Joshua S. Beckmann

Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat.

It has been suggested that incentive salience plays a major role in drug abuse and the development of addiction. Additionally, novelty seeking has been identified as a significant risk factor for drug abuse. However, how differences in the readiness to attribute incentive salience relate to novelty seeking and drug abuse vulnerability has not been explored. The present experiments examined how individual differences in incentive salience attribution relate to novelty seeking and acquisition of cocaine self-administration in a preclinical model. Rats were first assessed in an inescapable novelty task and a novelty place preference task (measures of novelty seeking), followed by a Pavlovian conditioned approach task for food (a measure of incentive salience attribution). Rats then were trained to self-administer cocaine (0.3 or 1.0 mg/kg/infusion) using an autoshaping procedure. The results demonstrate that animals that attributed incentive salience to a food-associated cue were higher novelty seekers and acquired cocaine self-administration more quickly at the lower dose. The results suggest that novelty-seeking behavior may be a mediator of incentive salience attribution and that incentive salience magnitude may be an indicator of drug reward.

Concurrent choice for social interaction and amphetamine using conditioned place preference in rats: Effects of age and housing condition

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Impulsivity affects suboptimal gambling-like choice by pigeons.

Pigeons prefer a low-probability, high-payoff but suboptimal alternative over a reliable low-payoff optimal alternative (i.e., one that results in more food). This finding is analogous to suboptimal human monetary gambling because in both cases there appears to be an overemphasis of the occurrence of the winning event (a jackpot) and an underemphasis of losing events. In the present research we found that pigeons chose suboptimally to the degree that they were impulsive as indexed by the steeper slope of the hyperbolic delay-discounting function (i.e., the shorter the delay they would accept in a smaller-sooner/larger-later procedure). These correlational findings have implications for the mechanisms underlying suboptimal choice by humans (e.g., problem gamblers) and they suggest that high baseline levels of impulsivity can enhance acquisition of a gambling habit.

Environmental enrichment reduces attribution of incentive salience to a food-associated stimulus.

Animals reared in an enriched environment are less vulnerable to abuse-like behavior and exhibit less persistent drug seeking, perhaps due to a decrease in the incentive value of stimuli associated with reward. The present study investigated the effects of environmental enrichment on Pavlovian conditioned approach (PCA) performance, a measure of incentive salience attribution. Rats were first reared from postnatal day 21 to postnatal day 51 in either an enriched environment with large cages, social cohorts and novel objects, or in an isolated environment with small, hanging cages, no social cohorts and no novel objects. Rats were then trained on a PCA task for 5 consecutive days, where a retractable lever was predictive of a food reward. Isolated rats predominantly exhibited sign-tracking responses directed toward the reward-predicted lever (indicative of incentive salience attribution), while enriched rats predominantly exhibited goal-tracking responses directed toward the location of food delivery. Both groups learned their respective response type at equal rates. The results indicate that environmental enrichment reduces the readiness to attribute incentive value to reward-associated cues, which may explain the enrichment-induced protection against addiction-like behaviors.

Isolating the incentive salience of reward-associated stimuli: value, choice, and persistence

Sign- and goal-tracking are differentially associated with drug abuse-related behavior. Recently, it has been hypothesized that sign- and goal-tracking behavior are mediated by different neurobehavioral valuation systems, including differential incentive salience attribution. Herein, we used different conditioned stimuli to preferentially elicit different response types to study the different incentive valuation characteristics of stimuli associated with sign- and goal-tracking within individuals. The results demonstrate that all stimuli used were equally effective conditioned stimuli; however, only a lever stimulus associated with sign-tracking behavior served as a robust conditioned reinforcer and was preferred over a tone associated with goal-tracking. Moreover, the incentive value attributed to the lever stimulus was capable of promoting suboptimal choice, leading to a significant reduction in reinforcers (food) earned. Furthermore, sign-tracking to a lever was more persistent than goal-tracking to a tone under omission and extinction contingencies. Finally, a conditional discrimination procedure demonstrated that sign-tracking to a lever and goal-tracking to a tone were dependent on learned stimulus-reinforcer relations. Collectively, these results suggest that the different neurobehavioral valuation processes proposed to govern sign- and goal-tracking behavior are independent but parallel processes within individuals. Examining these systems within individuals will provide a better understanding of how one system comes to dominate stimulus-reward learning, thus leading to the differential role these systems play in abuse-related behavior.

Methylphenidate as a reinforcer for rats: contingent delivery and intake escalation.

