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  • Review Article
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Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain

Nature Reviews Drug Discovery volume 12, pages 866–885 (2013)Cite this article

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Key Points

  • Glycine is released from presynaptic terminals as a classical inhibitory neurotransmitter that hyperpolarizes the postsynaptic membrane through the activation of glycine receptors, which have an integral anion channel. Glycine also modulates the activity of excitatory NMDA (N-methyl-D-aspartate)-selective glutamate receptors at excitatory synapses by acting as a co-agonist.

  • The glycine transporters GlyT1 and GlyT2 are expressed in neurons and in astrocytes that ensheath synapses. At inhibitory glycinergic synapses, GlyT1 terminates neurotransmission, whereas GlyT2 regulates the recycling of glycine into presynaptic terminals. At excitatory synapses, GlyT1 also controls the extracellular concentration of glycine near NMDA receptors.

  • Constitutive disruption of the genes encoding GlyT1 or GlyT2 leads to early postnatal fatality in mouse models, whereas mutations in the GLYT2 gene have been linked to startle disease in humans and other species. In the adult central nervous system, the balance between inhibitory and excitatory signalling in multiple neural pathways remains susceptible to modulation by GlyT1 and GlyT2, and therefore glycine transporters are potential new targets for the treatment of several neuropsychiatric conditions.

  • GlyT1 inhibition can facilitate NMDA receptor activity and is therefore primarily conceived as a potential remedy against the cognitive and affective deficiencies in schizophrenia, which are due to an underlying impairment in NMDA receptor signalling. The clinical efficacy of GlyT1 inhibitors as an adjunct therapy to improve global functioning in patients with schizophrenia is supported by the Phase II trials of bitopertin, which is currently under Phase III evaluation.

  • Preclinical models have shown that inhibition of GlyT1 can suppress alcohol intake and relapses in rats, and suggest a new application for GlyT1 inhibitors in the treatment of alcohol dependence. The anti-alcohol effect is attributed to the potentiation of glycinergic inhibition via the activation of glycine receptors in central reward pathways, which may be relevant to addiction in general.

  • The transmission of pain signals from the spinal cord to the brain is regulated by glycinergic inhibition in the dorsal horn mediated by signalling pathways converging on glycine receptors containing the α3 subunit. The local inhibition of GlyT1 or GlyT2 can effectively suppress pain transmission through the enhancement of local neuronal inhibition mediated by glycine receptors.

  • Further applications of glycine reuptake inhibition therapy to other diseases, such as obsessive-compulsive disorder, depression and epilepsy, have been proposed but the precise brain mechanisms involved in these disorders are less clear. In this Review, we consider potential factors that may determine the clinical efficacy of glycine reuptake inhibition therapy in these conditions, such as pharmacokinetics, brain circuitry and the localization of the relevant glycine transporters.

Abstract

Glycine transporters are endogenous regulators of the dual functions of glycine, which acts as a classical inhibitory neurotransmitter at glycinergic synapses and as a modulator of neuronal excitation mediated by NMDA (N-methyl-D-aspartate) receptors at glutamatergic synapses. The two major subtypes of glycine transporters, GlyT1 and GlyT2, have been linked to the pathogenesis and/or treatment of central and peripheral nervous system disorders, including schizophrenia and related affective and cognitive disturbances, alcohol dependence, pain, epilepsy, breathing disorders and startle disease (also known as hyperekplexia). This Review examines the rationale for the therapeutic potential of GlyT1 and GlyT2 inhibition, and surveys the latest advances in the biology of glycine reuptake and transport as well as the drug discovery and clinical development of compounds that block glycine transporters.

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Figure 1: The regulation of neurotransmission at glycinergic and glutamatergic synapses by glycine transporters.
Figure 2: Distribution patterns of glycine, GlyT1 and GlyT2 in the rat brain.
Figure 3: Antipsychotic effects that could result from GlyT1 inhibition.
Figure 4: GlyT1 inhibition can modulate the mesolimbic dopamine reward pathway.
Figure 5: Inhibition of GlyT1 and GlyT2 can suppress pain signals.

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Acknowledgements

R.J.H. is supported by the Medical Research Council (Grants G0500833, G0601585 and J004049) and Action Medical Research (Grant 1966). B.K.Y. is supported by the US National Institutes of Health (NIH) (Grant R01MH083973), and the Legacy Foundation Grant, and would like to acknowledge former support from the Swiss National Science Foundation (Grant: 3100-066855), the Swiss National Center of Competence in Research Neural Plasticity and Repair, and the Swiss Federal Institute of Technology, Zurich.

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  1. Department of Pharmacology, University College London School of Pharmacy, 29–39 Brunswick Square, London, WC1N 1AX, UK

    Robert J. Harvey

  2. Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, 1225 NE Second Avenue, Portland, 97232, Oregon, USA

    Benjamin K. Yee

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Correspondence to Robert J. Harvey or Benjamin K. Yee.

