Trends in Neurosciences
ReviewHooked on benzodiazepines: GABAA receptor subtypes and addiction
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
References (117)
- et al.
The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?
Neurosci. Biobehav. Rev.
(2006) GABAB receptors: physiological functions and mechanisms of diversity
Adv. Pharmacol.
(2010)Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement
J. Biol. Chem.
(2002)Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why?
Prog. Biophys. Mol. Biol.
(2005)- et al.
The benzodiazepine binding site of GABAA receptors
Trends Pharmacol. Sci.
(1997) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding
J. Biol. Chem.
(1992)Pharmacology of recombinant gamma-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated alpha-subunits
FEBS Lett.
(1998)- et al.
Natural mutation of GABAA receptor alpha 6 subunit alters benzodiazepine affinity but not allosteric GABA effects
Eur. J. Pharmacol.
(1993) Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site
Eur. J. Pharmacol.
(1995)Neuron-specific expression of GABAA-receptor subtypes: differential association of the alpha 1- and alpha 3-subunits with serotonergic and GABAergic neurons
Neuroscience
(1993)
Addictive drugs modulate GIRK-channel signaling by regulating RGS proteins
Trends Pharmacol. Sci.
Inhibition of non-dopamine cells in the ventral tegmental area by benzodiazepines: relationship to A10 dopamine cell activity
Eur. J. Pharmacol.
Opposite effects of midazolam and beta-carboline-3-carboxylate ethyl ester on the release of dopamine from rat nucleus accumbens measured by in vivo microdialysis
Eur. J. Pharmacol.
Both systemic and local administration of benzodiazepine agonists inhibit the in vivo release of 5-HT from ventral hippocampus
Neuropharmacology
Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study
Brain Res.
Measuring the modulatory effects of RGS proteins on GIRK channels
Meth. Enzymol.
Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons
Neuron
Barbiturates require the N terminus and first transmembrane domain of the delta subunit for enhancement of alpha1beta3delta GABAA receptor currents
J. Biol. Chem.
Tonic for what ails us?. high-affinity GABAA receptors and alcohol
Alcohol
Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro
Brain Res.
Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons
Eur. J. Pharmacol.
Dependence on zolpidem: a report of two cases. (In French.)
L’Encéphale
Extensive craving in high dose zolpidem dependency
Prog. Neuropsychopharmacol. Biol. Psychiatry
Imidazenil: a low efficacy agonist at alpha1- but high efficacy at alpha5-GABAA receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem
Neuropharmacology
Anticonvulsant, anxiolytic, and non-sedating actions of imidazenil and other imidazo-benzodiazepine carboxamide derivatives
Pharmacol. Biochem. Behav.
Addiction to benzodiazepines
Psy. Quart.
Nursing Spectrum Drug Handbook
The benzodiazepine story
J. Psychoact. Drugs
Benzodiazepines: use, abuse, and consequences
Pharmacol. Rev.
A neural substrate of prediction and reward
Science
Dopamine signals for reward value and risk: basic and recent data
Behav. Brain Funct.
Effect of chronic ‘binge cocaine’ on basal levels and cocaine-induced increases of dopamine in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice
Synapse
Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists
Neuropsychopharmacology
Neural bases for addictive properties of benzodiazepines
Nature
Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons
Nature
Is there a common molecular pathway for addiction?
Nat. Neurosci.
GABAC receptor ion channels
Clin. Exp. Pharmacol. Physiol.
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update
Pharmacol. Rev.
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function
Pharmacol. Rev.
cDNA cloning and expression of a gamma-aminobutyric acid A receptor epsilon-subunit in rat brain
Eur. J. Neurosci.
Subunit composition, distribution and function of GABA(A) receptor subtypes
Curr. Top. Med. Chem.
Stoichiometry of a recombinant GABAA receptor
J. Neurosci.
Cerebellar GABAA receptor selective for a behavioural alcohol antagonist
Nature
Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells
J. Neurosci.
Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors
Nat. Rev. Neurosci.
Benzodiazepine receptor: demonstration in the central nervous system
Science
Molecular biological insights into GABA and benzodiazepine receptor structure
Prog. Clin. Biol. Res.
Mapping of the benzodiazepine recognition site on GABA(A) receptors
Cur. Top. Med. Chem.
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes
Nature
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype
Nat. Neurosci.
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