Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.

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Opinion Statement Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940’s, and during the last 10–15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d-amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

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The opioid crisis is a significant public health issue with more than 115 people dying from opioid overdose per day in the United States. The aim of the present study was to characterize the in vitro and in vivo pharmacological effects of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(indole-7-carboxamido)morphinan (NAN), a μ opioid receptor (MOR) ligand that may be a potential candidate for opioid use disorder treatment that produces less withdrawal signs than naltrexone. The efficacy of NAN was compared to varying efficacy ligands at the MOR, and determined at the δ opioid receptor (DOR) and κ opioid receptor (KOR). NAN was identified as a low efficacy partial agonist for G-protein activation at the MOR and DOR, but had relatively high efficacy at the KOR. In contrast to high efficacy MOR agonists, NAN did not induce MOR internalization, downregulation, or desensitization, but it antagonized agonist-induced MOR internalization and stimulation of intracellular Ca2+ release. Opioid withdrawal studies conducted using morphine-pelleted mice demonstrated that NAN precipitated significantly less withdrawal signs than naltrexone at similar doses. Furthermore, NAN failed to produce fentanyl-like discriminative stimulus effects in rats up to doses that produced dose- and time-dependent antagonism of fentanyl. Overall, these results provide converging lines of evidence that NAN functions mainly as a MOR antagonist and support further consideration of NAN as a candidate medication for opioid use disorder treatment.

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Background Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice.In addition, 7-day cocaine treatment effects were also examined. Methods Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1 mg/kg/h), methylphenidate (0.032-0.32 mg/kg/h), or cocaine (0.1-0.32 mg/kg/h). Results During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1 mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. Conclusions The present subchronic treatment resultssupport the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice.

Sex differences in mu-opioid receptor agonist-induced antinociception have been reported in nonhuman primates. The degree to which mu-opioid receptor agonist sex differences in nonhuman primates extend to other behavioral endpoints remains unknown. The present study compared the behavioral effects of three mu-opioid receptor ligands (fentanyl, buprenorphine and naltrexone) that varied in efficacy to stimulate [ 35 S]-GTPγS binding (from highest to lowest: fentanyl, buprenorphine and naltrexone) in male and female rhesus monkeys. Male (n=3) and female (n=3) monkeys were trained to respond under a fixed-ratio 10 schedule of food presentation during daily sessions consisting of multiple components. Once rates of responding were stable, cumulative dose-effect functions were determined for intramuscular fentanyl (0.00032-0.032 mg/kg), buprenorphine (0.001-1 mg/kg) and naltrexone (0.01-0.1 mg/kg). Fentanyl dose-dependently decreased rates of responding in both sexes and the corresponding ED 50 values were not significantly different. Buprenorphine dose-dependently decreased rates of responding in females, but not males. Naltrexone did not significantly alter behavior in either females or males. Overall, these results suggest the expression of sex differences in MOR pharmacology depends upon both the efficacy of the MOR ligand and the behavioral endpoint.