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Substance use disorder (SUD) and drug overdose deaths represent major economic, health, and safety issues in the United States. The psychology of uncertainty provides a mechanism for understanding, reducing, and controlling the damage from substance misuse. Illicit drugs (such as heroin or cocaine) are uncertain in their availability, quality, and acquisition (the time and effort required to obtain them) compared with nondrug-related alternatives (such as consumable goods, hobbies, or paychecks). Furthermore, the severity and likelihood of negative outcomes associated with drug use likewise are uncertain. Such uncertainties worsen substance use outcomes. The current review conveys what is known about the impact of uncertainty on substance use: laboratory investigations of uncertain time and effort required to obtain a substance and uncertain drug quality show uncertainty exacerbates harm. Furthermore, uncertain negative outcomes are not likely to deter substance use in individuals with a SUD. Finally, several policy implications include access to agonist medications; creating a safer drug supply; access to clean syringes/needles, naloxone, and safe-injection sites; and ending incarceration for substance use.

Illicit drugs like cocaine may be uncertain in terms of the time and effort required to obtain them. Behavior maintained by variable schedules resembles excessive drug-taking compared with fixed schedules. However, no prior research has examined fixed versus variable schedules in drug versus nondrug choice. The present study evaluated cocaine versus food choice under fixed- (FR) and variable-ratio (VR) schedules. The simpler food versus food and cocaine versus cocaine arrangements also were included. Adult female (

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 were 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.

Kappa-opioid receptor (KOR) agonists are antinociceptive but have side effects that limit their therapeutic utility. New KOR agonists have been developed that are fully efficacious at the KOR but may produce fewer or reduced side effects that are typical of KOR agonists. We determined behavioral profiles for typical and atypical KOR agonists purported to differ in intracellular-signaling profiles as well as a mu-opioid receptor (MOR) agonist, oxycodone, using a behavioral scoring system based on Novak et al. (Am J Primatol 28:124-138, 1992, Am J Primatol 46:213-227, 1998) and modified to quantify drug-induced effects (e.g., Duke et al. J Pharmacol Exp Ther 366:145-157, 2018). Six adult male rhesus monkeys were administered a range of doses of the typical KOR agonists, U50-488H (0.0032–0.1 mg/kg) and salvinorin A (0.00032–0.01 mg/kg); the atypical KOR agonists, nalfurafine (0.0001–0.001 mg/kg) and triazole 1.1 (0.01–0.32 mg/kg); the MOR agonist, oxycodone (0.0032–0.32 mg/kg); and as controls, cocaine (0.032–0.32 mg/kg) and ketamine (0.32–10 mg/kg). For time-course determinations, the largest dose of each KOR agonist or MOR agonist was administered across timepoints (10–320 min). In mixture conditions, oxycodone (0.1 mg/kg) was followed by KOR-agonist administration. Typical KOR agonists produced sedative-like and motor-impairing effects. Nalfurafine was similar to typical KOR agonists on most outcomes, and triazole 1.1 produced no effects on its own except for reducing scratch during time-course determinations. In the mixture, all KOR agonists reduced oxycodone-induced scratching, U50-488H and nalfurafine reduced species-typical activity, and U50-488H increased rest/sleep posture. Atypical “biased” KOR agonists produce side-effect profiles that are relatively benign (triazole 1.1) or reduced (nalfurafine) compared to typical KOR agonists.

Science evolves from prior approximations of its current form. Interest in changes in species over time was not a new concept when Darwin made his famous voyage to the Galapagos Islands; concern with speciation stretches back throughout the history of modern thought. Behavioral science also does and must evolve. Such change can be difficult, but it can also yield great dividends. The focus of the current special section is on a common mutation that appears to have emerged across these areas and the critical features that define an emerging research area-applied quantitative analysis of behavior (AQAB). In this introduction to the "Special Issue on Applications of Quantitative Methods," we will outline some of the common characteristics of research in this area, an exercise that will surely be outdated as the research area continues to progress. In doing so, we also describe how AQAB is relevant to theory, behavioral pharmacology, applied behavior analysis, and health behaviors. Finally, we provide a summary for the articles that appear in this special issue. The authors of these papers are all thinking outside the Skinner box, creating new tools and approaches, and testing them against relevant data. If we can keep up this evolution of methods and ideas, behavior analysis will regain its place at the head of the table!