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Glossary

Interneurons

Nerve cells that form short, local (mostly inhibitory) connections with nearby neurons within a single area of the brain. They are to be distinguished from principal or projection neurons that extend axonal connections to distal regions of the nervous system.

Forebrain

An area of the brain that comprises two main sections: the diencephalon and the telencephalon. It covers the entire cerebral cortex, limbic cortices, thalamus and striatum, and governs sensory and motor information processing, language and memory function.

Affects

The experience and expression of feelings or emotions that can be positive or negative; the psychological processes involved are often contrasted with (but cannot be entirely disentangled from) cognition and thought processes.

Executive functions

A broad number of cognitive processes including planning, working memory, attention, problem solving, reasoning, inhibition, mental flexibility and task switching, as well as the initiation and monitoring of these cognitive processes.

Positive allosteric modulatory sites

Binding sites on a receptor or channel that are distinct from the active site. These sites allow regulatory ligands (that have an affinity to these sites) to enhance the biochemical response that is associated with the activation of the active site.

Glutamate hypothesis

A hypothesis of the pathophysiology of schizophrenia that attributes the production of schizophrenia symptoms to the underactivity of the glutamatergic neurotransmission system — in particular, to the transmission of neural signals via NMDA (N-methyl-D-aspartate) receptors.

Glyt1+/− mice

Constitutive heterozygous knockout mice that lack one allele of the glycine transporter 1 gene (Glyt1; also known as Slc6a9), and have GlyT1 expression levels that are ∼50% lower than those of wild-type mice.

Glyt1fl/fl:CamKIIα–Cre+/− conditional knockout mice

Conditional knockout mutant mice in which the expression of the glycine transporter 1 gene (Glyt1; also known as Slc6a9) is disrupted in forebrain principal neurons.

Telencephalon

The largest and most highly developed part of the human brain that is involved in many higher brain functions including intelligence, personality and interpretation of sensory information; often referred to as the cerebrum or cerebral cortex in the literature.

Nucleus accumbens

The main component of the ventral (or limbic) striatum that receives ascending dopaminergic innervation and limbic glutamatergic inputs, and is involved in reward, motivation and attention.

Clozapine

8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine); the prototypical second-generation antipsychotic drug, which is associated with fewer motor side effects. It is commonly prescribed to patients with schizophrenia who do not respond to first-generation antipsychotic drugs.

Glyt1fl/fl:EMX1–Cre+/− mice

Mice in which expression of the glycine transporter 1 gene (Glyt1; also known as Slc6a9) in the dorsal telencephalon is disrupted so that all cells in the cerebral cortex including the limbic cortices (the hippocampus and amygdala) lack GlyT1, but GlyT1 expression is retained in the striatum.

Pavlovian fear conditioning

A behavioural paradigm in which organisms learn to anticipate an aversive event by learning to associate the aversive stimulus (for example, an electrical shock) with a neutral stimulus (for example, a tone), which results in the expression of fear responses (for example, freezing or immobility) to the originally neutral stimulus.

Porsolt forced swim test

A rodent test that is used for determining the effects of antidepressant drugs. Such drugs can increase the length of time before a rodent gives up swimming or struggling and begins to float when left in a cylinder of water without any possibility of escaping.

Prepulse inhibition

A cross-species translational paradigm that is sensitive to an early attentional deficit in schizophrenia, which measures the inhibition of a startle response to an intense acoustic stimulus (that is, a pulse) induced by a weak non-startling stimulus (that is, a prepulse).

Adjunctive design

A clinical trial that is designed to test the efficacy of a given treatment that is administered as an add-on to the medications that the patients are already receiving; clinical outcomes are compared with placebo add-on.

Negative symptom factor score

A summary score, derived from the Positive and Negative Syndrome Scale (PANSS), to index the change in the negative symptoms of schizophrenia between the treatment and placebo arms in a clinical trial.

Complete Freund's adjuvant

A water-in-oil emulsion that contains heat-killed mycobacteria or mycobacterial cell wall components, and is used to induce an inflammatory response and pain in animal models.

Gabapentin

(2-[1-(aminomethyl)cyclohexyl]acetic acid). An analogue of GABA (γ-aminobutyric acid) that is currently used for the treatment of neuropathic pain but was originally developed as an anti-epileptic drug.

Allodynia

A form of pain caused by a thermal or physical stimulus that does not normally elicit pain sensation and can occur following injury.

Epileptic foci

Localized areas of the brain where a crucial number of pathologically discharging neurons reside; these neurons have the potential to give rise to widespread brain seizures.

NMDA autoreceptors

NMDA (N-methyl-D-aspartate) receptors that are located on presynaptic nerve cell membranes. They may provide tonic facilitation of neural transmission, contribute to neural plasticity such as long-term depression or be part of a negative feedback loop to reduce glutamate release.

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Harvey, R., Yee, B. Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov 12, 866–885 (2013). https://doi.org/10.1038/nrd3893

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