The neuropharmacological most compelling molecular target is the GABAA receptor. It's the brain regulator of inhibitory neurotransmission, which mediates excitability in the brain and keeps the CNS excitatory and inhibitory signals in equilibrium. Deficits in GABAA receptors have been associated with many neurological and psychiatric disorders such as epilepsy, anxiety, depression, insomnia and neurodegenerative diseases.

Figure 1. Neurons expressing surface GABAA receptors contain both the neurotransmitter GABA and its degradative enzyme GABA transaminase. (Wang P, et al.; 2015)

GABAA receptors in drugs, in particular, have been studied for new medications to counter such disorders. But it will take a new, costly method of representing and measuring in the living world the structure, distribution and activity of GABAA receptors, and the modulation they undergo via drugs, to keep up. And that's where receptor imaging technologies enter the picture.

This article is about using GABAA receptor imaging to develop drugs, imaging and how we are using imaging today, what GABAA receptors are doing in disease, and imaging for quicker discovery of new therapies.

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GABAA Receptors Imaging Analysis

GABAA Receptors and Their Role in the Brain

And before we go to imaging, consider the biology of GABAA receptors in the brain. They are ion channels that coordinate inhibitory function of gamma-aminobutyric acid (GABA), the central inhibitory neurotransmitter in the CNS. Binding GABAA receptors opens chloride ion channels, and hyperpolarises and dulls neurons.

GABAA receptors must work – and then, in order for the brain to maintain this balance of excitability and inhibition. It has been linked to neurological and psychiatric diseases: a dysregulation of this balance was known to cause dysfunction:

In epilepsy: in epilepsy, neurons get excited over inhibitory feedback. Impairment of the GABAA receptors depresses inhibitory neurotransmission, which explains seizure disease.

Depression and Anxiety: GABAA receptor toxicity is associated with mood disorders such as anxiety and depression too. Most sedative-hypnotics (benzodiazepines among them) trigger GABAergic signalling via GABAA receptors to deal with anxiety and insomnia.

Neurodegenerative Diseases: GABAergic signalling has altered during neurodegenerative disorders like Alzheimer's disease which suggests the disease is related to GABAA receptors.

Because GABAA receptors are crucial in these disorders, understanding exactly how they operate, spread and are pharmacologically modulated is important to develop a treatment plan. And that's where receptor imaging tools come in.

Imaging Methods to Study GABAA Receptors

Explicit, live imaging and modelling of GABAA receptors transformed neuroscience and the development of drugs. There are now imaging methods that let researchers study the presence, number and activity of GABAA receptors in both animal and human bodies. These are some of the most used ones:

1. Positron Emission Tomography (PET)

You'll be able to see molecules with positron emission tomography (PET), an imaging tool that helps you see exactly those molecules. When PET scans the receptors that are GABAA, these receptors are targeted by radiolabelled ligands. These radioligands can be changes in GABA or molecules very close to GABAA receptors.

The brain's concentration of GABAA receptors, their status and number can be quantified and interpreted with PET. This works especially well for neurologic disorders and testing of GABAA-receptor antagonists.

In epileptic patients, for example, PET scans of GABAA receptor distribution can tell us about the pathophysiology of GABAA receptor dysfunction in seizures. So too can PET, which can detect receptor-binding changes to assess whether new GABAA-targeting medications (eg, benzodiazepines and new anxiolytics) work.

2. Single-Photon Emission Computed Tomography (SPECT)

A third nuclear imaging method of the GABAA receptors is single-photon emission computed tomography (SPECT). It's radiolabeled ligands in SPECT too, but not positrons, but gamma rays of the tracers that are picked up. SPECT is better resolvable than PET, but still useful for receptors and their distribution in the brain.

The patient changes in GABAA receptors were studied by SPECT scans in anxiety disorders, schizophrenia and neurodegenerative disease. It is even able to tell us when drugs affect the availability of GABAA receptors, useful data for drug design.