A growing empirical literature supports contingency management (CM) as an efficacious treatment for substance use disorders, especially when reinforcers are immediate, frequent, and of sufficient magnitude on escalating schedules. However, in real world-practice, CM is often conducted in ways that are inconsistent with research protocols. One reason for these inconsistencies may be due to pragmatic challenges inherent in conducting CM. In this article, we described an outpatient CM treatment program for drug use disorders and several specific challenges associated with adherence to CM parameters from research protocols. Finally, we propose possible solutions for these challenges and discuss implications for practice.

RATIONALE: Combinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive-ratio (PR) schedule of reinforcement. METHODS: In separate experiments, adult male rhesus monkeys (N=4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01–0.1 mg/kg/injection) alone and combined with salvinorin A (Experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (Experiment 2; 0.0001–0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine’s effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-Binaltorphimine (nor-BNI; 10 mg/kg; i.m.). RESULTS: All subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (Experiment 1) or to levels that were significantly lower than oxycodone alone (Experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI. CONCLUSIONS: These results demonstrate that KOR agonists, including the clinically-used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys, and that nalfurafine’s punishing effect is KOR dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.

Compounds lacking efficacy at the α1 subunit–containing GABAA (α1GABAA) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience. We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at αGABAA receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of ⍺1GABAA receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure. One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003–0.1 mg/kg/injection), zolpidem (0.003–0.3 mg/kg/injection), or L-838-417 (0.01–0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own. Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in three of four subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject. Compounds that lack efficacy at α1GABAA receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context-dependent.

Drug self-administration has been regarded as a gold-standard preclinical model of addiction and substance-use disorder (SUD). However, investigators are becoming increasingly aware, that certain aspects of addiction or SUDs experienced by humans are not accurately captured in our preclinical self-administration models. The current review will focus on two such aspects of current preclinical drug self-administration models: 1) Predictable vs. unpredictable drug access in terms of the time and effort put into obtaining drugs (i.e., response requirement) and drug quality (i.e., amount) and 2) rich vs. lean access to drugs. Some behavioral and neurobiological mechanisms that could contribute to excessive allocation of behavior toward drug-seeking and drug-taking at the expense of engaging in nondrug-related activities are discussed, and some directions for future research are identified. Based on the experiments reviewed, lean and unpredictable drug access could worsen drug-seeking and drug-taking behavior in individuals with SUDs. Once more fully explored, this area of research will help determine whether and how unpredictable and lean cost requirements affect drug self-administration in preclinical laboratory studies with nonhuman subjects and will help determine whether incorporating these conditions in current self-administration models will increase their predictive validity.

The schedule of drug availability may enhance choice of a drug. In non-human subjects, reinforcers are chosen more often when available under variable schedules of reinforcement relative to fixed schedules. To determine whether variable-drug access is an important determinant of cocaine choice by manipulating the schedule, drug dose, and combination of schedule + dose. Four male rhesus monkeys chose between cocaine doses (0.025–0.4 mg/kg/injection). In control conditions, the schedule and dose of each drug delivery were fixed. In other conditions, the reinforcement schedule (i.e., variable-ratio schedule), dose of each cocaine delivery, or both were variable on one lever while all aspects on the other lever remained fixed. When cocaine dose was equal on average (0.1 mg/kg/injection), 2 of 4 subjects chose cocaine associated with the variable schedule more than the fixed schedule. All subjects chose the variable dose that was equal on average to the fixed dose, and this difference was statistically significant. Three of 4 subjects chose cocaine associated with the variable combination over the fixed option (when the dose was equal on average). During dose-response determinations (when dose on the variable and fixed options were not equal), making the schedule, dose, or both variable generally did not alter cocaine’s potency as a reinforcer. While many factors contribute to drug choice, unpredictable drug access is a feature that may be common in the natural environment and could play a key role in the allocation of behavior to drug alternatives by patients with substance-use disorders.

