Elevated Dopamine D1 Receptor Availability in Striatum of Göttingen Minipigs after Electroconvulsive Therapy
This week we profile a recent publication in the Journal of Cerebral Blood Flow and Metabolism from
Dr. Doris Doudet at the University of British Columbia.
Can you provide a brief overview of your current research focus?
My lab’s primary focus is to understand the function and the role of a group of chemicals called monoamines in the brain. Monoamines, such as dopamine, noradrenaline and serotonin, are among the common chemicals used by brain cells, neurons, to communicate with one another and as such, are also involved in a variety of brain disorders, most famously in Parkinson’s disease, addiction and mood disorders such as depression. Not only are deficits or overexpression of these chemicals related to clinical symptoms, they play a role in therapy and manipulation of their levels in the brain may restore brain health or at least contribute to it. My lab main tool to uncover their involvement is pharmacological imaging. I use specifically the in vivo capabilities of positron emission tomography (PET) in combination with a variety of selective and specific radioactive tracers to track down their part in disease and effective therapeutic approaches. For several decades, we have had 2 main focus: Parkinson’s disease and the therapeutic mechanism of non invasive stimulation therapies such as vagal nerve stimulation (VNS), electroconvulsive therapy (ECT, the most effective antidepressant currently known) and transcranial magnetic stimulation (TMS, a possible adjunct tool to the antidepressant battery).
What is the significance of the findings in this publication?
It has been known for years, mostly from anecdotal reports and a few trials, that ECT not only improves the symptoms of depression, but also has a positive effect on the symptoms of Parkinson’s disease, often on a different timeline than it antidepressant effects. Yet, despite years of research, understanding of the effect of ECT remain elusive. In recent years, my lab has conducted PET studies trying to understand its mechanism of action and maybe determine why a small percentage of people remain refractory to the effects of ECT (and other antidepressant). My lab uses large animal models, such as pigs or primates, which allow us to use the same devices, parameters, general anesthesia and overall administration protocols as are used in human subjects. Furthermore, we can then use the same scanner and same radiotracers to ask question and translate the answers to the clinic more rapidly. The recent paper reports on the effect of a clinical course of ECT applied to minipigs on the dopamine system. The work was performed in a lab in Denmark where I continue to spend a portion of my time following a sabbatical year a decade ago. We found 1) that, in every animal studied, a clinical course of ECT stimulates the production and release of dopamine which is consistent with its effect in Parkinson’s disease (a disorder characterized by a degeneration of the dopamine cells in the brain) and 2) the magnitude of the effect is dependent on the baseline state of the dopaminergic receptors on the striatal dendritic spines. The major use of ECT is as a treatment for depressed patients refractory to common drug antidepressants. This finding suggests that the lack of response of some patients to ECT may be, in part, due to the poor binding capacity of the dopaminergic receptors and hence, an inability to respond to stimulation. Of course, this is only a very small part in the entire depressive puzzle and dopamine is only one among many of brain transmitters involved. We have already applied similar methodology to probing serotonergic and noradrenergic brain transmission following ECT. The results (recently submitted for publication) suggest that non-response to anti-depressant effects may stem as much from innate properties of some monoaminergic neurons as much as treatment parameters or type of depressive symptoms.
Briefly, what are the next steps for this research?
Non invasive stimulation therapies present a significant opportunity to manipulate brain chemistry and the way brain cells interact and connect. While non invasive and highly effective, ECT is associated with fear and stigma in the general population. It also produces, in a small percentage of subjects, some memory loss, often transient but bothersome, maybe due to its shunting of the entire brain. Fortunately, alternative forms of more focal brain stimulations are becoming available, including magnetic seizure stimulation (MST) and TMS. Both stimulation therapies have a more local effect, especially TMS, and can be applied with a variety of parameters that allows fine modulation and maybe in the near future, personalized therapeutics. The lab is currently pursuing an investigation of the effects of a newer form of TMS, using PET as well as magnetic resonance imaging (MRI) and magnetic spectroscopy (MRS) to uncover the cellular and chemical effects of focal stimulations, both locally and across brain networks.
This project was supported by:
The Parkinson Society Canada (post doctoral fellowship to AML) and the Danish Medical Research Council and Aarhus PET Center provided funding for these studies.