Vol 9, No 4 - Addictive Substances
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Poster Individual variation in response to µ opiate receptor challenge—past, present, and future: a “personal” history of investigation Margret R. Hoehe, MD, PhD Copyright © 2007 LLS SAS. All rights reserved Individual differences in response to addictive substances may provide important clues to the mechanisms underlying drug action, addiction, reward, and reward-related disease states. Early psychoneuroendocrinological studies have led to the distinction of responders and nonresponders upon µ opiate receptor agonist administration. The systematic analysis of the gene encoding the µ opiate receptor reveals abundant DNA sequence diversity, suggesting numerous individually different forms of the gene. The present work illustrates the challenges of establishing complex geno- type-phenotype relationships in the presence of high natural sequence variation, and provides some preliminary solu- tions. Progress in the future is expected to come from whole systems analysis-based approaches, integrating variation in all genes in all pathways.   © 2007, LLS SAS Dialogues Clin Neurosci. 2007;9:471-475. The examination of human individual differences at all lev- els  of  biological  and  phenotypic  analysis  will  provide important insights into the mechanisms underlying com- plex traits. In particular, individual differences in response to addictive substances may help to elucidate the mecha- nisms  underlying  drug  action, addiction, reward, and reward-related disease states.“The individual” has, both conceptually and concretely, been banned for far too long from approaches to scientific investigation.At the heart of endeavours to describe the functions and dysfunctions of “the” organism was the determination of mean values, as the averages of all individual values, and a standard error that indicated the extent of deviation of the individual val- ues from the “mean,” or “true” value. In other words, indi- vidual variation was conceived exclusively as the result of errors introduced in the process of measurement. At its extreme, the mean value would describe an effect that did not apply to any of the individuals studied. In this para- digm, the approach to gaining insight into the mechanisms underlying disease was based on the comparison of mean values between patients and healthy controls,usually result- ing from a one-off experiment. Thus, in order to test an involvement of the opioidergic system in depressive disor- ders, we  compared  neuroendocrine  and  behavioral responses to the highly potent µ opiate receptor agonist fentanyl, both in patients and controls.At the time, insights into central receptor functions in humans were to be gained only indirectly: pharmacological substances known to inter- act with central nervous system receptors were adminis- tered intravenously, and receptor-mediated effects such as the release of hormones were measured peripherally as indicators of receptor function. Evidence for individual variation in response to µ opiate receptor agonist administration In order to prepare the ground for such an opiate challenge in patients, we had performed, first, a systematic dose- response study in normal volunteers. Doses of 0.1, 0.2, and 0.25 mg fentanyl per 70 kg body weight were tested in a randomized design at 3-week intervals, and specific dose- related effects on the release of prolactin, growth hormone, cortisol, catecholamines, and euphoric responses were able to be demonstrated. In particular, this work presented the first experimental evidence of a dose-dependent increase in the rewarding properties of fentanyl.A dose of 0.2 mg