RATIONALE. Compounds lacking efficacy at the α1 subunit-containing GABA(A) (α1GABA(A)) receptor appear to have reduced abuse potential compared with those having measurable efficacy at this receptor, though their self-administration in nonhuman primates is dependent upon past drug experience. OBJECTIVES. We used a drug vs. drug choice procedure to evaluate the hypothesis that L-838,417, a compound lacking efficacy at α1GABA(A) receptors, would not enhance cocaine choice in monkeys trained to self-administer cocaine. We also hypothesized that zolpidem, a compound with preferential modulation of α1GABA(A) receptors and midazolam, a nonselective benzodiazepine, would enhance cocaine choice in this procedure. METHODS. One female and three male rhesus monkeys chose between cocaine alone (0.1 mg/kg/injection) vs. the same dose of cocaine combined with midazolam (0.003-0.1 mg/kg/injection), zolpidem (0.003-0.3 mg/kg/injection), or L-838-417 (0.01-0.1 mg/kg/injection). In addition, we evaluated choice between saline and L-838,417 at select doses to determine whether L-838,417 would function as a reinforcer on its own. RESULTS. Consistent with our hypotheses, midazolam- and zolpidem-cocaine mixtures were chosen over cocaine alone at sufficiently high doses. However, L-838,417-cocaine mixtures also were chosen over cocaine alone in 3 of 4 subjects with at least one dose. When available alone vs. saline, L-838,417 did not function as a reinforcer in any subject. CONCLUSION. Compounds that lack efficacy at α1GABA(A) receptors may have low abuse potential compared to classic benzodiazepines, but self-administration of these compounds is context dependent.

Huskinson et al. (2015) recently examined delay discounting in monkeys choosing between an immediate drug (cocaine) reinforcer and a delayed nondrug (food) reinforcer. The present experiment examined the reverse situation: choice between immediate nondrug (food) and delayed drug (cocaine) reinforcers. Whereas the former choice situation exemplifies drug abuse from a delay-discounting perspective, our interest in the latter choice situation is derived from the observation that drug abusers, who characteristically are associated with impulsive choice, typically must devote considerable time to procuring drugs, often at the expense of immediate nondrug alternatives. Accordingly, we analyzed 3 male rhesus monkeys' choices between immediate food and delayed cocaine (0.1 and 0.2 mg/kg/injection) using a hyperbolic model that allowed us to compare discounting rates between qualitatively different reinforcers. Choice of immediate food increased with food amount, and choice functions generally shifted leftward as delay to cocaine increased, indicating a decrease in the subjective value of cocaine. Compared with our previous delay-discounting experiment with immediate cocaine versus delayed food, both doses of delayed cocaine were discounted at a shallow rate. The present results demonstrate that rhesus monkeys will tolerate relatively long delays in an immediate-food versus delayed-drug situation, suggesting that in intertemporal choices between cocaine and food, the subjective value of cocaine is less affected by the delay until reinforcement than is the subjective value of delayed food. More generally, the present findings suggest that although drug abusers may choose impulsively when immediate drug reinforcement is available, they exercise self-control in the acquisition of a highly preferred, delayed drug reinforcer. (PsycINFO Database Record

Synthetic cathinones have become increasingly available as drugs of abuse. Distribution of these drugs is made possible by altering the chemical structures of prohibited cathinones and marketing them under misleading labels. Very little is known about the relative reinforcing effectiveness of new synthetic cathinones relative to known drugs of abuse. We examined self-administration of three second-generation synthetic cathinones: alpha-pyrrolidinopentiophenone (alpha-PVP), 4-methyl-N-ethylcathinone (4-MEC), and 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP) relative to methamphetamine. Male, Sprague-Dawley rats, implanted with intravenous catheters, were trained to self-administer methamphetamine (0.05 mg/kg/injection) under a fixed-ratio schedule. Following training, various doses of methamphetamine (0.006-0.1 mg/kg/injection), alpha-PVP (0.0015-0.1 mg/kg/injection), 4-MEC (0.1-3.2 mg/kg/injection), or 4-MePPP (0.1-0.8 mg/kg/injection) were available for self-administration in separate groups, followed by a behavioral-economics evaluation of the reinforcing effectiveness of each drug. For all drugs, at least one dose functioned as a reinforcer. Alpha-PVP and 4-MePPP maintained the highest numbers of infusions per session and both were more effective reinforcers relative to methamphetamine. 4-MEC and methamphetamine were not significantly different in terms of infusions per session or reinforcing effectiveness. Emerging synthetic cathinones whose primary pharmacological mechanism is to block dopamine uptake but with little effects on monoamine release or serotonin uptake may have a greater degree of abuse potential compared with known abused stimulants.

