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Risky choice is the tendency to choose a large, uncertain reward over a small, certain reward, and is typically measured with probability discounting, in which the probability of obtaining the large reinforcer decreases across blocks of trials. One caveat to traditional procedures is that independent schedules are used, in which subjects can show exclusive preference for one alternative relative to the other. For example, some rats show exclusive preference for the small, certain reinforcer as soon as delivery of the large reinforcer becomes probabilistic. Therefore, determining if a drug increases risk aversion (i.e., decreases responding for the probabilistic alternative) is difficult (due to floor effects). The overall goal of this experiment was to use a concurrent-chains procedure that incorporated a dependent schedule during the initial link, thus preventing animals from showing exclusive preference for one alternative relative to the other. To determine how pharmacological manipulations alter performance in this task, male Sprague-Dawley rats (n = 8) received injections of amphetamine (0, 0.25, 0.5, 1.0 mg/kg), methylphenidate (0, 0.3, 1.0, 3.0 mg/kg), and methamphetamine (0, 0.5, 1.0, 2.0 mg/kg). Amphetamine (0.25 mg/kg) and methylphenidate (3.0 mg/kg) selectively increased risky choice, whereas higher doses of amphetamine (0.5 and 1.0 kg/mg) and each dose of methamphetamine impaired stimulus control (i.e., flattened the discounting function). These results show that dependent schedules can be used to measure risk-taking behavior and that psychostimulants promote suboptimal choice when this schedule is used. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Because risky choice is associated with several psychiatric conditions, recent research has focused on examining the underlying neurochemical processes that control risk-based decision-making. Not surprisingly, several tasks have been developed to study the neural mechanisms involved in risky choice. The current review will briefly discuss the major tasks used to measure risky choice and will summarize the contribution of several major neurotransmitter systems to this behavior. To date, the most common measures of risky choice are the probability discounting task, the risky decision task, and the rat gambling task. Across these three tasks, the contribution of the dopaminergic system has been most studied, although the effects of serotonergic, adrenergic, cholinergic, and glutamatergic ligands will be discussed. Drug effects across these tasks have been inconsistent, which makes determining the precise role of neurotransmitter systems in risky choice somewhat difficult. Furthermore, procedural differences can modulate drug effects in these procedures, and the way data are analyzed can alter the interpretations one makes concerning pharmacological manipulations. By taking these methodological/analytic considerations into account, we may better elucidate the neurochemistry of risky decision-making. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

RATIONALE. Risky choice can be measured using the risky decision task (RDT). In the RDT, animals choose between a large, risky option that is paired with probabilistic foot shock and a small, safe option that is never paired with shock. To date, studies examining the neurochemical basis of decision making in the RDT have focused primarily on the dopaminergic system but have not focused on the glutamatergic system, which has been implicated in risky decision making. OBJECTIVES. Because glutamate is known to play a critical role in decision making, we wanted to determine the contribution of the glutamatergic system to performance in the RDT. METHODS. In the experiment, 32 rats (16 male; 16 female) were tested in the RDT. The probability of receiving a foot shock increased across the session (ascending schedule) for half of the rats but decreased across the session (descending schedule) for half of the rats. Following training, rats received injections of the N-methyl-D-aspartate (NMDA) receptor competitive antagonist CGS 19755 (0, 1.0, 2.5, 5.0 mg/kg; s.c.) and the GluN2B-selective antagonist Ro 63–1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). RESULTS. CGS 19755 (2.5 and 5.0 mg/kg) increased risky choice in males and females trained on the ascending schedule. Ro 63–1908 (1.0 mg/kg) decreased risky choice, but only in male rats trained on the ascending schedule. CONCLUSIONS. Although NMDA receptor antagonists differentially alter risky choice in the RDT, the current results show that NMDA receptors are an important mediator of decision making involving probabilistic delivery of positive punishment.

Probability discounting is often measured with independent schedules. Independent schedules have several limitations, such as confounding preference for one alternative with frequency of reward presentation and generating ceiling/floor effects at certain probabilities. To address this potential caveat, a controlled reinforcer frequency schedule can be used, in which the manipulandum that leads to reinforcement is pseudo-randomly determined before each trial. This schedule ensures subjects receive equal presentations of the small and large magnitude reinforcers across each block of trials. A total of 24 pair-housed and 11 individually housed female Sprague Dawley rats were tested in a controlled reinforcer frequency procedure. For half of the rats, the odds against (OA) receiving the large magnitude reinforcer increased across the session (ascending schedule); the OA decreased across the session for half of the rats (descending schedule). Following training, rats received treatments of amphetamine (AMPH; 0, 0.25, 0.5, 1.0 mg/kg; s.c.). For pair-housed rats, AMPH (0.5 mg/kg) increased risky choice, regardless of probability presentation order, whereas a higher dose of AMPH (1.0 mg/kg) decreased discriminability of reinforcer magnitude for rats trained on the descending schedule only. For individually housed rats, probability presentation order modulated the effects of AMPH on probability discounting, as AMPH (0.25 and 0.5 mg/kg) increased risky choice in rats trained on the ascending schedule but not on the descending schedule. These results show that pair-housing animals, but not using a controlled reinforcer frequency procedure, attenuates the modulatory effects of probability presentation order on drug effects on risky choice.

