Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity—yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research. Am. J. Primatol. 76:801–827, 2014. © 2014 Wiley Periodicals, Inc.

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. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. We report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which has partial agonist activity at both NOP and MOP receptors. AT-121 suppressed oxycodone's reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse.

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Preclinical studies have documented that serotonin (5-HT) can modulate the behavioral effects of cocaine. The present study examined the ability of 5-HT to attenuate the reinforcing and neurochemical effects of cocaine in nonhuman primates. In squirrel monkeys trained to self-administer cocaine (0.1 and 0.3 mg/injection) under a second-order schedule of i.v. drug delivery, the 5-HT uptake inhibitor alaproclate (3.0 and 10.0 mg/kg) and the 5-HT direct agonist quipazine (0.3-1.0 mg/kg) decreased response rates at doses that had no significant effect on behavior maintained by an identical schedule of stimulus termination. The neurochemical bases of the observed drug interactions on behavior were investigated further using in vivo microdialysis techniques in a separate group of awake monkeys to monitor drug-induced changes in extracellular dopamine (DA). Cocaine (1.0 mg/kg) elevated the concentration of DA in the caudate nucleus to approximately 300% of basal levels. Pretreatment with alaproclate or quipazine attenuated cocaine-induced increases in extracellular DA at the same pretreatment doses that decreased cocaine self-administration. The results obtained suggest that increasing brain 5-HT activity can attenuate the reinforcing effects of cocaine, ostensibly by decreasing the ability of cocaine to elevate extracellular DA in brain areas that mediate the behavioral effects. These findings extend those reported previously for the behavioral-stimulant effects of cocaine and identify a potential neurochemical mechanism underlying drug interactions on behavior.Abuse of stimulant drugs such as cocaine persists as a major health problem in the United States (Chilcoat and Johanson, 1998). Clearly, there is a great need for pharmacological treatments to combat abuse of these drugs; however, no pharmacotherapy has demonstrated sufficient efficacy for widespread clinical use (Carroll et al., 1999). A better understanding of the effects of cocaine on central nervous system neurochemistry will help identify effective approaches in developing medications for treating cocaine dependence.The behavioral-stimulant and reinforcing effects of cocaine have been linked to its ability to enhance dopaminergic neurotransmission by inhibiting DA uptake via transporter blockade (Ritz et al., 1987). The affinities of several cocainelike drugs for DA transporter correlate well with their potencies for supporting self-administration behavior (Ritz et al., 1987;Bergman et al., 1989). In humans, a significant correlation has been observed between DA transporter binding and the intensity of subjective effects produced by intravenous cocaine (Volkow et al., 1997). Cocaine affects neurotransmission in various brain DA systems, leading to a variety of behavioral effects. For example, the DA neurons of the substantia nigra pars compacta project to the caudate nucleus and putamen, the primate homologues of the rodent dorsal striatum (Parent et al., 1995), to modulate motor function. Facilitation of DA transmission in the nigrostriatal system...

The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy.