Indeed, as mentioned above, low doses of neuroactive steroids increased operant ethanol self-administration under some conditions,84 while neuroactive steroids reduce ethanol consumption at high doses82 or in ethanol-dependent rats.4 The relationship between HPA axis response, GABAergic neuroactive steroids, and alcohol drinking deserves further studies in nonhuman primates and humans. Figure 2 Schematic representation of the hypothetical role of neuroactive steroids in ethanol sensitivity and risk for alcoholism. GABA, γ-aminobutyric acid Summary and conclusions The effects of acute ethanol administration on neuroactive steroid levels found in rodents have
not been found in monkeys Inhibitors,research,lifescience,medical or humans. Does this mean that neuroactive steroids do not have an important role in ethanol action in these species? We doubt this conclusion, since monkeys exhibit discriminative stimulus properties Inhibitors,research,lifescience,medical of ethanol and neuroactive
steroids that are indistinguishable.62 Furthermore, the steroid biosynthesis inhibitor finasteride blocks the subjective effects of ethanol in humans.95 Primates may Gemcitabine manufacturer synthesize different GABAergic Inhibitors,research,lifescience,medical neuroactive steroids in response to ethanol challenge. These steroids may include 3α,5α- and 3α,5β-reduced derivatives of progesterone, DOC, and testosterone, all of which have potent GABAergic activity. Further studies are needed to translate a large body of rodent research on GABAergic neuroactive steroids to better understand the role of endocrine factors in alcohol sensitivity and risk for alcoholism. Selected abbreviations and acronyms 3α-HSD 3α hydroxy steroid dehydrogenase 3α,5α-THDOC 3α,21-dihydroxy-5α-pregnan-20-one 3α,5α-THP 3α-hydroxy-5α-pregnan-20-one ACTH adrenocorticotropic hormone CRF corticotropin-releasing factor DOC deoxycorticosterone Inhibitors,research,lifescience,medical GABA γ-aminobutyric acid HPA hypothalamic-pituitary-adrenal PMDD premenstrual dysphoric disorder Inhibitors,research,lifescience,medical Notes This work was supported by NIH grants R37 AA10564 (ALM) and U01 AA13515 (ALM) and U01 AA13510 (KAG).
Recent reports have highlighted
the imbalance between rising costs in drug discovery and the production of new molecular entities for the market,1,2 leading to a. long-term loss of efficiency Remarkably, this decline in productivity has occurred despite the fact that, biomedical research benefits from large governmental and private investments, and despite the comprehensive improvements in our knowledge of Parvulin human genes resulting from large sequencing projects. The tremendous efforts that have to be invested for drug target identification, follow-up validation studies, and clinical trials, in combination with the high failure rate as a. consequence of individual response to drugs, has imposed high costs on the development of drugs. Understanding individual response to a drug, what, determines its efficacy and tolerability in the patient’s body, is the major bottleneck in drug development, and clinical trials.