Risperidone is an atypical antipsychotic drug used increasingly in children to manage symptoms of ADHD and conduct disorder. In rats, developmental risperidone administration is accompanied by increased locomotor activity during adulthood, as well as heightened sensitivity to the locomotor stimulating effects of amphetamine. This study compared sensitivity to the rewarding effects of amphetamine, as measured by conditioned place preference (CPP), between groups of rats administered chronic risperidone (3.0 mg/kg, s.c.) during development (postnatal days 14–42) or adulthood (postnatal days 77–105). Locomotor activity in a novel test cage and amphetamine-induced CPP were measured beginning three and four weeks, respectively, after the final risperidone injection. Female rats administered risperidone early in life were more active than any other group tested. Previous risperidone administration enhanced amphetamine CPP regardless of sex, and this effect appeared more prominent in the developmentally treated group. The density of forebrain dopamine transporters, a primary target of amphetamine, was also quantified in rats administered risperidone early in life and found to be reduced in the medial anterior, posterior, and ventral caudate nucleus. These results suggest that chronic risperidone treatment modifies later locomotor activity and sensitivity to the reinforcing effects of amphetamine, perhaps via a mechanism related to decreased forebrain dopamine transporter density.

The contribution of the GluN2B subunit of the NMDA receptor to impulsive/risky choice has recently been examined. Ro 63–1908, a highly selective antagonist for GluN2B-containing NMDA receptors, decreases impulsive choice. Because the order in which delays are presented modulates drug effects in discounting procedures, one goal of the current study was to determine the effects of Ro 63–1908 in delay discounting procedures in which the delays to obtaining the large reinforcer either increase or decrease across the session. We also determined if Ro 63–1908 differentially alters risky choice in probability discounting procedures that use ascending/descending schedules. Male rats were trained in either delay (n = 24) or probability (n = 24) discounting in which the delay to/odds against reinforcement were presented in either ascending or descending order (n = 12 each schedule). Following training, rats received the GluN2B antagonists Ro 63–1908 (0, 0.1, 0.3, 1.0 mg/kg) and CP-101,606 (0, 0.3, 1.0, 3.0 mg/kg) in a counterbalanced order. In delay discounting, Ro 63–1908 (1.0 mg/kg), but not CP-101,606, decreased choice for the large reinforcer, but only when the delays decreased across the session. In probability discounting, Ro 63–1908 (0.3 mg/kg)/CP-101,606 (1.0 mg/kg) increased choice for the large reinforcer when the probability of obtaining this alternative decreased across the session, but Ro 63–1908 (1.0 mg/kg)/CP-101,606 (3.0 mg/kg) decreased choice when the probabilities increased. These results show that the GluN2B is a mediator of impulsive/risky choice, but the effects of GluN2B antagonists are dependent on the order in which delays/probabilities are presented.

BACKGROUND: An important factor that can lead to drug relapse is to re-associate with drug-using social peers, but there is little literature on the effect of social peers on relapse in animal models. METHODS: The current study used a dual-compartment operant conditioning apparatus that allowed adult male rats to respond for cocaine in the presence of a conspecific. In Experiment 1, rats were trained to self-administer cocaine in the presence of a social peer that was separated by a wire screen partition and then that peer was used as a reinstatement cue following a period of extinction. In the next experiments, rats were trained on alternating sessions to self-administer cocaine in the presence of one peer and to self-administer saline in the presence of a different peer using either a single active lever procedure (Experiment 2) or a double active lever procedure (Experiment 3). Following extinction of responding in the absence of the peers, the effect of re-exposure to the cocaine- and saline-associated peers on reinstatement of drug seeking was determined. This was tested using both single- and double-active lever procedures. RESULTS: In Experiment 1, a peer that was present throughout cocaine self-administration was able to reinstate cocaine seeking following a period of extinction. In Experiments 2 and 3, drug seeking was reinstated by the cocaine-associated peer (S+), but not the saline-associated peer (S-). This discrimination occurred when using either the single active lever procedure or double active lever procedure. CONCLUSION: These results indicate that a social peer can be used as a discriminative stimulus to signal cocaine availability and that re-introduction of a peer previously paired with cocaine can reinstate cocaine seeking, confirming clinical reports that peer affiliation among abstinent cocaine users is an important determinant of relapse.

Background Excessive risk taking is a characteristic trait of several psychiatric conditions, including substance use disorders. High risk-taking (HiR) rats self-administer more cocaine compared to low risk-taking (LoR) rats. However, research has not determined if risk taking is associated with enhanced cocaine conditioned place preference (CPP). Methods Male and female Sprague Dawley rats (n = 48 each sex) were first tested in the risky decision task (RDT), in which a response on one lever resulted in safe delivery of one food pellet, and a response on a different lever resulted in delivery of two pellets and probabilistic delivery of foot shock. Following RDT training, rats were tested for cocaine CPP. The first session was a pretest that measured rats’ preference for three compartments that provided different visual and tactile cues. Rats then learned to associate one compartment with cocaine (either 10.0 mg/kg or 20.0 mg/kg; i.p.) and one compartment with saline (1.0 ml/kg; i.p.) across eight conditioning sessions. Finally, rats explored all three compartments in a drug-free state. Results Sex significantly moderated the association between risky decision making and cocaine CPP. While increased risk aversion was somewhat positively associated with cocaine CPP in males, increased risk taking was positively correlated with cocaine CPP in females. Conclusions These results highlight the moderating role of sex on the relationship between risky decision making and cocaine reward.

