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.