3. Magnetic Resonance Imaging (MRI) and Functional MRI (fMRI)

MRI is an imaging procedure whereby non-invasively applied magnetic fields and radio waves generate detailed brain scans. MRI doesn't measure GABAA receptors themselves, but other techniques are used to investigate brain structure and function.

A form of MRI called functional MRI (fMRI) tracks changes in blood oxygenation and thus can be used as a proxy for neural activity. fMRI can't detect GABAA receptors but it can detect changes in GABAergic signalling to brain activity during real-time. It can be particularly useful when trying out a drug that modifies the GABAA receptors, such as anxiolytics or anticonvulsants.

4. Optogenetics and Chemogenetics

There are also advanced methods of optogenetics and chemogenetics, both of which allow researchers to manipulate and monitor neuronal activity with great accuracy. These are not imaging procedures in themselves, but can be layered on top of imaging methods to study GABAA receptors in specific brain areas.

Optogenetics uses light to direct morphologically engineered neurons containing light-sensitive ion channels. In chemogenetics, designer drugs are applied to fire or kill subsets of neurons. Through these methods combined with real-time imaging, they could study the effects of GABAA receptor modulation on brain and behaviour in animals.

What GABAA Receptor Imaging Can Do for Drug Development?

Imagery of GABAA receptors helps us to identify what kinds of drugs work with GABAA receptors and regulate neural activity. Voici some of the main areas where GABAA receptor imaging has been used in drug discovery:

1. Target Validation

A potential new drug target on the GABAA receptors must be proven a candidate therapeutic target for an illness before it can be conceived. With imaging such as PET and SPECT, this change in GABAA receptor activity can be demonstrated to be directly related to pathology, a compelling case for GABAAR modulation as a potential therapy for the condition.

In epilepsy, anxiety and schizophrenia, for instance, changes in the GABAA receptor density have been detected with PET imaging. These experiments also help to unravel how these diseases work, and pinpoint which subtypes of GABAA receptors are best targeted for therapy.

2. Drug Screening and Efficacy Testing

After finding a drug candidate, it is possible to measure the binding affinity, pharmacokinetics and pharmacodynamics of that drug using GABAA receptor imaging in animals. It's especially relevant for designing drugs that inhibit certain GABAA receptor subtypes or alter receptor function in a specific part of the brain.

Images can be used to track the interactions of a drug with GABAA receptors in real-time, allowing us to understand what's working and what's not. In patients, PET scans can be used to observe whether a radiolabelled substance binds to GABAA receptors; this can tell us about the distribution of the substance in the brain and its effects on receptor availability.

3. Studying Drug-Drug Interactions

There are a wide variety of drugs that interfere with GABAA receptors – from benzodiazepines to barbiturates – that we use in combination with each other. How these drugs work together on the GABAA receptor is important for treatment planning.

You can imaging GABAA receptors to observe the impact of various drugs on receptor ligation and activity. Through such tests, researchers can see which interactions with the drugs might be risky for adverse effects – including sedation, brain damage or respiratory depression.

4. Personalized Medicine

Imagery of patient GABAA receptors will lead to more individualised drug design. If clinicians can learn how a patient's GABAA receptors are doing, they can modify treatment based on receptor concentration, density and activity.

For instance, PET or SPECT scans might tell whether the patient's GABAA receptors are deranged, and then pick the most effective treatment for them. This tailored therapy could lead to better treatment results and fewer side-effects.

Conclusion

GABAA receptors are the basis of brain excitability regulation, and their dysfunction is responsible for many neurological and psychiatric conditions. The imaging of GABAA receptors in living tissues via techniques such as PET, SPECT and fMRI has changed the way we think about their disease-related roles and their drug-induced modulations.

Among drug development applications, GABAA receptor imaging is used for target validation, drug screening, efficacy studies, and drug-drug interactions. The next generation of neuroimaging is bound to give us even more tools to come to make effective, personalised therapies for disorders that involve GABAA receptor dysfunction. In sum, GABAA receptor imaging could speed up new therapies and improve outcomes for patients around the world.

1. Wang P, et al.; Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA. Front Cell Neurosci. 2015, 9:188.

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