Background Methamphetamine abuse has increased significantly in recent years. Currently, there are no FDA-approved pharmacotherapies for the treatment of methamphetamine use disorder. The goal of the current study was to determine if the N-methyl- d -aspartate (NMDA) GluN2B-selective antagonist Ro 63-1908 can block the conditioned rewarding effects of methamphetamine as assessed in conditioned place preference (CPP). Methods Two main experiments were conducted. In the first experiment, male (n = 24) and female (n = 24) rats received either vehicle or Ro 63-1908 (1.0–10.0 mg/kg) 30 min prior to the posttest to determine if blocking the GluN2B subunit attenuates expression of methamphetamine CPP. In the second experiment, male (n = 18) and female (n = 18) rats received either vehicle or Ro 63-1908 (1.0 or 3.0 mg/kg) 30 min prior to each conditioning session to determine if blocking the GluN2B subunit attenuates acquisition of methamphetamine CPP. Results Ro 63-1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, but only attenuated CPP in female rats. Ro 63-1908 did not alter expression of CPP in either sex. Increasing the dose of Ro 63-1908 (10.0 mg/kg) failed to block acquisition of CPP in an additional group of female rats (n = 6). A control experiment showed that Ro 63-1908 (3.0 mg/kg) did not produce CPP or conditioned place aversion in male rats (n = 6) or in female rats (n = 6). Conclusions The results of this study show that Ro 63-1908 is able to decrease the conditioned rewarding effects of methamphetamine.

Rats raised in an enriched condition (EC) show decreased stimulant self-administration relative to rats reared in an isolated condition (IC). However, few studies have examined the behavioral mechanisms underlying this environment-induced difference in self-administration. Because economic demand for drugs of abuse predicts addiction-like behavior in both humans and animals, we applied a behavioral economic analysis to cocaine self-administration data in EC and IC rats. During cocaine self-administration, the dose decreased across blocks of trials (0.75-0.003 mg/kg/inf), which allowed for a determination of demand intensity and demand elasticity. Demand intensity did not differ between EC and IC rats; however, cocaine was more elastic in EC rats relative to IC rats (i.e. EC rats were less willing to respond for cocaine as the unit price increased). When EC rats were placed in an isolated condition, demand elasticity decreased, whereas elasticity increased for IC rats placed in an enriched condition. Additionally, we applied behavioral economic analyses to previously published self-administration data and found that our results replicate past findings with cocaine and methylphenidate. To determine if differences in demand elasticity are specific to drug reinforcement, a separate group of rats was tested in sucrose or saccharin self-administration. Results showed that sucrose and saccharin were more elastic in EC rats relative to IC rats, and demand intensity was lower for saccharin in EC rats relative to IC rats. Overall, drug and nondrug reinforcers are more elastic in EC rats, which may account for the protective effects of environmental enrichment against stimulant self-administration.

Nucleus accumbens core (NAcc) has been implicated in impulsive choice, as measured in delay discounting. The role of dopamine (DA) in impulsive choice has received considerable attention, whereas glutamate (Glu) has recently been shown to be an important mediator of discounting. However, research has not examined how DA or Glu receptors in NAcc mediate different aspects of delay discounting performance, that is, (a) sensitivity to reinforcer magnitude and (b) sensitivity to delayed reinforcement. Adult male Sprague-Dawley rats were first trained in a delay discounting task, in which the delay to a large magnitude food reinforcer increased across blocks of trials. Following behavioral training, rats received bilateral implantation of guide cannulas into NAcc. Half of the rats (n = 12) received infusions of the DA-selective ligands SKF 38393 (D1-like agonist: 0.03 or 0.1 μg), SCH 23390 (D1-like antagonist: 0.3 or 1.0 μg), quinpirole (D2-like agonist: 0.3 or 1.0 μg), and eticlopride (D2-like antagonist: 0.3 or 1.0 μg). The other half received infusions of the ionotropic Glu ligands MK-801 (NMDA uncompetitive antagonist: 0.3 or 1.0 μg), AP-5 (NMDA competitive antagonist: 0.3 or 1.0 μg), ifenprodil (noncompetitive antagonist at NR2B-containing NMDA receptors: 0.3 or 1.0 μg), and CNQX (AMPA competitive antagonist: 0.2 or 0.5 μg). Results showed that SCH 23390 (0.3 μg) decreased sensitivity to reinforcer magnitude without altering impulsive choice, whereas ifenprodil (1.0 μg) decreased sensitivity to delayed reinforcement (i.e., impulsive choice). The current results show that DA and NMDA receptors in NAcc mediate distinct aspects of discounting performance. (PsycINFO Database Record

