Friction and addiction: the use of illicit drugs in Australian research

06/08/2012

in Worldwide Psychedelic Research

Criminalisation of many drugs of abuse has done little to deter their use. Recent estimates tell us nearly one in 20 individuals aged between 15 and 64 are experimenting with illicit drug use worldwide.

But contrary to the recent statements by Professor David Nutt in the UK, legislation regarding the use of illicit drugs for research purposes has had little impact on the ability of Australian neuroscientists to conduct research – and that research is yielding significant results.

Researching with illicit drugs in Australia

Understandably, the use of illicit drugs for research purposes in Australia is tightly regulated. Yes, licences need to be obtained, and drugs need to be purchased from pharmaceutical companies and stored under lock and key.

The maximum quantities that can be kept on site for authorised research groups and/or organisations are small ranging from milligrams to a few grams depending on the drug under investigation.

Their use is stringently regulated by responsible parties approved under the Drugs, Poisons and Controlled Substances regulations. This includes monitoring of the quantities distributed, which is often maintained through log books requiring more than one signature each time a drug is accessed.

But in reality these procedures are no more involved than for individuals who wish to work with, say, viral vectors and genetically modified tissues.

Obtaining illicit drugs for research purposes is not the central issue. The real challenge lies in understanding the impact of those drugs on the brain, and how this subsequently drives addictive behaviours in some users.

It is estimated only 20% of individuals who engage in drug-taking will meet the criteria for dependence. So the question remains: what is different in the brain of these individuals that makes them compelled to go back for more?

The neuroscience of addiction

There is growing evidence that repeated drug use leads to neuroadaptive changes in the brain, which alter how information is processed and consequently the way the brain functions.

It is believed these adaptations drive the “switch” as an individual transitions from casual drug use to addiction. Furthermore, in individuals who display addictive behaviours these drug-induced alterations in the brain do not necessarily resolve following withdrawal from drug-taking. Indeed, those changes are sufficient to result in relapse even after extended periods of abstinence.

Consequently, behaviours associated with drug-taking are not “unlearned” once an individual stops taking a drug. New evidence suggests that for abstinence to be successfully maintained, the brain needs to be “reprogrammed” so that it learns to make new memories that are not associated with drug-taking.

So does the addicted brain behave the same way, whatever the drug? No, it doesn’t.

The need for illicit drugs

Why do researchers need access to illicit drugs instead of simply alcohol or tobacco to understand the role of these neuroadaptive processes?

As drugs of abuse have differing “pharmacological profiles” – different chemical compositions, uses, effects, rates of metabolism and sites of action in the brain – there’s a strong need to profile each drug individually.

A researcher will find one set of drug-induced alterations in the brain after studying the effects of alcohol consumption, which may differ markedly to those caused by cannabis or morphine, for example.

Adaptive processes can occur at many levels in the brain, including those regulating gene expressionneurotransmissionand synaptic plasticity.

These changes are influenced by not only the use of the drug itself but also environmental factors. They are complex and multifactorial.

While there is no one gene that predisposes an individual to becoming “addicted”, genes and the way they are expressed can increase a person’s vulnerability to addictive behaviours.

Epigenetic mechanisms

Australian researchers are increasingly focused on understanding the role of epigenetic mechanisms in mediating addictive behaviours. This process involves the integration of environmental influences to regulate either the switching “on” or “off” of gene expression, without changes to the genetic code itself.

Regulation of gene expression results in a functional end product (usually proteins) and is akin to pieces of a jigsaw coming together to form a picture.

How does the switching on and off of gene expression play a role in addiction? Our understanding of this process is relatively new. It’s believed that exposure to a drug has the potential to result in stable epigenetic modifications that alter gene expression and lead to neuroadaptive changes.

As the process incorporates environmental influences the resultant outcome will differ across individuals. Understanding the impact of epigenetic processes in addiction is complicated by the fact that the type of change can be heavily influenced by the drug’s unique pharmacological profile, whether it’s taken once or multiple times, and the period of time over which it is taken.

Furthermore, different epigenetic-mediated processes may occur during periods of withdrawal. These changes can also be specific to different regions of the brain and to different genes themselves.

Even if we have access to illicit drugs for research purposes, processes underlying addiction appear so complex we are forced to ask: will we ever be able to successfully treat addicts?

The rise of “optogenetics”

A dramatic leap forward in our ability to achieve this goal has arisen via the recent introduction of optogenetics. Hailed by Nature as the method of the year in 2010, optogenetics incorporates theories from optics, genetics and bioengineering to enable dissection of the microstructural pathways (i.e. at the level of neurotransmitters, receptors or synapses themselves) mediating addictive behaviours.

That process involves genetic modification of a target population of cells in the brain of animal models that can be activated (or inhibited) by light of particular wave lengths.

The process is rapid, precise and eliminates many of the issues associated with other techniques, such as experiments where discrete pathways are permanently lesioned to determine their function, or the use of transgenic “knockin” or “knockout” animal models.

In these models, the altered expression of a particular gene may result in secondary compensation of other systems during development. While conditional knockins/outs provide some improvement on this, they cannot be independently regulated.

Imaginably, through the use of optogenetics, a researcher would be able to mimic the activation of the circuitry responses believed to play a role in mediating addictive behaviours. Once achieved this has the potential to highlight target sites for intervention therapies.

Australian neuroscientists are at the forefront of research into the processes mediating addiction following illicit drug use. As long as these drugs remain available to us for research, we will continue to strive towards fully understanding the mechanisms contributing to this devastating disorder.

Our work tells us so clearly that addiction is an illness above all else, with those affected worthy of compassion and care in preference to damnation within the criminal justice system.

This is the first of two articles about the human testing of illicit drugs. You can read the second article here.

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