Research on delay discounting has focused largely on non-drug reinforcers in an isomorphic context in which choice is between alternatives that involve the same type of reinforcer. Less often, delay discounting has been studied with drug reinforcers in a more ecologically valid allomorphic context where choice is between alternatives involving different types of reinforcers. The present experiment is the first to examine discounting of drug and non-drug reinforcers in both isomorphic and allomorphic situations using a theoretical model (i.e., the hyperbolic discounting function) that allows for comparisons of discounting rates between reinforcer types and amounts. The goal of the current experiment was to examine discounting of a delayed, non-drug reinforcer (food) by male rhesus monkeys when the immediate alternative was either food (isomorphic situation) or cocaine (allomorphic situation). In addition, we sought to determine whether there was a magnitude effect with delayed food in the allomorphic situation. Choice of immediate food and immediate cocaine increased with amount and dose, respectively. Choice functions for immediate food and cocaine generally shifted leftward as delay increased. Compared to isomorphic situations in which food was the immediate alternative, delayed food was discounted more steeply in allomorphic situations where cocaine was the immediate alternative. Notably, discounting was not affected by the magnitude of the delayed reinforcer. These data indicate that how steeply a delayed non-drug reinforcer is discounted may depend more on the qualitative characteristics of the immediate reinforcer and less on the magnitude of the delayed one.

Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. This article is part of the Special Issue entitled 'CNS Stimulants'.

Cocaine and opioids are often co-abused. Laboratory research has focused largely on the reinforcing effects of mixtures of drugs relative to the drugs alone. Less research has examined drug mixing by the subject under concurrent-access conditions.Self-administration of various doses of cocaine and remifentanil was examined under concurrent-access conditions. It was hypothesized that if cocaine and opioid combinations were more effective reinforcers than the single drugs, subjects would mix the two drugs by adjusting their responding to cocaine and an opioid alternative to maintain an optimal ratio of cocaine/remifentanil intake.Three male rhesus monkeys were allowed to self-administer cocaine (0.05-0.2 mg/kg/inj) or saline on one lever and remifentanil (0.05-0.4 μg/kg/inj) or saline on the other lever under concurrent fixed-ratio (FR) 10 schedules. Daily sessions lasted 2 h, and there was a 1-s timeout after every 10-s injection.When saline and drug were concurrently available, responding on the saline-associated lever was low relative to the drug alternative. When cocaine and remifentanil were concurrently available, both drugs were self-administered above saline levels. Cocaine intake decreased, and remifentanil intake increased as a function of the remifentanil dose that was available. Conversely, cocaine intake and remifentanil intake did not change systematically as a function of the cocaine dose that was available.Monkeys will mix cocaine and an opioid when the two drugs are available concurrently. However, there was no indication that monkeys titrated drug intake to maintain an optimal ratio of intake of the two compounds.

Background Synthetic cathinones are beta-ketophenethylamine analogs manufactured to avoid legal restrictions placed on illicit stimulants like methamphetamine. Regulating these “emerging” designer drugs require scientific evidence of abuse potential. Methods The present study evaluated the discriminative-stimulus effects of three synthetic cathinones, recently identified in commercial and confiscated products, in male Sprague-Dawley rats trained to discriminate methamphetamine (1.0 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food delivery. Three synthetic cathinones, 4-methyl-N-ethylcathinone (4-MEC; 1.0–8.0 mg/kg), 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP; 4.0–16.0 mg/kg), and alpha-pyrrolidinopentiophenone (alpha-PVP; 0.25–2.0 mg/kg) were tested for their ability to substitute for methamphetamine. Results Full substitution for the training dose of methamphetamine occurred at the highest doses for both 4-MePPP and alpha-PVP, and 4-MEC did not substitute at any dose tested. Conclusions The present findings show that two synthetic cathinones, 4-MePPP and alpha-PVP, produced subjective effects similar to those of methamphetamine. The synthetic cathinone, 4-MEC, did not produce subjective effects similar to those of methamphetamine with the parameters used in the current experiment. Based on findings here and by others, these three compounds warrant further tests of abuse potential.