Antipsychotic drug prescriptions for pediatric populations have increased over the past 20 years, particularly the use of atypical antipsychotic drugs such as risperidone. Most antipsychotic drugs target forebrain dopamine systems, and early-life antipsychotic drug exposure could conceivably reset forebrain neurotransmitter function in a permanent manner that persists into adulthood. This study determined whether chronic risperidone administration during development modified locomotor responses to the dopamine/norepinephrine agonist, D-amphetamine, in adult rats. Thirty-five male Long-Evans rats received an injection of one of four doses of risperidone (vehicle, 0.3, 1.0, 3.0 mg/kg) each day from postnatal day 14 through 42. Locomotor activity was measured for 1 h on postnatal days 46 and 47, and then for 24 h once a week over the next two weeks. Beginning on postnatal day 75, rats received one of four doses of amphetamine (saline, 0.3, 1.0, 3.0 mg/kg) once a week for four weeks. Locomotor activity was measured for 27 h after amphetamine injection. Rats administered risperidone early in life demonstrated increased activity during the 1 and 24 h test sessions conducted prior to postnatal day 75. Taking into account baseline group differences, these same rats exhibited significantly more locomotor activity in response to the moderate dose of amphetamine relative to controls. These results suggest that early-life treatment with atypical antipsychotic drugs, like risperidone, permanently alters forebrain catecholamine function and increases sensitivity to drugs that target such function.

Metabotropic glutamate receptor 1 (mGluR1) blockade has been shown to decrease impulsive choice, as measured in delay discounting. However, several variables are known to influence an animal’s discounting, including sensitivity to delayed reinforcement and sensitivity to reinforcer magnitude. The goal of this experiment was to determine the effects of mGluR1, as well as mGluR5, antagonism on these parameters. Forty Sprague Dawley rats were trained in delay discounting, in which consistently choosing a small, immediate reward reflects impulsive choice. For half of the rats, the delay to the large reinforcer increased across blocks of trials, whereas the delay decreased across the session for half of the rats. Following training, half of the rats received injections of the mGluR1 antagonist JNJ 16259685 (JNJ; 0, 0.1, 0.3, or 1.0 mg/kg; i.p), and half received injections of the mGluR5 antagonist MPEP (0, 1.0, 3.0, or 10.0 mg/kg; i.p.). Administration of JNJ increased sensitivity to delayed reinforcement (i.e., promoted impulsive choice), regardless of which schedule was used. However, the order in which delays were presented modulated the effects of JNJ on sensitivity to reinforcer magnitude. Specifically, JNJ decreased sensitivity to reinforcer magnitude in rats trained on the descending schedule only. MPEP did not alter sensitivity to reinforcer magnitude or sensitivity to delayed reinforcement. These results show that mGluR1 is an important mediator of impulsive choice, and they provide further evidence that delay order presentation is an important variable that influences drug effects in delay discounting.

The glutamatergic system has been identified as an important mediator of risky choice. However, previous studies have focused primarily on ionotropic glutamate receptors (e.g., NMDA receptors). Little research has examined the contribution of metabotropic glutamate receptors (mGluRs) on risky choice. The goal of the current experiment was to determine the effects of mGluR 1 and mGluR5 antagonism on risky choice as assessed in probability discounting (PD). Male Sprague Dawley rats (n = 24) were trained in PD, in which consistently choosing a large, probabilistic reward (LR) reflects risky choice. For half of the rats, the odds against (OA) receiving the LR increased across blocks of trials, whereas the OA decreased across the session for half of the rats. Following training, rats received injections of the mGluR1 antagonist JNJ 16,259,685 (JNJ; 0, 0.1, 0.3, or 1.0 mg/kg; i.p) and the mGluR5 antagonist MTEP (0, 1.0, 3.0, or 10.0 mg/kg; i.p.). Regardless of which schedule was used, JNJ and MTEP decreased preference for the LR when its delivery was guaranteed. In contrast to delay discounting, in which blocking the mGluR 1 has been shown to alter impulsive choice, these results show that the Group I mGluR family does not selectively alter risky choice. Instead, blocking these receptors appears to impair discriminability of reinforcers of varying magnitudes in PD.

The N-methyl-D-aspartate (NMDA) receptor has been recently identified as an important mediator of impulsive choice, as assessed in delay discounting. Although discounting is independently influenced by sensitivity to reinforcer magnitude and delayed reinforcement, few studies have examined how NMDA receptor ligands differentially affect these parameters. The current study examined the effects of various NMDA receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure. Following behavioral training, rats received treatments of the following NMDA receptor ligands: the uncompetitive antagonists ketamine (0, 1.0, 5.0, or 10.0 mg/kg; i.p.), MK-801 (0, 0.003, 0.01, or 0.03 mg/kg; s.c.), and memantine (0, 2.5, 5.0, or 10.0 mg/kg; i.p.), the competitive antagonist CGS 19755 (0, 5.0, 10.0, or 20.0 mg/kg; s.c.), the non-competitive NR2B subunit-selective antagonist ifenprodil (0, 1.0, 3.0, or 10.0 mg/kg; i.p), and the partial agonist D-cycloserine (0, 3.25, 15.0, or 30.0 mg/kg; s.c.). When an exponential model was used to describe discounting, CGS 19755 (5.0 mg/kg) increased impulsive choice without altering sensitivity to reinforcer magnitude. Conversely, ketamine (10.0 mg/kg), memantine (5.0 mg/kg), and ifenprodil (10.0 mg/kg) decreased sensitivity to reinforcer magnitude without altering impulsive choice. MK-801 and D-cycloserine did not alter delay-discounting performance, although two-way ANOVA analyses indicated D-cycloserine (15.0 mg/kg) decreased impulsive choice. The behavioral changes observed in delay discounting following administration of NMDA receptor antagonists do not always reflect an alteration in impulsive choice. These results emphasize the utility in employing quantitative methods to assess drug effects in delay discounting.

