SERT & Drug Addiction
When thinking about addictions, most people tend to think primarily of dopamine. This is not surprising as dopamine plays a very important role in reward and all known drugs of abuse increase dopamine release within the forebrain. However, while dopamine is certainly closely related to the acute reinforcing effect of addictive substances, other neurotransmitters are definitely involved as well. In this project we focus primarily on the role of serotonin.
Genetic studies have indicated that alterations in the SERT transporter might make individuals more susceptible to the rewarding properties of drugs of abuse and increase the likelihood of becoming substance abusers. However, from studies in humans it is difficult to determine the causal relationship between genetic changes in the SERT and addictive disorders.
Therefore, in this overarching project, we investigate the effects of addictive substances in rats with a genetic reduction in the SERT. The project has both a behavioural and a biochemical, molecular component. Behaviourally we have already shown that rats with a genetic reduction in the SERT have an increased sensitivity to the rewarding effects of cocaine and MDMA (the active ingredient of ecstasy). However, they were not more sensitive to the rewarding effects of heroin. Currently we are looking at the rewarding properties of alcohol. This will be done both in SERT compromised animals as well as in their offspring to investigate whether drinking behaviour in the father affects the sensitivity of the children towards alcohol.
In addition to the behavioural changes induced by addictive substances we also investigate how such drugs affect the brain. Using an RNA sequencing technique, we found strong evidence that MDMA changes synaptic communication between cells, particularly glutamatergic neurotransmission which takes place on dendritic spines. Using a variety of techniques, such as Western Blot, quantitative PCR and RNAscope, we are now investigating this further. Additionally, we are looking at epigenetic changes (such as DNA methylation), particularly in the offspring of alcohol drinking rats.
These projects have in part been and are funded by grants
from the Neurological Foundation and the Catalyst: Seeding fund and are
performed in close collaboration with Drs Darren Day and Melanie McConnell from
the School of Biological Sciences as well as Prof Tomoaki Shirao from Gunma
University in Japan.