Methylphenidate (MPH) is one of the most widely prescribed drugs for treating attention-deficit hyperactivity disorder. Previous research suggested that MPH is a reinforcer for rats, but not all of the manipulations to show that lever pressing is controlled by the contingency to obtain MPH have been examined. In Experiment 1, responding for MPH on a progressive ratio (PR) schedule was assessed. Rats self-administered varying doses of MPH (0.056-1.0 mg/kg/infusion) on a PR schedule of reinforcement, and self-administered more MPH than saline, with maximal responding occurring at a unit dose of 0.56 mg/kg/infusion. Experiment 2 examined if there were differences in responding between contingent and noncontingent MPH (0.56 mg/kg/infusion) on a fixed ratio schedule of reinforcement. Results showed that rats responded for contingent MPH, and that responding was not maintained when MPH was delivered noncontingently. Experiment 3 examined self-administration of MPH (0.1 or 0.3 mg/kg/infusion) during long access (6 hr) compared to short access sessions (1 hr). Results showed that rats given long access to MPH showed an escalation of intake across sessions, with this escalation being more pronounced at the lower unit dose (0.1 mg/kg/infusion); in contrast, rats given short access to MPH did not show an increase in MPH self-administration across sessions at either MPH dose tested. Taken together, these results indicate that MPH is an effective intravenous reinforcer for rats and that, similar to other stimulants such as cocaine, amphetamine and methamphetamine, MPH is subject to abuse as reflected by dysregulated intake across repeated long access sessions.

Environmental enrichment during development decreases intravenous self-administration of methylphenidate at low unit doses in rats

Despite the efficacy and widespread use of methylphenidate (MPH) as a treatment modality for attention deficit hyperactivity disorder, clinical and preclinical findings indicate that it has abuse potential. Environmental enrichment reduces susceptibility to cocaine and amphetamine self-administration and decreases impulsive behavior, but its effects on MPH self-administration are unknown. The present experiments sought to determine the influence of environmental enrichment on MPH self-administration. Male rats were raised in an enriched condition (EC) or isolated condition (IC). They were trained to self-administer MPH (0.3 mg/kg/infusion) and then exposed to varying doses of MPH on either a fixed-ratio (experiment 1) or a progressive-ratio (experiment 2) schedule of reinforcement. EC rats earned significantly fewer infusions of MPH at low doses (0.03 and 0.056 mg/kg/infusion) compared with IC rats under both schedules; however, no differences were observed at high unit doses (0.1–1.0 mg/kg/infusion). During saline substitution at the end of MPH self-administration, EC rats also responded less for saline compared with IC rats, indicative of more rapid extinction. As with other stimulant drugs with different mechanisms of action, environmental enrichment during development protects against self-administration of MPH at low unit doses but not at high unit doses.

High impulsivity in rats predicts amphetamine conditioned place preference.

Stimulants such as d-amphetamine (AMPH) are used commonly to treat attention-deficit hyperactivity disorder (ADHD), but concerns have been raised regarding the use of AMPH due to its reinforcing and potentially addictive properties. The current study examined if individual differences in impulsive choice predict AMPH-induced hyperactivity and conditioned place preference (CPP). Rats were first tested in delay discounting using an adjusting delay procedure to measure impulsive choice and then were subsequently tested for AMPH CPP. High impulsive (HiI) and low impulsive (LoI) rats were conditioned across four sessions with 0.1, 0.5, or 1.5 mg/kg of AMPH. AMPH increased locomotor activity for HiI and LoI rats following 0.5 mg/kg but failed to increase activity following 0.1 and 1.5 mg/kg. CPP was established for HiI rats with both 0.5 and 1.5 mg/kg of AMPH, whereas LoI rats did not develop CPP following any dose of AMPH; HiI and LoI groups differed significantly following 0.5 mg/kg of AMPH. These results indicate that HiI rats are more sensitive to the rewarding effects of AMPH compared to LoI rats, which is consistent with research showing that high impulsive individuals may be more vulnerable to stimulant abuse.

Social facilitation of d-amphetamine self-administration in rats.

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 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 divider, and responding for sucrose or AMPH reward was measured. Rats were allowed to restabilize, and subsequently given an additional partner presentation. Presence of the social partner increased responding only during the first pairing with the AMPH 0.1 mg/kg/infusion unit dose, whereas inhibition of responding was observed during the first 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.

Suboptimal Choice in Pigeons: Stimulus Value Predicts Choice over Frequencies

Pigeons have shown suboptimal gambling-like behavior when preferring a stimulus that infrequently signals reliable reinforcement over alternatives that provide greater reinforcement overall. As a mechanism for this behavior, recent research proposed that the stimulus value of alternatives with more reliable signals for reinforcement will be preferred relatively independently of their frequencies. The present study tested this hypothesis using a simplified design of a Discriminative alternative that, 50% of the time, led to either a signal for 100% reinforcement or a blackout period indicative of 0% reinforcement against a Nondiscriminative alternative that always led to a signal that predicted 50% reinforcement. Pigeons showed a strong preference for the Discriminative alternative that remained despite reducing the frequency of the signal for reinforcement in subsequent phases to 25% and then 12.5%. In Experiment 2, using the original design of Experiment 1, the stimulus following choice of the Nondiscriminative alternative was increased to 75% and then to 100%. Results showed that preference for the Discriminative alternative decreased only when the signals for reinforcement for the two alternatives predicted the same probability of reinforcement. The ability of several models to predict this behavior are discussed, but the terminal link stimulus value offers the most parsimonious account of this suboptimal behavior.