Impulsivity is a multi-faceted personality construct that plays a prominent role in drug abuse vulnerability. Dysregulation of 5-hydroxytryptamine (serotonin, 5-HT) systems in subregions of the prefrontal cortex has been implicated in impulsivity. Extracellular 5-HT concentrations are regulated by 5-HT transporters (SERTs), indicating that these transporters may be important molecular targets underlying individual differences in impulsivity and drug abuse vulnerability. The present study evaluated the role of SERT in mediating individual differences in impulsivity. Rats were tested for both impulsive action using the cued go/no-go task and for impulsive choice using a delay discounting task in a counterbalanced design. Following behavioral evaluation, Km and Vmax were obtained from kinetic analysis of [(3)H]5-HT uptake by SERT using synaptosomes prepared from both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) obtained from each individual rat. Vmax for SERT in OFC, but not mPFC, was negatively correlated with mean adjusted delay scores in the delay discounting task. In contrast, Vmax for SERT in OFC and mPFC was not correlated with performance in the cued go/no-go task. To further evaluate the relationship between SERT function and impulsive choice, a selective SERT inhibitor, fluoxetine (0, 15, 50 and 150pmol/side) was microinjected bilaterally into OFC and effects on the delay discounting task determined. Following stabilization of behavior, fluoxetine increased mean adjusted delay scores (decreased impulsivity) in high impulsive rats compared to saline microinjection, but had no effect in low impulsive rats. These ex vivo and in vivo results suggest that enhanced SERT function in OFC underlies high impulsive choice behavior.

Negative urgency is a facet of impulsivity that reflects mood-based rash action and is associated with various maladaptive behaviors in humans. However, the underlying neural mechanisms of negative urgency are not fully understood. Several brain regions within the mesocorticolimbic pathway, as well as the neurotransmitters dopamine (DA) and serotonin (5-HT), have been implicated in impulsivity. Extracellular DA and 5-HT concentrations are regulated by DA transporters (DAT) and 5-HT transporters (SERT); thus, these transporters may be important molecular mechanisms underlying individual differences in negative urgency. The current study employed a reward omission task to model negative urgency in rats. During reward trials, a cue light signaled the non-contingent delivery of one sucrose pellet; immediately following the non-contingent reward, rats responded on a lever to earn sucrose pellets (operant phase). Omission trials were similar to reward trials, except that non-contingent sucrose was omitted following the cue light prior to the operant phase. As expected, contingent responding was higher following omission of expected reward than following delivery of expected reward, thus reflecting negative urgency. Upon completion of behavioral training, Vmax and Km were obtained from kinetic analysis of [3H]DA and [3H]5-HT uptake using synaptosomes prepared from nucleus accumbens (NAc), dorsal striatum (Str), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC) isolated from individual rats. Vmax for DAT in NAc and for SERT in OFC were positively correlated with negative urgency scores. The current findings suggest that mood-based impulsivity (negative urgency) is associated with enhanced DAT function in NAc and SERT function in OFC.

RATIONALE: Impulsive choice is often measured with delay discounting paradigms. Because there are multiple discounting procedures, as well as different statistical analyses that can be applied to data generated from these paradigms, there are some inconsistencies in the literature regarding drug effects on impulsive choice. OBJECTIVES: The goal of the current paper is to review the methodological and analytic approaches used to measure discounting and to discuss how these differences can account for differential drug effects observed across studies. RESULTS: Because some procedures/analyses use a single data point as the dependent variable, changes in this value following pharmacological treatment may be interpreted as alterations in sensitivity to delayed reinforcement, but when other procedures/analyses are used, no changes in behavior are observed. Even when multiple data points are included, some studies show that the statistical analysis (e.g., ANOVA on raw proportion of responses vs. using hyperbolic/exponential functions) can lead to different interpretations. Finally, procedural differences (e.g., delay presentation order, signaling the delay to reinforcement, etc.) in the same discounting paradigm can alter how drugs affect sensitivity to delayed reinforcement. CONCLUSIONS: Future studies should utilize paradigms that allow one to observe alterations in responding at each delay (e.g., concurrent-chains schedules). Concerning statistical analyses, using parameter estimates derived from nonlinear functions or incorporating the generalized matching law can allow one to determine if drugs affect sensitivity to delayed reinforcement or impair discrimination of the large and small magnitude reinforcers. Using these approaches can help further our understanding of the neurochemical underpinnings of delay discounting.

