Effects of self- and experimenter-administered cocaine on subsequent ethanol drinking in rhesus monkeys.

Background: One possible reason for the lack of FDA-approved pharmacotherapies to treat cocaine use disorder (CUD) is that, although cocaine is typically used in combination with alcohol, it is studied in isolation in preclinical studies. A better understanding of the cocaine-alcohol interactions that promote polysubstance use (PSU) will improve animal models of CUD and hasten pharmacotherapy development. We used a rhesus monkey model of cocaine-alcohol PSU to investigate one possible mechanism: that alcohol is used to mitigate negative effects associated with termination of cocaine use.

Influence of social rank on the development of long-term ethanol drinking trajectories in cynomolgus monkeys.

Background: Chronic stress contribute to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ethical constraints. Group-housed nonhuman primates develop social dominance hierarchies that represent a continuum of social experiences from enrichment in higher-ranked (dominant) monkeys to chronic social stress in lower-ranked (subordinate) individuals.

Association of dopamine D2-like and D receptor function with initial sensitivity to cocaine reinforcement in male rhesus monkeys.

Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [C]raclopride PET imaging and dopamine D receptor (DR) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve.

Effects of chronic cocaine and ethanol self-administration on brain dopamine receptors in a rhesus monkey model of polysubstance abuse.

Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group).

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.

Social dominance in monkeys: Lack of effect on ethanol self-administration during schedule induction.

Nonhuman primate models of alcohol use disorder (AUD) frequently utilize schedule-induced polydipsia to initiate ethanol drinking. Previous research has demonstrated that specific characteristics of drinking during the final phase of induction, in which monkeys consume 1.5 g/kg of ethanol per day, can predict whether monkeys become heavy or light drinkers when they subsequently have free access to ethanol (22 hours per day; Baker, Farro, Gonzales, Helms, & Grant, 2017; Grant et al.

Effects of Dopamine D1-Like Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys.

Although dopamine plays a prominent role in mediating cocaine's abuse-related effects, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2Rs) have been characterized, less is known about dopamine D1-like receptors (D1Rs). The present experiments examined the effects of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys.

Chronic levetiracetam (Keppra®) treatment increases the reinforcing strength of cocaine in rhesus monkeys.

Background: Drugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders.

Objective: The present study assessed the ability of chronically administered levetiracetam (Keppra®), a clinically available anticonvulsant drug that increases GABA by binding to synaptic vesicle glycoprotein 2A, to modulate the reinforcing strength of cocaine in monkeys.

Methods: Three adult male rhesus monkeys (Macaca mulatta) self-administered cocaine intravenously each day under a progressive-ratio (PR) schedule of reinforcement.

Effect of ethanol and cocaine on [C]MPC-6827 uptake in SH-SY5Y cells.

Microtubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions.

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.

Antinociceptive, reinforcing, and pruritic effects of the G-protein signalling-biased mu opioid receptor agonist PZM21 in non-human primates.

Background: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G activator with minimal β-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown.

Effects of the -2 Adrenergic Receptor Agonists Lofexidine and Guanfacine on Food-Cocaine Choice in Socially Housed Cynomolgus Monkeys.

Although norepinephrine (NE) does not appear to play a prominent role in mediating the abuse-related effects of cocaine, studies have indicated that NE -2 receptor agonists can attenuate reinstatement of extinguished cocaine self-administration in rats and monkeys and can decrease cocaine craving in humans. In the present studies, we examined the effects of two -2 receptor agonists, lofexidine and guanfacine, on choice between food and cocaine (0.0-0.

PET Imaging of [C]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 [C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain.

Evaluation of the Reinforcing Strength of Phendimetrazine Using a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys.

Stimulant abuse is a persistent public health problem with no Food and Drug Administration-approved pharmacotherapy. Although monoamine-releasing drugs such as -amphetamine can decrease cocaine self-administration in human and animal laboratory studies, their potential for abuse limits clinical utility. "Abuse-deterrent" formulations of monoamine releasers, such as prodrugs, hold greater clinical promise if their abuse potential is, as theorized, lower than that of cocaine.

Effects of the mGluR2/3 receptor agonist LY379268 on the reinforcing strength of cocaine in rhesus monkeys.

Rationale: Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly group II mGluRs which includes mGluR2 and mGluR3 receptors.

Objective: The present study examined the effects of the mGluR2/3 receptor-selective agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer.

Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys.

Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) can decrease ethanol drinking. We characterized the effects of the mu opioid peptide (MOP) receptor agonist buprenorphine and the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028), which stimulates MOP and NOP receptors, in a translational nonhuman primate model of AUD.

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates.

Background: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist.

Effect of menstrual cycle on ethanol drinking in rhesus monkeys.

Background: Sex differences in the abuse-related effects of alcohol have been demonstrated in the clinic and in preclinical animal models. Less is known about the influence of menstrual cycle phase on drinking.

Methods: In this study, we examined the relationship between menstrual cycle phase and intake of ethanol (EtOH) in five adult female rhesus monkeys.

A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.

Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting.

Yawning elicited by intravenous ethanol in rhesus monkeys with experience self-administering cocaine and ethanol: Involvement of dopamine D receptors.

Characterization of the effects of long-term alcohol consumption on the brain would be aided by the development of behavioral assays that are relatively easy to implement in animal models of alcohol use disorders. Assessing unconditioned behaviors, such as drug-elicited yawning in models that permit long-term alcohol ingestion, may be a valuable complement to more invasive and costly procedures. The present studies investigated previous unexpected findings of ethanol-induced yawning in nonhuman primates.

Effects of social reorganization on dopamine D2/D3 receptor availability and cocaine self-administration in male cynomolgus monkeys.

Rationale: Studies have demonstrated that brain dopamine D2/D3 receptors (D2/D3R) and the reinforcing effects of cocaine can be influenced by a monkey's position in the social dominance hierarchy.

Objective: In this study, we manipulated the social ranks of monkeys by reorganizing social groups and assessed effects on D2/D3R availability and cocaine self-administration.

Methods: Male cynomolgus monkeys (N = 12) had been trained to self-administer cocaine under a concurrent cocaine-food reinforcement schedule.

Utility of Nonhuman Primates in Substance Use Disorders Research.

Substance use disorders (i.e., drug addiction) constitute a global and insidious public health issue.