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
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.
When studying the role of serotonin in mood disorders there
is an obvious paradox. We know that one of the most effective treatment for
depression and anxiety disorders is blocking the SERT through selective
serotonin reuptake inhibitors (SSRIs), leading to an increase in extracellular
5-HT. On the other hand, a genetic reduction in the SERT, which equally leads
to increases in extracellular 5-HT, actually increased the risk of depression
and anxiety disorder.
One possible explanation for this apparent paradox lies in
the timing of the increases in extracellular 5-HT. Thus, in the case of a
genetic reduction in SERT, 5-HT levels are increased already at a very early
age. We know that 5-HT is critically involved in the development of the nervous
system. It is therefore conceivable that the brain (and body) of genetically
compromised SERT animals is fundamentally different from normal (so-called
Wildtype) rats. However, since 5-HT plays such as broad role in development it
is very hard to predict exactly what has changed in the SERT compromised animals.
In this project we therefore take a so-called
“hypothesis-free” approach. So rather than setting a hypothesis a-priori about
what may have changed, we aim to investigate as many changes as we can possible
find. For that we take two different approaches: MALDI-MS and metabolomics. With
MALDI-MS we carefully scan entire brain sections for regional changes in small
molecules such as neurotransmitters and neurotransmitter metabolites. In
metabolomics, we use brain or blood serum samples to investigate many different
This project is in part supported by a grant from the
Wellington Medical Research Foundation and is a collaboration with Drs Robert
Keyzers and Bill Jordan.
While 5-HT is best known for its role in mood, cognition and
reward, it also plays an important role in the development of the central nervous
system. Several studies have found that different serotonin receptors can
affect developmental processes such as axon and dendrite maturation, axon
guidance and spine formation. This latter is very important, as dendritic
spines are essential hubs for neuronal connections, especially excitatory
connections that use glutamate as a neurotransmitter. Moreover, dendritic spine
changes do not only occur during development, they are also a central element
in adult synaptic plasticity.
Serotonin transporter (SERT) knock-out rats have much higher
extracellular levels of 5-HT from very early on. Given its important role in neurodevelopment,
we hypothesize these animals to show changes in neuronal connectivity. In this
project we aim to investigate this with a variety of different techniques, such
as Western Blot, quantitative PCR, immunohistochemistry and RNAscope. We will
also grow neuronal cell cultures as it is easier to visualize dendritic spines
in such culture than in normal brain tissues. To evaluate the changes over time
we will study analyse the brain of young (first two weeks after birth) as well
as adult rat brain tissues.
This project is a collaboration with Dr Darren Day from the
School of Biological Sciences.
People with psychiatric disorders such as major depression
and anxiety disorders are much more likely to also suffer from with heart
problems than the general population. Likewise, individuals suffering from
heart problems are more likely to develop major depression or anxiety
disorders. In other words, there seems to a causal link between depression,
anxiety and heart disease.
In this project we investigate the hypothesis that high
levels of serotonin (5-HT) early in life may be this causal link. The reasoning
behind this is that genetic reductions in the SERT are a vulnerability factor
for major depression, anxiety disorders and heart disease and leads to high
levels of 5-HT already very early on in life. From studies in rats and mice, we
have learned that 5-HT, during development, plays an important role in shaping
the structure and function of the brain as well as the heart.
For this project we will change the extracellular levels of 5-HT early in life through pharmacological means and subsequently investigate whether this leads to changes in the body and behaviour. Behaviourally, we will investigate depressive and anxiety-like symptoms. We will also assess changes in heart rate and especially heart rate variability. In addition, we will investigate changes in the structure and functioning of the brain and heart using immunohistochemistry.
This project is supported by a grant from the New Zealand Heart Foundation