Basic Drug Challenge Designs 1041 Acute Model

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The most basic form of an phMRI experiment is to monitor signal changes (either BOLD or IRON) using a baseline condition followed by administration of the drug of interest (see also Chapter 11, Section 11.3). The relative nature of the signal changes measured by either BOLD or IRON CBV methods means that comparisons to absolute changes in metabolism are either difficult or impossible. The ability to measure an absolute metabolic parameter makes one capable of monitoring the chronic effects of a drug challenge. Such experiments have been performed, for instance, in PET studies concerning the effects of haloperidol (a rather dirty dopamine D2 antagonist).

These studies have shown decreases in glucose metabolism after chronic administration of the drug. Optimally, in such a case a technique is required that can measure absolute changes in the parameter of interest (CBV, CBF, CMRglc, etc.). The only MR technique that can be envisioned as of use for this purpose is that of arterial spin labeling which is capable of measuring absolute CBF. However, the low sensitivity of this technique has precluded its full exploration in such a context. In situations where one might expect the changes to be regional, it is possible that measurements of relative CBV might be of some value. Thus, while certainly feasible, most studies will probably continue to be performed as acute drug challenges. There is another point to be made with regard to the acute drug challenge model. Often, one is interested not in metabolic perturbations that may have resulted from administration of a drug, but in the pattern of receptor alterations that may have been induced by a drug. Our studies of the dopamine system have resulted in the conclusion that the dynamics and populations of the dopamine receptors have a major influence upon the metabolic changes induced by the acute administration of a dopaminergic drug such as amphetamine. Thus, one can interpret the acute administration of a drug as a means of indirectly probing the population and circuitry involved with a particular receptor population. Clearly, this type of interpretation has to be proved for each new ligand and receptor system. However, once such a conclusion can be made, the drug challenge becomes a means to probe such circuitry.

A schematic of data from an IRON experiment is depicted in Figure 10.5. In this experiment, baseline signal is measured in a number of images, then an iron oxide contrast agent is administered. Administration of this agent (as discussed above) leads to a loss of signal (an increase in R2) proportional to the cerebral blood volume. Then, a drug such as amphetamine is injected, all the while imaging continuously. The signal changes are monitored for as long as one anticipates the drug of choice to have an effect. In instances where such a time period may be unknown, one might image as long as the animal remains physiologically stable. Increasing the number of images will obviously increase the statistical power of the experiment, assuming of course that everything is stable. In cases where there may be signal drift over a long period of time this must be accounted for (see also Chapter 11, Section 11.3).

In this regard it should be kept in mind that the pharmacodynamic profile of various drugs can often be very different even when targeted towards the same receptor system. For instance, cocaine and amphetamine have very similar effects upon the synaptic dopamine concentration, however, cocaine has a much shorter time course. In addition, cocaine has effects that are extremely sensitive to the method of administration. A similar effect upon synaptic dopamine changes and hemodynamic changes that occurs for cocaine at a dose of say 1 mg/kg i.v. requires about 10 mg/kg i.p. or p.o. For amphetamine, the relative difference for i.p. vs. i.v. challenge is about 30% less for the i.p. administration compared with the factor of 10 for cocaine. Thus, it cannot be stressed enough, to understand as much as possible about the pharmacodynamic profile of the drug of choice before performing the experiment. On the other hand, maybe phMRI will become a useful adjunct for performing such pharmacodynamic screening. Along these lines it is useful to note that the dissociation between direct vascular effects of the drug of choice and stimulation of the receptors must be examined. It is quite possible that the acute hemodynamics effects of a drug may be different from those that occur when, for instance, the drug reaches its peak concentration in brain tissue.

A permutation on the basic acute drug challenge is repeated administration of a drug with a relatively short time course. In this case, one can study, for instance, the effects of acute tolerance. Such experiments are feasible with drugs such as cocaine or nicotine, both of whose hemodynamic effects last for about 20 min. It is not necessarily feasible with drugs such as amphetamine that have very long time courses.

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