Neurosteroids and the central actions of alcohol
Lead Research Organisation:
Imperial College London
Department Name: Life Sciences - Cell & Molecular Biology
Abstract
Alcohol abuse is now a tremendous problem in the UK. In the mid-20th century, the UK had a relatively low levels of alcohol consumption compared to other parts of Europe. However, alcohol consumption has fallen in many of these countries over the last 50 years, whereas it has increased in Britain. On average, we now have one of the highest levels of alcohol intake in the world. This has lead to marked increases in numbers of people suffering alcohol-related diseases. Alcohol-related deaths have doubled since the early 1990s, while the annual number of people being treated for alcohol-related mental health issues has increased by 10, 000. In 2001, treating these problems cost the NHS #~1.6 million, while alcohol related crime cost #7.3 million. As the numbers of Britons drinking to excess continues to rise, so will the effects of alcohol on public health.
It is estimated that 8 million British adults drink excessively, of whom 3 million are believed to be dependent on alcohol. Chronic drinking changes many aspects of brain function which can make it extremely difficult for people to reduce their alcohol intake. Thus, many people will need medication to help wean themselves off drink and an important challenge for medical research is to develop safe, effective pharmaceuticals for this purpose. To do this, we must first understand exactly how alcohol affects the activity of the brain and what aspects of brain function change after years of drinking. It is well known that some people are more sensitive to the effects of alcohol than others. This has a genetic basis and it is clear that some people?s genetic make-up means that they are at much greater risk of becoming addicted to alcohol than others. Understanding why this is will improve the success of treatments.
This research addresses these two fundamental questions: (1) how does alcohol influence brain function and (2) how is this influenced by a gene that is strongly linked to alcoholism.
It is estimated that 8 million British adults drink excessively, of whom 3 million are believed to be dependent on alcohol. Chronic drinking changes many aspects of brain function which can make it extremely difficult for people to reduce their alcohol intake. Thus, many people will need medication to help wean themselves off drink and an important challenge for medical research is to develop safe, effective pharmaceuticals for this purpose. To do this, we must first understand exactly how alcohol affects the activity of the brain and what aspects of brain function change after years of drinking. It is well known that some people are more sensitive to the effects of alcohol than others. This has a genetic basis and it is clear that some people?s genetic make-up means that they are at much greater risk of becoming addicted to alcohol than others. Understanding why this is will improve the success of treatments.
This research addresses these two fundamental questions: (1) how does alcohol influence brain function and (2) how is this influenced by a gene that is strongly linked to alcoholism.
Technical Summary
Alcohol abuse is a tremendous problem in the UK. Approximately 8 million adults drink excessively, of whom 3 million are believed to be dependent on alcohol. As these numbers continue to rise, it is vital that we tackle problem drinking and the harm that this does to society.
Pharmacological treatments are a powerful means of combating alcoholism. Currently, several drugs that target the GABAergic system are being investigated. GABA-A receptors play a vital role in the control of neuronal excitability and have long been thought to underpin many of the intoxicating effects of alcohol. However, the means by which alcohol enhances GABAergic signalling is hotly contested. Although polymorphisms in GABA-A receptor genes are strongly linked to alcoholism, it is not known how these affect the actions of the drug, nor even if the receptors encoded by these genes are influenced by alcohol at all.
This research programme addresses two fundamental questions that are crucial to understanding how alcohol?s effect on brain function can lead to addiction. Firstly, identifying the means by which alcohol enhances GABAergic transmission, and, secondly, whether it acts at synapses containing the GABA-A receptor subtype most strongly linked to alcoholism. We will test the hypothesis that the neurosteroid allopregnanolone (ALLO) plays a critical role in mediating alcohol enhancement of GABA-A receptors.
ALLO binds directly to GABA-A receptors and potentiates their activity. Alcohol consumption greatly increases ALLO synthesis in neurons and, in humans, blocking this attenuates many of the subjective effects of drinking. It is striking that these subjective effects are influenced by polymorphisms in a GABA-A receptor gene linked to alcoholism. This suggests ALLO may help mediate the intoxicating effects of drink, and, that disruption of this system increases the risks of alcohol abuse. However, a lack of suitable pharmaceuticals has made it impossible to demonstrate a causal link between alcohol, ALLO and the potentiation of GABA-A receptors.
We recently identified the ALLO binding site on GABA-A receptors. This allows us to manipulate neuronal steroid sensitivity via gene transfer techniques. Using lentivirus, we will disrupt the steroid binding site of specific GABA-A receptor subtypes in the hippocampus, a brain region that is thought to play a crucial role in the anxiolytic and rewarding effects of alcohol. We will demonstrate unequivocally whether ALLO mediates alcohol enhancement of GABAergic signalling, and, if the close proximity of steroidogenic enzymes to specific synapses underlies alcohol poteniation of the GABA-A receptor subtype most strongly linked to alcoholism.
Pharmacological treatments are a powerful means of combating alcoholism. Currently, several drugs that target the GABAergic system are being investigated. GABA-A receptors play a vital role in the control of neuronal excitability and have long been thought to underpin many of the intoxicating effects of alcohol. However, the means by which alcohol enhances GABAergic signalling is hotly contested. Although polymorphisms in GABA-A receptor genes are strongly linked to alcoholism, it is not known how these affect the actions of the drug, nor even if the receptors encoded by these genes are influenced by alcohol at all.
This research programme addresses two fundamental questions that are crucial to understanding how alcohol?s effect on brain function can lead to addiction. Firstly, identifying the means by which alcohol enhances GABAergic transmission, and, secondly, whether it acts at synapses containing the GABA-A receptor subtype most strongly linked to alcoholism. We will test the hypothesis that the neurosteroid allopregnanolone (ALLO) plays a critical role in mediating alcohol enhancement of GABA-A receptors.
ALLO binds directly to GABA-A receptors and potentiates their activity. Alcohol consumption greatly increases ALLO synthesis in neurons and, in humans, blocking this attenuates many of the subjective effects of drinking. It is striking that these subjective effects are influenced by polymorphisms in a GABA-A receptor gene linked to alcoholism. This suggests ALLO may help mediate the intoxicating effects of drink, and, that disruption of this system increases the risks of alcohol abuse. However, a lack of suitable pharmaceuticals has made it impossible to demonstrate a causal link between alcohol, ALLO and the potentiation of GABA-A receptors.
We recently identified the ALLO binding site on GABA-A receptors. This allows us to manipulate neuronal steroid sensitivity via gene transfer techniques. Using lentivirus, we will disrupt the steroid binding site of specific GABA-A receptor subtypes in the hippocampus, a brain region that is thought to play a crucial role in the anxiolytic and rewarding effects of alcohol. We will demonstrate unequivocally whether ALLO mediates alcohol enhancement of GABAergic signalling, and, if the close proximity of steroidogenic enzymes to specific synapses underlies alcohol poteniation of the GABA-A receptor subtype most strongly linked to alcoholism.
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| Stephen Brickley (Principal Investigator) |