Impulsive choice is often assessed in rodents using a delay discounting (DD) paradigm in which the delay to a large reinforcer (LR) increases across the session. This procedure allows one to test the effects of pharmacological manipulations within a single session. Because discounting is influenced by sensitivity to reinforcer magnitude (SRM) and sensitivity to delayed reinforcement (SDR), applying quantitative analyses (e.g., fitting hyperbolic function) is important for determining the precise behavioral mechanisms being altered following drug administration. One caveat to this approach is that observing increases in SMR/SDR can be difficult (e.g., most rats choose the LR when its delivery is immediate, whereas some rats may show exclusive preference for the small reinforcer [SR] when a delay on the LR is imposed). We utilized a variant of a concurrent-chains procedure in which rats (n = 8) could not show exclusive preference for either reinforcer, thus allowing one to observe increases/decreases in responding at each delay. The NMDAr antagonists MK-801 (0, 0.003, 0.01, 0.03 mg/kg), ketamine (0, 1.0, 5.0, 10.0 mg/kg), and memantine (0, 2.5, 5.0, 7.5 mg/kg) were administered following baseline training because this receptor has recently been implicated in DD. MK-801 (0.03 mg/kg) decreased SRM and SDR. Memantine (7.5 mg/kg) decreased SRM only. These results show that this variant of the concurrent-chains procedure can be used to study the effects of pharmacological manipulations on distinct aspects of DD.

Procedural modifications can modulate drug effects in delay discounting, such as signaling the delay to reinforcement and altering the order in which delays are presented. Although the schedule of reinforcement can alter the rate at which animals discount a reinforcer, research has not determined if animals trained on different schedules of reinforcement are differentially affected by pharmacological manipulations. Similarly, research has not determined if using different delays to reinforcement can modulate drug effects in delay discounting. Male Sprague Dawley rats (n = 36) were split into four groups and were trained in a delay-discounting procedure. The schedule of reinforcement (fixed ratio [FR] 1 vs. FR 10) and delays to reinforcement (0, 5, 10, 20, and 50 s vs. 0, 10, 30, 60, 100 s) were manipulated for each group. Following behavioral training, rats were treated with d -amphetamine (0, 0.25, 0.5, and 1.0 mg/kg) and MK-801 (0, 0.03, and 0.06 mg/kg). Results showed that amphetamine decreased impulsive choice when a FR 1 schedule was used, but only when the short delay sequence was used. Conversely, amphetamine decreased impulsive choice when a FR 10 schedule was used, but only when rats were trained on the long delay sequence. MK-801 decreased impulsive choice in rats trained on a FR 1 schedule, regardless of delay sequence, but did not alter choice in rats trained on a FR 10 schedule. These results show that schedule of reinforcement and delay length can modulate drug effects in delay discounting.

Rats raised in an isolated condition (IC) are impulsive and hyperactive compared to rats raised in an enriched condition (EC), suggesting that isolation rearing may be a preclinical model of attention-deficit/hyperactivity disorder (ADHD). The current study determined if administration of methylphenidate (MPH), a dopamine transporter (DAT) blocker used in the treatment of ADHD, reduces the hyperactivity observed in IC rats toward levels observed in EC rats. Another goal was to determine if chronic MPH treatment differentially alters DAT function in EC and IC rats in medial prefrontal cortex (mPFC) or orbitofrontal cortex (OFC). IC and EC rats were treated with either MPH (1.5 mg/kg, p.o.) or vehicle from postnatal days (PND) 28–51. On PND 28 and 51, rats were evaluated for MPH-induced locomotor activity. On PND 55–63, in vitro [3H]DA uptake assays were performed in mPFC and OFC. At both PND 28 and 51, IC rats were hyperactive compared to EC rats. At PND 28, MPH increased activity in EC rats only. At PND 51, MPH did not alter locomotor activity in IC or EC rats. Beginning at PND 55, basal uptake of [3H]dopamine in IC rats was higher in mPFC and lower in OFC compared to EC rats. The basal differences in DAT function were normalized by MPH treatment in mPFC, but not in OFC. These findings suggest that isolation rearing may not represent a valid predictive model for screening effective medications in the treatment of hyperactivity associated with ADHD.

The link between social influence and drug abuse has long been established in humans. However, preclinical animal models of drug abuse have only recently begun to consider the role of social influence. Since social factors influence the initiation and maintenance of drug use in humans, it is important to include these factors in preclinical animal models. The current study examined the effects of the presence of a social partner on responding for sucrose pellets under various motivational conditions, as well as on d-amphetamine (AMPH) self-administration. Rats were trained to lever press for either sucrose pellets or AMPH (0.01 or 0.1 mg/kg/infusion unit dose). Following response stability, a novel same-sex conspecific was presented in an adjacent compartment separated by a clear Plexiglas wall, and responding for sucrose or AMPH reward was measured. Rats were allowed to restabilize, and were subsequently given an additional partner presentation. Presence of the social partner increased responding only during the first partner pairing in the AMPH 0.1 mg/kg/infusion unit dose, whereas inhibition of responding was observed during the first partner pairing during access to the 0.01 mg/kg/infusion unit dose. Under free feed conditions, inhibition of sucrose pellet responding was observed in the presence of the social partner, but this effect was attenuated under food restriction. In contrast, the results demonstrate social facilitation of AMPH self-administration at a high unit dose, thus extending the influence of social factors to an operant conditioning task. This model of social facilitation may have important implications as a preclinical model of social influence on drug abuse.

