Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

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A defining characteristic of individuals diagnosed with alcohol use disorder (AUD) is that negative outcomes related to drinking do not lead them to reduce their alcohol use. In rodent models of AUD, this characteristic has been studied by adding the bitter tastant quinine to an ethanol solution. In this study, we extended this approach to a nonhuman primate model in which the ability of quinine to decrease the choice of a 4% ethanol solution vs. water was measured. Five adult female rhesus monkeys with 7.3 years of experience drinking ethanol were given access to a 4% ethanol solution and water for 3 h per day. When ethanol choice was stable, a single quinine concentration (0.03–5.6g/L) was added to the ethanol solution for 1 day until a quinine concentration-effect curve was generated. After determining the quinine concentration that reduced ethanol choice by half (the quinine EC50), the relative reinforcing strength of ethanol was manipulated by adding quinine or sucrose to the water alternative depending on the monkey’s baseline choice. Adding quinine to ethanol produced a concentration-dependent decrease in ethanol choice and intake. Importantly, water intake increased, indicating an effect on response allocation rather than simply a decrease in fluid consumption. Consistent with this conclusion, the addition of quinine or sucrose to the water alternative resulted in predictable increases and decreases, respectively, in ethanol choice. These studies establish a model of punishment of ethanol choice in nonhuman primates that can be used to understand the contextual, biologic and pharmacologic factors that influence sensitivity to the punishment of alcohol drinking.

Gabapentin (Neurontin) is synthetic analog of GABA that functions as a voltage‐gated calcium channel (VDCC) blocker and is FDA approved for the management of neuropathic pain and seizure disorders. While not a controlled substance, gabapentin misuse is associated with illicit opioid use, suggesting, along with anecdotal reports, that gabapentin may elicit positive subjective effects. The present study was conducted to examine the subjective effects of gabapentin using rats (N=10) trained to discriminate a 30.0 mg/kg dose of gabapentin (60 min pretreatment time) versus saline in a two‐choice drug discrimination task. The discrimination was acquired in all 10 animals (M = 67.4 sessions, +/− 7.2 SEM). A time course assessment using the gabapentin training dose revealed full substitution (> 80% Gabapentin‐appropriate responding) at 30 and 60 minutes post‐injection. In addition to the training dose, full substitution also occurred for a 60 and 120 mg/kg dose of Gabapentin. Full substitution was shown for the barbiturate and GABAA receptor positive modulator pentobarbital and for the gabapentin analog and VDCC blocker pregabalin. Partial substitution was shown with the psychostimulant d‐amphetamine and the anxiolytic drug and 5‐HT1A partial agonist buspirone. The present findings demonstrate gabapentin's discriminative stimulus effects appear to be primarily mediated by GABAA receptors and VDCC blockade and partially mediated by dopamine and 5‐HT receptors. Full substitution by pentobarbital and partial substitution by amphetamine suggests the potential for positive subjective effects produced by gabapentin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

In the United States there are approximately 14.4 million adults diagnosed with alcohol use disorder (AUD). Despite this, there is an incomplete understanding of how chronic stress influences the development of AUD. Previous studies have shown that long‐term alcohol drinking negatively impacts cognitive flexibility (the ability to alter behavior in response to changing contingencies) and impulsive choice (the tendency to overvalue smaller, immediate rewards compared to larger, delayed rewards). However, the timing and extent of deficits that result from specific drinking patterns have not been well‐characterized. A better understanding of the progression of cognitive dysfunction is critical because deficits in these processes can perpetuate problematic alcohol use. In the present study, group‐housed adult male cynomolgus monkeys formed social hierarchies, which represent a continuum from environmental enrichment in high‐ranking (dominant; DOM; n=6) monkeys to chronic social stress in low‐ranking (subordinate; SUB; n=6) monkeys. Monkeys were trained to drink an unflavored 4% ethanol (EtOH) solution via schedule induction, then had access to self‐administer EtOH 22 hours/day, 4 days/week in the home cage (“free access”) while concurrently pressing a lever to deliver food pellets. To assess the effects of EtOH consumption on cognitive flexibility, monkeys performed a stimulus discrimination and reversal task (SD/SDR) on non‐drinking days using home cage touchscreen technology. Three stimuli appeared on the screen and the task ended when the monkey chose the correct stimulus on 18 of 20 consecutive trials. The task was administered just after induction and again after 6 months of free access. At this point, two modifications were made to increase task difficulty. First, two stimuli were added as additional distractors. In addition, the session was extended to 90 minutes and the total number of reversals was measured. We also characterized impulsive choice using a mean adjusted delay discounting task just after induction and after 4 months of free access. We hypothesized that subordinate monkeys would have greater EtOH intakes versus dominant monkeys and, as a result, would show greater cognitive dysfunction. As hypothesized, subordinate monkeys maintained greater (1.77 ± 0.95 g/kg) mean daily EtOH intakes compared to dominant monkeys (0.85 ± 0.91 g/kg) during 6 months of free access. However, there were no significant differences between dominant and subordinate monkeys in discrimination or reversal trials to criterion, or number of errors at baseline or after 6 months of free access using the 3‐stimuli SD/SDR task. There were also no rank‐related differences in these dependent variables (or number of reversals completed) when the task was modified to include 5 stimuli. Regarding the delay discounting task, both groups showed decreased impulsive choice from baseline to 4 months of free access, however the effect was lesser in subordinates. Although there are rank‐related differences in mean EtOH intake, monkeys do no...