Evaluation of samidorphan, a µ-opioid antagonist, in a drug discrimination assay in rats.

Preclinical Research & Development Background: Samidorphan, a µ-opioid receptor antagonist, is in clinical development for central nervous system related diseases. The discriminative stimulus effects of samidorphan were assessed in rats trained to discriminate the effects of a known morphinan of abuse, morphine, from that of saline. METHODS: Escalating doses of samidorphan were substituted for morphine and rats were allowed to respond on two levers for food reward. Doses of samidorphan were chosen based on other pharmacodynamic assays in which samidorphan blocked the effects of morphine (such as blocking analgesia in a hot plate test; data not shown). In addition, a pharmacokinetic study was conducted to determine if these doses would reflect predicted exposure levels that translate to human equivalent doses. RESULTS: Rats discriminating morphine from vehicle responded predominantly on the vehicle lever after receiving samidorphan. In addition, samidorphan was rapidly absorbed, and plasma concentrations of the doses tested in this study bracket therapeutically relevant concentrations. CONCLUSIONS: In summary, samidorphan produced saline-like behavioral responses over a wide dose range.

Translational Biomarkers of Neurotoxicity: A Health and Environmental Sciences Institute Perspective on the Way Forward.

Neurotoxicity has been linked to a number of common drugs and chemicals, yet efficient and accurate methods to detect it are lacking. There is a need for more sensitive and specific biomarkers of neurotoxicity that can help diagnose and predict neurotoxicity that are relevant across animal models and translational from nonclinical to clinical data. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling compared with tissues. Increasing evidence supports the potential utility of fluid-based biomarkers of neurotoxicity such as microRNAs, F2-isoprostanes, translocator protein, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1, myelin basic protein, microtubule-associated protein-2, and total tau. However, some of these biomarkers such as those in CSF require invasive sampling or are specific to one disease such as Alzheimer's, while others require further validation. Additionally, neuroimaging methodologies, including magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, may also serve as potential biomarkers and have several advantages including being minimally invasive. The development of biomarkers of neurotoxicity is a goal shared by scientists across academia, government, and industry and is an ideal topic to be addressed via the Health and Environmental Sciences Institute (HESI) framework which provides a forum to collaborate on key challenging scientific topics. Here we utilize the HESI framework to propose a consensus on the relative potential of currently described biomarkers of neurotoxicity to assess utility of the selected biomarkers using a nonclinical model.

Improvements in self-administration studies based on changes in skin button type and surgical technique.

INTRODUCTION: These studies, ranging in duration from 3 to 8months, evaluated the patency and longevity of the intravenous (IV) self-administration surgical model in male Sprague Dawley rats. Surgeries were categorized and assessed based on the number of catheter and/or skin button repairs required per animal across four separate self-administration studies. Design improvements in skin button types and changes in surgical procedures were chronologically tracked and assessed. METHODS: Animals were evaluated under a self-administration paradigm in which they were trained to respond for a food reward under a fixed ratio schedule (FR5 or FR10). Animals were then surgically prepared with a femoral catheter and skin button port. Following recovery, animals were returned to food-maintained responding for at least 5 sessions and subsequently trained to respond for injections of a reinforcing drug. Once drug training criteria was established, the effects of vehicle or varying doses of test articles were evaluated. Animals were tested in operant chambers one hour each day 5days a week and the length of each study was recorded. Differences in the number of repairs per study as well as the total number of repairs were tabulated. RESULTS: Study length was directly correlated to the mean number of repairs occurring per study, with study length increasing as the total number of repairs increased. The majority of repairs were skin button-related issues. Multiple combinations of skin button types and surgical techniques were implemented across time to evaluate model efficiency and decrease overall cycle time per study. Initial combinations produced a greater number of repairs on a per study basis. However, the skin button type and surgical technique combination that resulted in the fewest number of total repairs used a lateral incision with a dorsal biopsy punch. DISCUSSION: The combination of improvements in skin button type and surgical techniques drastically decreased the number of surgical repairs required per study, increasing efficiency and thereby decreasing the overall cycle time for study completion.

A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder.

RATIONALE: Treatment of attention-deficit/hyperactivity disorder (ADHD) has for many years relied on psychostimulants, particularly various formulations of amphetamines and methylphenidate. These are central nervous system stimulants and are scheduled because of their abuse potential. Atomoxetine (atomoxetine hydrochloride; Strattera®) was approved in 2002 for treatment of ADHD, and was the first nonstimulant medication approved for this disorder. It was classified as an unscheduled medication indicating a low potential for abuse. However, the abuse potential of atomoxetine has not been reviewed. OBJECTIVES: In this article, we review the evidence regarding abuse potential of atomoxetine, a selective inhibitor of the presynaptic norepinephrine transporter, which is unscheduled/unrestricted in all countries where it is approved. METHODS: Results from receptor binding, in vitro electrophysiology, in vivo microdialysis, preclinical behavioral, and human laboratory studies have been reviewed. RESULTS: Atomoxetine has no appreciable affinity for, or action at, central receptors through which drugs of abuse typically act, i.e., dopamine transporters, GABA(A) receptors, and opioid µ receptors. In behavioral experiments in rodents, atomoxetine does not increase locomotor activity, and in drug discrimination studies, its profile is similar to that of drugs without abuse potential. Atomoxetine does not serve as a reinforcer in monkey self-administration studies, and human laboratory studies suggest that atomoxetine does not induce subjective effects indicative of abuse. CONCLUSION: Neurochemical, preclinical, and early clinical studies predicted and supported a lack of abuse potential of atomoxetine, which is consistent with the clinical trial and postmarketing spontaneous event data in the past 10 years.