23 February 2012
Tiny zebrafish – measuring less than the length of a little finger – may seem unlikely subjects for furthering our understanding of human addiction. However, Dr Caroline Brennan has found plenty of similarity between the way that fish and humans function, and this has proved extremely helpful in understanding the genetics of human behaviour.
“In terms of the basic patterns made by neurons firing in the brain, we have a lot to learn from the fish,” she says. “Their responses to certain substances, such as nicotine and ethanol share many features with human addictive behaviour. After a period of exposure the fish clearly model aspects of addictive behaviour such as drug seeking despite adverse consequences and stress or drug induced relapse even after prolonged abstinence’ (Kily et al 2008, Brennan et al 2010).
In itself, the fact that the fish display addictive behaviour does not shed any light on the human condition – what makes the fish so special is that it is possible to manipulate their genetic makeup and determine the impact on behaviour.
“Our fish come to us from the Sanger Institute as very clear breeding lines with each line having different genetic sequence. And because the zebrafish genome has been fully mapped,” Caroline Brennan explains, “we are getting closer to being able to identify the individual genes responsible for certain behavioural responses using SNP (single nucleotide polymorphism) analysis of lines with different behaviours. Put simply, we can see that certain families of fish become ‘addicted’ more quickly and find it harder to quit and relate this behaviour to their genetic makeup.”
In order to establish and measure addictive behaviour in the fish, Caroline Brennan uses a method known as ‘Conditioned Place Preference’ (CPP) where drug exposure is paired with environmental cues. Fish are ‘trained’ through being rewarded when seeking exposure to the addictive substance.
Other tests have been designed to identify some of the predisposing factors – such as a greater tendency towards impulsive behaviour – or difficulty sustaining attention – both of which tend to lead to a greater incidence of psychological disorders later in life.
In turn, the results of these tests may make it possible to identify the genetic factors that may predispose individuals to a whole range of psychological conditions – from ADHD to schizophrenia.
Of course, biological disposition is only one factor of many that play a part in establishing an addiction – from social deprivation to peer group pressure.
However, understanding the role that genes play will help enormously in developing targeted drug treatments, for example: a drug that makes relapse less likely after successful treatment. A better understanding of the genetic factors at work may also help to screen high-risk families and alert them to the dangers they face.
Caroline Brennan is working with Professor Robert Walton in the School of Medicine and Dentistry to identify the genes that play a part in nicotine addiction. Robert is involved in a longitudinal study of nicotine addiction and dependence, with a view to creating tailored drug treatments for nicotine dependence.
Working collaboratively allows a fruitful exchange of knowledge: Caroline is able to identify genes based on her knowledge of neuroscience, neurobiology and zebrafish trials, while Robert draws on his work with longitudinal study participants and experience of human genome sequencing to work towards the same aim.
“The fish we use are completely transparent in the early stages of their development,” Caroline explains. “This means we can see their neural activity alongside their behaviour. We can also follow their embryonic neural development.” These unusual properties enable researchers to conduct more comprehensive tests.
A well-established zebrafish expert, Caroline has designed and developed numerous tests over the years. Her knowledge of what the fish can and can’t do, along with a thorough understanding of their neurobiology and genetic provenance open up a whole range of possibilities. As well as understanding more about the genetics of addiction, zebrafish may give us insight into a whole range of human conditions in the future.
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