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N -methyl- d -aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n = 8) or decreased (n = 8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03 mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0 mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0 mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03 mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making.

Impulsivity, which can be subdivided into impulsive action and impulsive choice, is implicated as a factor underlying drug abuse vulnerability. Although previous research has shown that dopamine (DA) systems in prefrontal cortex are involved in impulsivity and substance abuse, it is not known if inherent variation in DA transporter (DAT) function contributes to impulsivity. The current study determined if individual differences in either impulsive action or impulsive choice are related to DAT function in orbitofrontal (OFC) and/or medial prefrontal cortex (mPFC). Rats were first tested both for impulsive action in a cued go/no-go task and for impulsive choice in a delay-discounting task. Following behavioral evaluation, in vitro [(3)H]DA uptake assays were performed in OFC and mPFC isolated from individual rats. Vmax in OFC, but not mPFC, was correlated with performance in the cued go/no-go task, with decreased OFC DAT function being associated with high impulsive action. In contrast, Vmax in OFC and mPFC was not correlated with performance in the delay-discounting task. The current results demonstrate that impulsive behavior in cued go/no-go performance is associated with decreased DAT function in OFC, suggesting that hyperdopaminergic tone in this prefrontal subregion mediates, at least in part, increased impulsive action.

Interaction with social peers may increase rates of drug self-administration, but a recent study from our laboratory showed that social interaction may serve as a type of alternative reward that competes with drug taking in adolescent male rats. Based on those previous results, the current study examined sex differences in preference for social interaction compared with amphetamine (AMPH) in adolescent rats using the conditioned place preference (CPP) paradigm. Similar to previous results with males, females showed AMPH CPP regardless of whether they were individual- or pair-housed. In contrast to males, however, females failed to show social CPP, and they did not prefer a peer-associated compartment over an AMPH-associated compartment in a free-choice test. In separate experiments, dopamine (DA) and serotonin (5-HT) metabolite levels were measured in adolescent males and females that were exposed acutely to peer interaction, no peer interaction, AMPH, or saline. In amygdala, levels of the DA metabolite dihydroxyphenylacetic acid (DOPAC) were altered more in response to peer interaction in males than females; in contrast, there was a greater amygdala DOPAC response to AMPH in females. Furthermore, there were greater changes in the 5-HT metabolite hydroxyindoleacetic acid (5-HIAA) in females than in males following social interaction. These results indicate that the ability of peer interactions to reduce drug reward is greater in adolescent males than females, perhaps due to a greater ability of social cues to activate limbic reward mechanisms in males or a greater ability of AMPH cues to activate limbic reward mechanisms in females.

Conditioned place preference (CPP) is established by pairing a context conditioned stimulus with an abused drug. With repeated context-drug pairings, the context alone acquires positive incentive value that elicits approach behavior. While CPP can be and is frequently applied to identify the reinforcing effects of drugs, this chapter will instead cover different applications: (1) efficacy studies in developing novel pharmacotherapies for drug abuse and (2) preclinical safety assessment of the abuse liability of novel drugs in the development of medications. Depending on when a potential pharmacotherapeutic is administered, either acquisition or expression of drug CPP can be blocked. In addition, following a period of extinction to the context, a pharmacotherapeutic may block reinstatement of drug seeking. Some results obtained with stimulant-, opioid-, and ethanol-induced reward are covered to illustrate the versatility of CPP for identifying novel targets for medication development.

Performance in an adjusting delay discounting procedure is predictive of drug abuse vulnerability; however, the shared underlying specific prefrontal neural systems linking delay discounting and increased addiction-like behaviors are unclear. Rats received direct infusions of methylphenidate (MPH; 6.25, 25.0, or 100 μg), amphetamine (AMPH; 0.25, 1.0, or 4.0 μg), or atomoxetine (ATO; 1.0, 4.0, or 16.0 μg) into either medial prefrontal cortex (mPFC) or orbitofrontal cortex (OFC) immediately prior to performance in an adjusting delay task. These drugs were examined because they are efficacious in treating impulse control disorders. Because dopamine (DA) and serotonin (5-HT) receptors are implicated in impulsive behavior, separate groups of rats received microinfusions of the DA receptor-selective drugs SKF 81297 (0.1 or 0.4 μg), SCH 23390 (0.25 or 1.0 μg), quinpirole (1.25 or 5.0 μg), and eticlopride (0.25 or 1.0 μg), or received microinfusions of the 5-HT receptor-selective drugs 8-OH-DPAT (0.025 or 0.1 μg), WAY 100635 (0.01 or 0.04 μg), DOI (2.5 or 10.0 μg), and ketanserin (0.1 or 0.4 μg). Impulsive choice was not altered significantly by MPH, AMPH, or ATO into either mPFC or OFC, indicating that neither of these prefrontal regions alone may mediate the systemic effect of ADHD medications on impulsive choice. However, quinpriole (1.25 μg) and eticlopride infused into mPFC increased impulsive choice, whereas 8-OH-DPAT infused into OFC decreased impulsive choice. These latter results demonstrate that blockade of DA D2 receptors in mPFC or activation of 5-HT1A receptors in OFC increases impulsive choice in the adjusting delay procedure.

