, reduction of anxiety, suppression of epileptic seizures or relaxation of muscle spasms (Box 1). BDZs can also induce anterograde amnesia, which can be considered as an adverse side-effect at times, but loss of memory for unpleasant events could also be a useful effect, for example during invasive medical procedures (Box 1). In general, BDZs are safe and effective for short-term treatment; however, long-term use is controversial due to the development of tolerance (see Glossary) and their liability for physical dependence [4]. The Drug Abuse Warning Network, which monitors prescription and illicit drug use, found that two of the most frequently reported prescription medications in drug abuse-related cases are opioid-based pain relievers and BDZs (http://www.nida.nih.gov). Furthermore, BDZ abuse often occurs in conjunction with the abuse of another substance (e.g. alcohol or cocaine), making treatment approaches even more difficult. The knowledge of how BDZs induce addiction might help in the development of anxiolytics and hypnotics with lower addictive liability.

All addictive drugs, as well as natural rewards, increase dopamine (DA) levels in the mesolimbic dopamine (DA) system, also termed the reward system (Box 2). Several landmark studies with monkeys have shown that DA neurons play a role in signaling ‘reward error prediction’, and thus are involved in learning processes related to reward and intrinsic value. Specifically, DA neurons are excited following the presentation of an unexpected reward. Once this reward becomes predictable (by an experimentally controlled cue), DA neurons shift their phasic activation from the reward to the cue. Finally, when the cue is present but the reward is withheld, DA neurons are inhibited 5, 6. Unlike natural rewards, addictive drugs always cause an increase in DA levels upon drug exposure even after repeated trials [7]. This interruption of normal DA signaling mechanisms could allow addictive drugs to hijack the reward system and lead to the malfunction of mechanisms controlling learning and memory.

Recent findings have demonstrated that BDZs engage pharmacological and cellular mechanisms in the mesolimbic DA system 8, 9 that are similar in nature to those previously identified for other drugs of abuse 10, 11, 12. In this review we provide an overview of the current understanding of the molecular mechanisms that could underlie the addictive properties of BDZs. Furthermore, we discuss how such knowledge of the neural basis of BDZ could be harnessed to design new BDZs with lower addiction liability.

Section snippets

GABAA receptor diversity

BDZs are positive allosteric modulators of the γ-aminobutyric acid type A receptors (GABAARs) (Box 3). GABAARs are ligand-gated chloride-selective ion channels that are physiologically activated by GABA, the major inhibitory neurotransmitter in the brain. In addition to GABAARs, GABA also activates GABABRs and GABACRs. GABABRs are metabotropic receptors involved in slow inhibitory neurotransmission [13]. GABACRs are ionotropic receptors composed of ρ (rho) subunits that are both related to and

Towards a GABAAR subtype-specific BDZ pharmacology

Pharmacological and behavioral studies in KI mice have led to correlations between a specific α subunit isoform and one or several of the five major effects of BDZs described above (Box 1). These studies have revealed that GABAARs containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam 33, 34. GABAARs containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects 35, 38. GABAARs containing α3 and α5

Benzodiazepines

BDZs have a stronger impact on GABA neurons than on DA neurons. At baseline, miniature IPSCs of GABA neurons are slower and bigger than those of DA neurons. In the presence of BDZs the spontaneous IPSC frequency is increased in GABA neurons and decreased in DA neurons [9]. As a result, GABA neurons are more strongly hyperpolarized in the presence of BDZs and no longer inhibit DA neurons as seen with in vivo single-unit recordings [9] (Figure 1). This cellular mechanism is termed the

Drug-evoked plasticity in VTA synapses

Apart from the actual presence of the drug in the brain, drug-evoked plasticity of glutamatergic synapses represents a first trace of drug exposure; it is in fact a hallmark feature of all addictive drugs 58, 59. A single dose of cocaine, nicotine, or morphine induces a rectification of the current/voltage (I/V) curve of AMPAR-mediated excitatory postsynaptic currents (EPSCs), and increases the AMPA/NMDA ratio 58, 59. Electrophysiological investigations together with electron microscopy (EM)

Other drugs which have pharmacological actions at GABAARs

In addition to the GABA site to which the experimental compound muscimol binds, GABAARs possess additional allosteric modulatory sites at which several other drugs including barbiturates and ethanol exert their effects. Barbiturates were largely replaced by BDZs in the 1960 s for clinical purposes [71] because BDZs have a significantly lower potential for overdose. In addition, barbiturates have a strong liability for dependence and addiction, which was not observed with BDZs at that time.

Blueprint for designing a BDZ without addiction liability

In summary, recent work on the neural basis of the addictive properties of BDZs suggests that receptors that contain the GABAAR α1 subunit are important for triggering drug-evoked synaptic plasticity at VTA synapses – an important first step underlying drug reinforcement. Although many outstanding questions remain to be addressed in future experiments (Box 4), current findings suggest that BDZs that act non-selectively at GABAAR subtypes, and/or drugs which target α1-containing GABAARs, have a

Acknowledgments

This work is supported by the National Institute on Drug Abuse (NIDA; grant DA019022 to C.L. and P. Slesinger), the Swiss National Science Foundation and the Swiss Initiative in Systems Biology (Neurochoice). 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.

Glossary

AMPA/NMDA ratio
ratio of the amplitudes of EPSCs mediated by AMPARs and NMDARs, respectively. An increase in the AMPA/NMDA ratio could be due to enhanced AMPAR transmission, reduced NMDAR transmission, or a concomitant change in both components. Changes in the AMPA/NMDA ratio are considered to be a hallmark of synaptic plasticity.
Deactivation of receptor
the process by which activated receptors relax toward the resting state.
Desensitization of receptor
the decay in receptor efficacy produced in

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