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Abstract: (+)-Methamphetamine (MA) is an illicit psychostimulant that can be synthesized from the nonprescription nasal decongestant, (+)-pseudoephedrine (PE). While MA is widely abused, PE appears to have little or no abuse liability in currently available formulations. However, PE produces centrally-mediated dopaminergic effects that are linked to the reinforcing effects of MA and other illicit psychostimulants and has been reported to function as a positive reinforcer in non-human primates. There has yet to be an assessment of the relative reinforcing effects of MA and PE. Therefore, the current study compared the reinforcing potency and strength of MA and PE, alone and combined, in four rhesus monkeys that were allowed to self-administer MA (0.003–0.3mg/kg/inj), PE (0.1–3.0mg/kg/inj), or combinations of the two under a progressive-ratio schedule of reinforcement. (+)-Methamphetamine functioned as a positive reinforcer in a dose-dependent manner. (+)-Pseudoephedrine also functioned as a positive reinforcer, but was less potent than MA. There were no differences in maximum injections between MA, PE, or any of the combinations of the two. Dose-addition analysis and the interaction index indicated that combinations of PE and MA were either additive or sub-additive in their reinforcing effects. These results suggest that, while MA is a more potent reinforcer than PE, the two drugs are comparable in terms of reinforcing strength. However, MA and PE do not appear to interact in a manner that enhances their relative reinforcing effects. [Copyright &y& Elsevier]

The concurrent use of cocaine and nicotine is associated with increases in their relative rates of intake. While this increase could be due to a high reinforcing effect of the drug combination, higher rates of intake could also be explained by a decrease in the drugs’ relative reinforcing effects. To determine if nicotine could modulate cocaine’s reinforcing effects, the current study compared the reinforcing potency and strength of cocaine to cocaine mixed with various concentrations of nicotine. Five rhesus monkeys were allowed to self-administer cocaine (25–400 µg/kg/inj), nicotine (12–50 µg/kg/inj), or combinations of the two under a progressive ratio schedule of reinforcement. Nicotine alone did not function as a reinforcer. Cocaine injections increased in a dose-dependent manner when taken alone and when taken as a mixture with nicotine. Furthermore, adding nicotine to cocaine shifted the cocaine dose−response function to the left in four of the five monkeys. Analysis of the ED50 values for cocaine and the mixtures indicated that some mixtures of cocaine and nicotine were more potent than cocaine alone. There were no differences in maximum injections between cocaine or any of the mixtures of cocaine and nicotine. These results suggest that nicotine, under certain conditions, can increase cocaine’s potency as a reinforcer without affecting its maximum reinforcing strength. [ABSTRACT FROM AUTHOR]

Abstract: The value of a reinforcer decreases as the time until its receipt increases, a phenomenon referred to as delay discounting. Although delay discounting of non-drug reinforcers has been studied extensively in a number of species, our knowledge of discounting in non-human primates is limited. In the present study, rhesus monkeys were allowed to choose in discrete trials between 0.05% saccharin delivered in different amounts and with different delays. Indifference points were calculated and discounting functions were established. Discounting functions for saccharin were well described by a hyperbolic function. Moreover, the discounting rates for saccharin in all six monkeys were comparable to those of other non-human animals responding for non-drug reinforcers. Also consistent with other studies of non-human animals, changing the amount of a saccharin reinforcer available after a 10-s delay did not affect its relative subjective value. Discounting functions for saccharin were steeper than we found in a previous study with cocaine, raising the possibility that drugs such as cocaine may be discounted less steeply than non-drug reinforcers. [Copyright &y& Elsevier]

Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure. Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8 mg/kg), nalfurafine (0.001-0.0056 mg/kg), or mixtures (1.0 mg/kg oxycodone/0.001-0.0056 mg/kg nalfurafine) in a Jell-O vehicle at multiple timepoints (10-320 min). Species-typical and drug-induced behaviors were recorded by observers blinded to conditions. Oxycodone alone significantly increased scratch and face-rub behaviors without affecting other behaviors. Nalfurafine decreased baseline levels of scratch without affecting other behaviors, and oxycodone-nalfurafine combinations resulted in reduced oxycodone-induced scratching at a dose (0.001 mg/kg) that did not produce sedation-like effects. Oxycodone combined with larger nalfurafine doses (0.0032-0.0056 mg/kg) also reduced oxycodone induced scratch that were accompanied with sedation-like effects (i.e., increased lip droop). Nalfurafine was orally active in rhesus monkeys, and it reduced oxycodone-induced pruritus at a dose that did not produce sedation-like effects that are commonly observed with prototypical KOR agonists. Combinations of low doses of nalfurafine with MOR agonists such as oxycodone may be well-tolerated by humans who are prescribed MOR agonists for the treatment of pain. • Orally administered nalfurafine-oxycodone combinations have not been evaluated. • Nalfurafine was orally active in male rhesus monkeys. • Nalfurafine reduced oxycodone-induced pruritis at a dose that did not produce sedation. • Low doses of nalfurafine combined with MOR agonists may be well-tolerated by humans. [ABSTRACT FROM AUTHOR]

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01–0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.32–1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01–0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0–56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias. • Some atypical KOR agonists are purportedly biased toward G-protein signaling. • Biased KOR agonists with reduced side-effects may be useful therapeutics. • All KOR agonists reduced oxycodone-induced scratch. • U50-488H and nalfurafine produced sedative-like and motor-impairing effects. • Triazole 1.1 had a reduced side-effect profile, alone and when combined with oxycodone. [ABSTRACT FROM AUTHOR]