Discounting of delayed and probabilistic reinforcement is linked to increased drug use and pathological gambling. Understanding the neurobiology of discounting is important for designing treatments for these disorders. Glutamate is considered to be involved in addiction-like behaviors; however, the role of ionotropic glutamate receptors (iGluRs) in discounting remains unclear.The current study examined the effects of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor blockade on performance in delay and probability discounting tasks.Following training in either delay or probability discounting, rats (n = 12, each task) received pretreatments of the NMDA receptor antagonists MK-801 (0, 0.01, 0.03, 0.1, or 0.3 mg/kg, s.c.) or ketamine (0, 1.0, 5.0, or 10.0 mg/kg, i.p.), as well as the AMPA receptor antagonist CNQX (0, 1.0, 3.0, or 5.6 mg/kg, i.p.). Hyperbolic discounting functions were used to estimate sensitivity to delayed/probabilistic reinforcement and sensitivity to reinforcer amount.An intermediate dose of MK-801 (0.03 mg/kg) decreased sensitivity to both delayed and probabilistic reinforcement. In contrast, ketamine did not affect the rate of discounting in either task but decreased sensitivity to reinforcer amount. CNQX did not alter sensitivity to reinforcer amount or delayed/probabilistic reinforcement.These results show that blockade of NMDA receptors, but not AMPA receptors, decreases sensitivity to delayed/probabilistic reinforcement (MK-801) and sensitivity to reinforcer amount (ketamine). The differential effects of MK-801 and ketamine demonstrate that sensitivities to delayed/probabilistic reinforcement and reinforcer amount are pharmacologically dissociable.

Social interaction can serve as a natural reward that attenuates drug reward in rats; however, it is unknown if age or housing conditions alter the choice between social interaction and drug.Individually- and pair-housed adolescent and adult male rats were tested using conditioned place preference (CPP) in separate experiments in which: (1) social interaction was conditioned against no social interaction; (2) amphetamine (AMPH; 1mg/kg, s.c.) was conditioned against saline; or (3) social interaction was conditioned against AMPH.Social interaction CPP was obtained only in individually-housed adolescents, whereas AMPH CPP was obtained in both individually-housed adolescents and adults; however, the effect of AMPH was not statistically significant in pair-housed adults. When allowed to choose concurrently between compartments paired with either social interaction or AMPH, individually-housed adolescents preferred the compartment paired with social interaction, whereas pair-housed adolescents preferred the compartment paired with AMPH. Regardless of housing condition, adults showed a similar preference for the compartments paired with either social interaction or AMPH.Although some caution is needed in interpreting cross-experiment comparisons, the overall results suggest that individually-housed adolescents were most sensitive to the rewarding effect of social interaction, and this hypersensitivity to social reward effectively competed with AMPH reward.

Laboratory tasks that measure various facets of impulsivity derived from self-report questionnaires are important for elucidating the behavioral consequences of impulsivity in humans and for back-translating these facets to non-human species. Negative urgency, or mood-based rash action, is a self-report facet of impulsivity linked to problem substance use; however, a valid behavioral task is lacking.The current studies were designed to bridge self-report questionnaire and behavioral measures of negative urgency in humans and to determine if this could be back-translated to rats.Humans scoring high in negative urgency showed greater behavioral responding and increased frustration following unexpected reward omission on a monetary-based task compared to subjects low in negative urgency. Rats also showed elevated responding for either sucrose pellets or intravenous amphetamine following unexpected reward omission.These results suggest that impulsive behavior engendered by unexpected reward omission may represent a valid behavioral model of negative urgency linked to substance abuse.

Drug and Alcohol Dependence 156 (2015) e183–e245 e237 However, a small subgroup of participants exhibited a worsening course, characterizedby the initiationofheroinuseand/or injection opioid use. Financial support: NIDA grants U10 DA15831. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.637 Sex differences in dopamine and serotonin activation of brain pathways in adolescent rats exposed to social partners or amphetamine Virginia G. Weiss1,∗, Rebecca S. Hofford1, Justin R. Yates2, Michael T. Bardo1 1 University of Kentucky, Lexington, KY, United States 2 Northern Kentucky University, Newport, KY, United

of this age: Chinese, 13%; Asian Indian, 12%; Filipino, 22%; Vietnamese, 18%. With respect to the targeted migrant hypothesis, for 12–30 yr old Japan-born JA, estimated prevalence is 32%, for US-born JA counterparts, the corresponding estimate is 25% – i.e., noteworthy but not statistically significant. Note that 47% of Japanborn 12-30 yr old JA males were current smokers, as compared to 28% of the US-born JA. Conclusions: Against a background of remarkably large smoking prevalence estimates for some youthful subgroups in US, this study provides a range of novel estimates that are pertinent to 21st century tobacco control policies, and sets a stage for new research on migration and smoking. Financial support: T32DA021129 (WX); MSU(CLQ); K05DA15799 (JCA).