Category: We are working on…

Nicotine and tobacco addiction

There are over a billion smokers worldwide, costing an estimated $5.6M annually in New Zealand (NZ) alone. High tobacco taxes in NZ, while effective in triggering smoking, have had serious financial impacts on those unable to stop smoking and their families. Smoking remains a big problem largely because smoking is very addictive. However, we now know that tobacco dependence is more complex than “just” the effect of nicotine. In fact tobacco smoke contains many hundreds of different compounds.

Within this project we aim to investigate which of these components could potentiate the addictive properties of nicotine, focussing predominantly on monoamine oxidase (MAO) inhibitors. As the term implies, MAO is involved in the breakdown of monoamines such as dopamine, noradrenaline and serotonin. In fact there are two different forms of MAO, with MAO-A more involved in the metabolism of noradrenaline and serotonin and MAO-B more involved in the metabolism of dopamine. Given that all drugs of abuse (including nicotine) increase dopamine neurotransmission, MAO inhibitors could contribute to the rewarding properties of such drugs by blocking the subsequent breakdown of dopamine.

Together with Drs Penny Truman and Rob Keijzers as well as AProf Paul Teresdale Spittle, we have identified several MAO inhibitors in the tobacco smoke and we are now investigating whether these components, alone or in combination with each other, enhance the rewarding properties of nicotine. To that extent we will use several behavioural paradigms such as conditioned place preference and self-administration.

This research is supported by grants from the Health Research Council and the NZ Ministry of Business, Innovation and Employment.

Methodology

The brain is undoubtedly the most complex organ in our body and analysis of its function requires a large variety of specialisms, such as behavioural analysis, electrophysiological analysis, cellular, molecular and biochemical techniques. While our research group traditionally focussed on behaviour, we have also often included immunohistochemical techniques to assess brain activity and cellular functioning.

In recent years, mainly through the collaboration with Dr Darren Day from the School of Biological Sciences, we have expanded our portfolio to include a variety of additional techniques, such as quantitative PCR, Western blot and primary cell cultures. Recently we also implemented the RNAscope technique. This technique allows us to assess mRNA and proteins within the same brain section with high sensitivity and accuracy.

Several of our projects focus around further developing and assessing the value of specific methodologies.

Maternal Immune Activation (MIA)

While we know that most psychiatric disorders have a strong genetic component, we equally know that none are purely determined by genetic factors alone. Studies in monozygotic (identical twins) show that if one half of the twin has a mental disorder, the other has a chance of about 40 to 60% of also developing the disorder. While this is much higher than the risk in the general population it is also much less than 100% even though both twins share all of their genes. This clearly indicates that non-genetic, environmental factors must also contribute to the development of mental disorders, such as major depression, schizophrenia and autism spectrum disorders. Unfortunately, environmental factors are much more difficult to identify than genetic factors. This is in part due to the fact that environmental factors often affect individuals long before the actual disorder develops and therefore are often only identified in retrospect. Genetic factors, on the other hand are in general constant and can be identified at any point in time.

One of the environmental factors that has often been implicated in mental disorders is a viral or bacterial infection during pregnancy. Over the last two decades, multiple epidemiological studies have linked such infections to the development of autism spectrum disorder and schizophrenia. However, recent studies have also provided evidence that such infections can increase the risk of substance abuse disorders and affective disorders such as anxiety disorder, major depression and bipolar disorders).

To investigate the long-term consequences of such infections, we use two different animal models using prenatal injections of either polyI:C or LPS leading to maternal immune activation (MIA). The reasons for using these drugs rather than actual infections, is partly because it is difficult to limit an infection to a single mother. Additionally, by using drugs we have more control regarding the duration of the maternal immune response, allowing us to investigate whether MIA at different points during development leads to different long-term changes.

THE SEROTONIN TRANSPORTER (SERT) IN HEALTH AND DISEASE

Much of the research within the Behavioural Neurogenetics group focusses around investigating how genetic and/or environmental factors shape our brain and behaviour. With respect to the genetic factor, we are fortunate to have several genetic models in our group that we developed over the years. One of these is the serotonin transporter knock-out rat (SERT KO). The SERT is a protein that is specifically involved in the removal of serotonin (5—hydroxytryptamine, 5-HT) from the extracellular space back into the neurons. Thus, a reduction in SERT activity will lead to an increase in extracellular 5-HT. Importantly, many genetic studies in humans have found that a genetic reduction in SERT activity enhances the risk for different psychiatric disorders, such as major depression, anxiety disorders, autism spectrum disorder and drug addiction. Unfortunately, it is very difficult to assess from studies in humans whether a genetic change is causally linked to a disorder, as individuals often have multiple other genetic changes as well. Moreover, we know that environmental factors interact with genetic components, and of course people have different life histories. With animal research, on the other hand, we can ensure a similar genetic and environmental background thus allowing us to investigate the causality between genetic factor and behavioural/brain changes.

We have several different projects comparing normal (so-called wildtype, WT) rats with both heterozygous (SET HET) and homozygous (SERT HOM) knock-out rats. The SERT HET rats have about 50% of the SERT proteins compared to the WT, which is a similar reduction to that seen in humans with the genetic alteration in the SERT. The SERT HOM rats, on the other hand, have no SERT proteins at all. While this has not been observed in humans, it is often useful to investigate both SERT HET and SET HOM rats to see whether the effects get more intense with fewer SERT molecules (i.e. a so-called gene-dose effect).