Obesity is associated with abnormal brain reactivity in response to palatable food consumption, a factor that may contribute to non-homeostatic eating. However, little is known about how obesity interacts with the reinforcing effects of highly palatable constituents of food (e.g., fat), and if altered reinforcement processes associated with obesity generalize to non-food reinforcers. The current study compared the reinforcing effects of a fat (corn oil) and a drug of abuse (cocaine) in obese and lean Zucker rats. Specifically, obese and lean Zucker rats self-administered corn oil or intravenous cocaine in a behavioral economic demand procedure. For corn oil, maximum demand was higher and demand elasticity was lower in the obese rats compared to their lean counterparts. However, there were no differences in demand for cocaine between the obese and lean rats. These results demonstrate that a fat in the form of corn oil is a more effective reinforcer in obese Zucker rats. However, the fact that demand for cocaine was not different between the obese and lean rats suggests that differences in reward mechanisms may be reinforcer-specific and do not necessarily generalize to non-food reinforcers.

In delay discounting, choice is between two reinforcers that differ in amount and delay, and the subjective value of either reinforcer decreases as a function of delay to its receipt. The steepness of the discounting function is thought to reflect the degree of impulsive choice. Many factors can influence impulsive choice, including the addition of a constant delay or response requirement to the smaller sooner (SS) and larger later (LL) reinforcers. A delay-discounting procedure developed by Evenden and Ryan (1996) is commonly used in behavioral research, yet effects of adding a response requirement to both alternatives with this procedure has not been examined. If different delay-discounting procedures are measuring the same phenomenon, preference reversals should occur with the Evenden and Ryan procedure as they do with other procedures with an added response requirement. The current experiment used an Evenden and Ryan procedure, and choice was examined when the response requirement was a small, intermediate, and large fixed ratio (FR). Fewer LL choices occurred with the small FR, and more LL choices occurred with the intermediate and large FR. The present experiment extends preference-reversal findings to a different and commonly used delay-discounting procedure.

Impulsive choice is often examined using a delay-discounting procedure, where there is a choice between two reinforcers of different magnitudes presented at varying delays. Individual discounting rates can be influenced by many factors including strain differences and drug effects. Lewis (LEW) and Fischer 344 (F344) rats have behavioral and neurochemical differences relevant to delay discounting and were used to examine effects of acute and chronic administration of diazepam on impulsive choice. Consistent with the previous literature, larger-reinforcer choice decreased as a function of increasing delays for all rats, and steeper discounting functions were obtained for LEW relative to F344 rats. Acute and chronic administration of diazepam resulted in differential effects between rat strains and sometimes between subjects within the same rat strain. Overall, larger-reinforcer choice remained unchanged across multiple phases of the experiment for LEW rats. For F344 rats, larger-reinforcer choice increased following the acute administration of smaller doses of diazepam and decreased following the acute administration of the largest dose tested. Decreases in larger-reinforcer choice occurred for F344 rats during chronic and postchronic administration and persisted throughout a nondrug return-to-baseline phase. These results suggest potential directions for future investigation of environmental, genetic, and neurochemical variables involved in delay discounting.

Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n=8) and F344 (n=8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice.

