Effects of glyceryl trinitrate and calcitonin gene-related peptide on BOLD signal and arterial diameter: methodological studies by fMRI and MRA.

Over the last decades MRI has proved to be very useful in the field of drug development and drug discovery. Pharmacological MRI (phMRI) explores the interaction between brain physiology, neuronal activity and drugs. The BOLD signal is an indirect method to investigate brain activity by way of measuring task related hemodynamic changes. Pharmacological substances that induce hemodynamic changes can therefore potentially alter the BOLD signal and in turn falsely can be interpreted as changes in neuronal activity. It is therefore important to characterize possible effects of a pharmacological substance on the BOLD response per se before that substance can be used in an fMRI experimental setup in order to avoid false positive or false negative results. Furthermore MRI and MRA is useful in determining the vascular site-of-action of vasoactive substances. Four substances; acetazolamide, GTN, CGRP and sumatriptan has been examined in double-blind placebo controlled crossover studies. The present thesis includes three papers with the aim to determine the site-of-action and to explore the effects of the pharmacological agents on the BOLD signal. Study I showed that acetazolamide depressed the BOLD signal by increasing CBF. GTN is known to increase CBV but had surprisingly no effect on the BOLD signal. This is probably because the GTN induces CBV increase is limited to the large arteries whereas the hemodynamic changes associated with the BOLD signal are anatomically located in the capillaries and venoules. Study II and III showed that systemic administration of CGRP induces immediate headache and dilates the MMA but contrarily to previous belief does not dilate the MCA. Nor does CGRP increase brain activity per se. Sumatriptan ameliorates headache, contracts MMA and marginally contrasts MCA without altering brain activity. In conclusion we found that acetazolamide depresses the BOLD signal while GTN does not alter the BOLD signal. While systemic administration of CGRP or sumatriptan has no direct effects on brain activity in healthy volunteers. Instead it seems that both migraine provoking peptide CGRP and anti-migraine drug sumatriptan exert their actions outside of the BBB. This thesis shows that phMRI is a powerful tool in understanding mechanisms and site-of-action of pharmacological compounds. phMRI could be a useful addition to the existing methods for development of future drugs.