Saturday, 26 April 2014

Substance Addiction - Potential For A Cure?

I’ve written previously about the neural basis of addiction, but only focused on those involving behaviours. I thought it would be interesting to consider substance-related addictions, or more specifically, an addiction to a drug of abuse. Drugs of abuse include (but are not limited to) opiates, alcohol and amphetamines - such as cocaine, MDMA and heroin.

Substance addictions as a general term are defined as a primary, chronic disease of brain reward, motivation, memory and related circuitry (by the American Society of Addiction Medicine). The implications from the decision to name an addiction as a disease show it as a pathological condition that the sufferer seemingly has no hold over - as opposed to describing it as a behaviour or repetitive trait. 

As described in my previous post, even though behavioural addictions are met with controversy with regards to their “realness”, brain imaging shows that both forms of addictions (behavioural or substance) are similar neurologically. Regardless of an addicts' vice, the neural pathways activated and responses provoked are common to all individuals.

Those that suffer from an addiction do so partly due to structural changes in the brain that can occur as a result of their continued substance abuse. These physical changes are referred to as neuroplasticity. Although the fact that the actual structure of your brain can change in response to chronic drug abuse is a daunting thought, in realising this researchers have opened a door for a potential cure to addiction.

Let’s take this down to a molecular scale. In order for there to be structural changes in the brain, the neurons in that area of the brain need to change structurally too. For this to happen, there is be a chain of events that have led to the neuron developing differently. The beginning of this chain is gene expression. In the case of addiction, gene expression is controlled by transcription factors. A transcription factor is a protein that can control the flow of genetic information, either by promoting or blocking it. One of the main transcription factors controlling gene expression in the case of addiction is delta-FosB (ΔFosB).

Normally, ΔFosB binds to the regulatory region of a gene, and promotes expression of a gene, which will eventually be translated into a protein. In the case of addiction when a drug of abuse is taken, ΔFosB is activated and so promotes expression of a protein. The effect of this depends on whether administration of the drug abuse is acute or chronic. If acute, transcription factors are induced and an unstable protein is expressed, but after 4-12 hours the accumulation of this expressed protein is resolved. With continued use of a substance of abuse however, these proteins can begin to accumulate in a stable form in the brain. The accumulation of these grows each time the drug is taken and eventually can result in changes to both the structure of the brain. These will in time affect the behaviour of the individual.

Aside from ΔFosB, there are other substances that occur naturally in the body that can result in structural changes in the brain. For example, glutamate is another neurotransmitter but with a primarily stimulatory role. Studies show that drug seeking behaviour can be characterised by an increase in the release of glutamate in relevant areas of the brain. However, an imbalance of glutamate in the brain can result in a person suffering from a reduced ability to mediate their response to a drug. This imbalance can cause neuroplastic alterations and change the ability of different areas of their brain to communicate.

A PET scan showing chemical differences in the brains of those suffering from various addictions.

Interestingly, there are new developments in the neuroscientific field that may be able to one day provide relief to sufferers of substance-related addictions.  For example, researchers have discovered that there is potential for the use of ΔFosB antagonists as treatment. An antagonist is a substance that competes with the ΔFosB and so would reduce its efficiency at promoting gene expression, and therefore reduce the accumulation of stable forms of the protein that results in neuroplasticity changes.
Another possible treatment, in the case of glutamate, would be use of antagonists of metabotropic glutamate receptors (mGluRs). A study conducted on mice showed that when given the opportunity to self-administer cocaine, those with inactive mGluRs self-administered a significantly lower amount of the drug than those with active mGluRs. The implications of this study are that rendering addicts’ mGluRs inactive may result in an increased ability to mediate their response to cocaine. However, this application is only effective on one drug of abuse and indeed so far only on mice, and therefore there is potential for development.

Through the identification of the mechanisms at fault in the brains of those suffering from an addiction, a new field of research has begun to develop. The discovery of these mechanisms provides potential for the innovation of treatments and/or pharmaceuticals that may be able to one day offer those suffering from an addiction with relief. 

However, in my opinion there are some ethical implications of developing these treatments. If you change someone's behaviours or preferences (by methods as drastic as deactivating receptors in their brain), are you changing the fundamental principles that make you you? Or is this common practice in neuroscience? Consider the mechanisms by which most pharmaceuticals work - many over-the-counter painkillers such as neurofen and ibruprofen do not work by physically stopping the pain you feel in an area of your body, but work by blocking pain receptors in your brain so that you are no longer aware of the pain. Although these effects are short-term, the implication is still that the pharmaceutical industry can and has developed drugs that will change thoughts/reactions/behaviours.

What are your thoughts? Feel free to comment below!


Post a Comment