Punishment of ethanol choice in rhesus monkeys.

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 (0.03-5.6 g /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 EC 50 ), 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.

Effect of chronic binge-like ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys.

BACKGROUND: Although most individuals with cocaine use disorder also abuse alcohol, little is known about the behavioral and pharmacological mechanisms that promote co-abuse. For example, it is unclear whether prior experience with alcohol renders individuals more sensitive to cocaine when it is subsequently experienced. METHODS: This study examined the effects of chronic ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys. Six monkeys consumed 2.0 g/kg ethanol in a binge-drinking paradigm and 6 monkeys drank a non-alcoholic solution 5 days per week. After 9 months, each monkey's sensitivity to acquiring cocaine self-administration was determined. Monkeys performed an operant response resulting in food pellet delivery under a fixed-ratio 30 schedule of reinforcement. Saline, then ascending doses of cocaine, were substituted for food pellets until a cocaine dose was reached at which the number of cocaine injections delivered differed significantly from saline injections delivered. Following acquisition, a complete cocaine dose-effect curve was generated to determine whether ethanol consumption altered the reinforcing potency of cocaine determined by calculating the ED50 of the ascending limb of each subject's curve. RESULTS: Although individual variability was observed, the cocaine dose which initially served as a reinforcer did not differ between ethanol-drinking and control groups and, within the ethanol-drinking group, was not related to the amount of ethanol consumed. Moreover, the reinforcing potency of cocaine did not differ between groups. CONCLUSION: Taken together, the data suggest that a history of binge-like alcohol consumption does not affect sensitivity to cocaine when it is subsequently first experienced.

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains.

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.