pubmed.ncbi.nlm.nih.gov

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators? - PubMed

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators?

Christiaan H Vinkers et al. Adv Pharmacol Sci. 2012.

Abstract

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABA(A) receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABA(A) receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site.

PubMed Disclaimer

Figures

Figure 1
Figure 1

Representation of the GABAA receptor structure. The inhibitory GABAA receptor consists of five subunits that together form a ligand-gated chloride (Cl−) channel (a). When GABA binds (between the α and the β subunit of the GABAA receptor), chloride ions flow into the neuron, resulting in a hyperpolarization of the cell membrane (a). Classical nonselective benzodiazepines allosterically enhance the inhibitory actions of GABA by binding between the α 1, α 2, α 3, or α 5 subunit and the γ subunit (b). Although the GABAA receptor displays a large molecular heterogeneity depending on the subunit composition, the most common subtype is a pentamer with 2α, 2β, and 1γ subunit.

Figure 2
Figure 2

GABAA  receptor trafficking and associated proteins. GABAA receptors are assembled from individual subunits in the endoplasmatic reticulum (ER) where the chaperones BiP and Calnexin assist in quality control. Unassembled GABAA receptor subunits that are to be targeted for ER-associated degradation are ubiquitinated and degraded in the proteasome. The ubiquitin-like protein PLIC can interact with GABAA receptors thereby inhibiting their targeting for proteasomal degradation. Assembled pentameric GABAA receptors exit the ER and bind the guanidine exchange factor brefeldin-A-inhibited GDP/GTP exchange factor 2 (BIG2) in the Golgi. Here they also interact with the palmitoylase transferase GODZ and Gamma-aminobutyric acid receptor-associated protein (GABARAP). GABARAP interacts with the NEM sensitive fusion (NSF) protein, as does the GABAA receptor β subunit, and this association may facilitate transport of the receptor complexes to the cell surface. GABAA receptors are inserted at extrasynaptic sites and can diffuse along the plasma membrane in and out of synaptic domains. At synapses they are stabilized by an interaction with the scaffolding protein Gephyrin. The interaction of the GABAA receptor intracellular loops with the μ2 subunit of the adaptin complex AP2 is important for GABAA receptor internalization. GABAA receptors are delivered by a clathrin-mediated pathway to early endosomes where they can be targeted for degradation in the lysosome or for recycling upon binding of Huntington-associated protein (HAP1). Reprinted by permission from Elsevier, reprinted from [101].

Figure 3
Figure 3

Functional crosstalk between G-protein coupled receptors (GPCRs) (which are present in the serotonin, dopamine, acetylcholine system) and GABAA receptors is facilitated through multiple protein kinases and scaffold proteins. GABAA receptor β and γ2 subunits are phosphorylated (P) by PKA and PKC upon the activation of individual GPCRs for dopamine and serotonin. PKA phosphorylation of GABAA receptor β1 and β3 subunits is dependent upon AKAP150/79, which directly interacts with these receptor subunits. AKAP150/79 also binds inactive PKA composed of regulatory (R) and catalytic (C) subunits. In addition, PKC phosphorylates the receptor β1–3 and γ2 subunits. Upon the activation of the appropriate GPCR, PKC-mediated phosphorylation is facilitated by the direct (but independent) interaction of the receptor for activated C kinase (RACK-1) and the β isoform of PKC with the GABAA receptor β1–3 subunits. RACK-1 facilitates functional regulation of GABAA receptors by controlling the activity of PKC associated with these proteins. The GABAA receptor γ2 subunit is also phosphorylated by Src, and this kinase is capable of binding to receptor β and γ2 subunits. Finally, the functional effects of phosphorylation are diverse and range from inhibitions to enhancements of GABAA receptor activity, dependent upon the receptor subunit composition. Reprinted by permission from Elsevier, reprinted from [95].

Similar articles

Cited by

References

    1. Lader M. History of benzodiazepine dependence. Journal of Substance Abuse Treatment. 1991;8(1-2):53–59. - PubMed
    1. Owen RT, Tyrer P. Benzodiazepine dependence. A review of the evidence. Drugs. 1983;25(4):385–398. - PubMed
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 2000.
    1. Petursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455–1459. - PubMed
    1. Allison C, Pratt JA. Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence. Pharmacology and Therapeutics. 2003;98(2):171–195. - PubMed

LinkOut - more resources