This experiment reports on the ability of rimonabant to alter the reinforcing properties of food in the genetically obese Zucker (fa/fa) rat, a strain that exhibits higher levels of endocannabinoids in brain regions that correspond to heightened food intake. We characterized food reinforcement in obese and lean Zucker rats by placing behavior under progressive ratio schedules of sucrose reinforcement. Then, doses of rimonabant (1–10mg/kg), a CB1 receptor antagonist, were administered. Obese Zuckers had slightly higher breakpoints for sucrose under baseline conditions compared with leans, and also demonstrated significantly higher response rates than leans. Rimonabant dose-dependently decreased breakpoints and response rates for both groups, though only obese Zuckers demonstrated suppressed behavior under the 1mg/kg dose. The 10mg/kg dose of rimonabant reduced breakpoints equally for both groups (by about 60%). This dose of rimonabant also reduced food intake by 20% in lean Zuckers, and by 30% in obese Zuckers. These findings extend the literature that rimonabant reduces food reinforcer efficacy, and suggest that obese Zuckers may exhibit a heightened sensitivity to rimonabant. The findings also suggest that the effort required to obtain food reinforcement may also play a role in the efficacy of rimonabant. Behavioural Pharmacology 19:735–742 � c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2008, 19:735–742

s / Drug and Alcohol Dependence 156 (2015) e102–e182 e161 The role of carbonyl reductases in biotransformation of bupropion and 4-methylnitrozamino-1-(3-pyridyl)-1-butanone by human placenta Tatiana Nanovskaya1, Valentina M. Fokina1,2, X. Wang1, Cheryl Oncken3, Mahmoud S. Ahmed1, Gary Hankins1 1 OBG the reaction is catalyzed primarily by 11 hydroxisteroid dehydrogenase (11 -HSD) and aldoketoreductases. Maternal cigarette smoking has been associated with prenatal exposure to NNK, which is the most abundant and potent carcinogen of cigarette smoke. One of the metabolic pathways of NNK is carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)1-butanol (NNAL) that initiates NNK detoxification. The goal of the current investigation is to determine placental metabolism of NNK and to identify placental enzymes responsible for its reduction. Methods: Term placentas were collected from women who smoked during pregnancy and from non-smokers. NNK metabolism was determined in vitro using placental microsomal and cytosolic subcellular fractions; the formation of NNAL was quantified by HPLC-UV. Results: The apparent Km and Vmax values for the reaction in placental subcellular fractions were determined. The formation of NNAL in placentas of heavy smokers was lower than in placentas of non-smokers: 12.1±3.5 vs. 17±6.3nmolmgP−1 for cytosolic fraction (p methamphetamine>4-MePPP>4-MEC. Conclusions: The current findings demonstrated that three second-generation synthetic cathinones functioned as reinforcers in rats, providing some justification for permanent scheduling of these drugs by regulatory agencies. Future research in our laboratory will assess the reinforcing effectiveness of these three compounds with a behavioral economics approach. Financial support: This research was supported by the UMMC Drug Abuse Development Fund and R01 DA12970 to BB. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.439 Serotonin 5-HT2C receptors in the ventral subiculum regulate cocaine-evoked hyperactivity in rats Harshini Neelakantan1, Sonja J. Stutz1, Marcy J. Bubar1, Robert M. Sears3, Ralph J. DiLeone3, Kathryn A. Cunningham1,2 1 Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States 2 Department of Pharmacy, University of Texas Medical Branch, Galveston, TX, United States 3 Department of Psychiatry, Yale University, New Haven, CT, United States Aims: The ventral subiculum (vSUB) interconnects with limbiccorticostriatal circuit which regulates the behavioral effects of cocaine. Serotonin neurons innervate the vSUB, however, little is known about its role or the 5-HT receptors that are functionally relevant in this region. We investigated the vSUB localization of the 5-HT2C receptor (5-HT2CR) and its role in the control of cocaineevoked hyperactivity. Methods: The expression of the 5-HT2CR and co-localization with GAD 67 (marker for GABA) in the vSUB were evaluated using immunohistochemical analyses in rats (n=3).We employed virally mediated genetic knockdown strategy to test the hypothesis that knockdown of the 5-HT2CR in the vSUB of rats (n=5) will modulate cocaine-evoked hyperactivity. Motor activity was assessed after saline or cocaine (10–20mg/kg) in modified open-field chambers and analyzed using repeated measures two-way ANOVA. Results:Dense immunoreactivity (IR) for 5-HT2CRwasobserved throughout the vSUB. Only a small proportion of 5-HT2CR-IR was co-localized with GAD 67-IR that was restricted to the distal end