Cassandra D. Gipson

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.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.

Preference for 50% reinforcement over 75% reinforcement by pigeons

When pigeons are given a choice between an initial-link alternative that results in either a terminal-link stimulus correlated with 100% reinforcement or a stimulus correlated with 0% reinforcement (overall 50% reinforcement) and another initial-link alternative that always results in a terminal-link stimulus correlated with 100% reinforcement, some pigeons show a preference for the initial-link alternative correlated with 50% reinforcement. Using this procedure, in Experiment 1, we found a relatively modest preference for 100% over 50% reinforcement. In Experiment 2, we decreased the reinforcement density for the second initial-link alternative to 75% and found a significant preference for the 50% reinforcement initial-link alternative. It may be that this “maladaptive” behavior results from a positive contrast between the expectation of reinforcement correlated with the 50% reinforcement initial-link alternative and the terminal-link stimulus correlated with 100% reinforcement. But apparently, the complementary negative contrast does not develop between the expectation of reinforcement correlated with the 50% reinforcement initial-link alternative and the terminal-link stimulus correlated with 0% reinforcement that often follow. Such paradoxical choice may account for certain human appetitive risk-taking behavior (e.g., gambling) as well.

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.

Effect of environmental enrichment on dopamine and serotonin transporters and glutamate neurotransmission in medial prefrontal and orbitofrontal cortex.

Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [(3)H]dopamine uptake in mPFC, but increased Vmax for [(3)H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [(3)H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability.

Accumbens nNOS interneurons regulate cocaine relapse.

Relapse to drug use can be initiated by drug-associated cues. The intensity of cue-induced relapse is correlated with the induction of transient synaptic potentiation (t-SP) at glutamatergic synapses on medium spiny neurons (MSNs) in the nucleus accumbens core (NAcore) and requires spillover of glutamate from prefrontal cortical afferents. We used a rodent self-administration/reinstatement model of relapse to show that cue-induced t-SP and reinstated cocaine seeking result from glutamate spillover, initiating a metabotropic glutamate receptor 5 (mGluR5)-dependent increase in nitric oxide (NO) production. Pharmacological stimulation of mGluR5 in NAcore recapitulated cue-induced reinstatement in the absence of drug-associated cues. Using NO-sensitive electrodes, mGluR5 activation by glutamate was shown to stimulate NO production that depended on activation of neuronal nitric oxide synthase (nNOS). nNOS is expressed in ∼1% of NAcore neurons. Using a transgene strategy to express and stimulate designer receptors that mimicked mGluR5 signaling through Gq in nNOS interneurons, we recapitulated cue-induced reinstatement in the absence of cues. Conversely, using a transgenic caspase strategy, the intensity of cue-induced reinstatement was correlated with the extent of selective elimination of nNOS interneurons. The induction of t-SP during cued reinstatement depends on activating matrix metalloproteinases (MMPs) and selective chemogenetic stimulation of nNOS interneurons recapitulated MMP activation and t-SP induction (increase in AMPA currents in MSNs). These data demonstrate critical involvement of a sparse population of nNOS-expressing interneurons in cue-induced cocaine seeking, revealing a bottleneck in brain processing of drug-associated cues where therapeutic interventions could be effective in treating drug addiction. SIGNIFICANCE STATEMENT Relapse to cocaine use in a rat model is associated with transient increases in synaptic strength at prefrontal cortex synapses in the nucleus accumbens. We demonstrate the sequence of events that mediates synaptic potentiation and reinstated cocaine seeking induced by cocaine-conditioned cues. Activation of prefrontal inputs to the accumbens by cues initiates spillover of synaptic glutamate, which stimulates metabotropic glutamate receptor 5 (mGluR5) on a small population of interneurons (∼1%) expressing neuronal nitric oxide synthase. Stimulating these glutamate receptors increases nitric oxide (NO) production, which stimulates matrix metalloprotease-2 (MMP-2) and MMP-9 activity in the extracellular space. Manipulating the interaction between mGluR5, NO production, or MMP-2 and MMP-9 pharmacologically or genetically is sufficient to recapitulate transient synaptic potentiation and reinstate cocaine seeking.

Isolation rearing as a preclinical model of attention/deficit-hyperactivity disorder

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 [(3)H]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 [(3)H]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.

Within-trial contrast: The effect of probability of reinforcement in training.

There is evidence that pigeons prefer conditioned reinforcers that are preceded by greater effort over those that are preceded by less effort (an effect that has been attributed to within-trial contrast). In past research the probability of reinforcement for correct choice of the conditioned reinforcer has been 100%, however, the high level of reinforcement for both alternatives in training may result in a performance ceiling when choice between those alternatives is provided on test trials. In the present study we tested this hypothesis by including a group for which the probability of reinforcement in training was only 50%. Pigeons were trained on two simultaneous discriminations, one that was preceded by a 30 peck requirement the other by a single peck requirement. On test trials, we found a significant preference for the S+ that required the greater effort in training for pigeons trained with 100% and a small but nonsignificant effect for pigeons trained with 50% reinforcement. Although the hypothesis that the within-trial contrast effect was constrained by a performance ceiling was not confirmed, we did find a reliable within-trial contrast effect with 100% reinforcement.

Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking.

Basic Science and Public Policy: Informed Regulation for Nicotine and Tobacco Products

Introduction Scientific discoveries over the past few decades have provided significant insight into the abuse liability and negative health consequences associated with tobacco and nicotine-containing products. While many of these advances have led to the development of policies and laws that regulate access to and formulations of these products, further research is critical to guide future regulatory efforts, especially as novel nicotine-containing products are introduced and selectively marketed to vulnerable populations. Discussion In this narrative review, we provide an overview of the scientific findings that have impacted regulatory policy and discuss considerations for further translation of science into policy decisions. We propose that open, bidirectional communication between scientists and policy makers is essential to develop transformative preventive- and intervention-focused policies and programs to reduce appeal, abuse liability, and toxicity of the products. Conclusions Through these types of interactions, collaborative efforts to inform and modify policy have the potential to significantly decrease the use of tobacco and alternative nicotine products and thus enhance health outcomes for individuals. Implications This work addresses current topics in the nicotine and tobacco research field to emphasize the importance of basic science research and provide examples of how it can be utilized to inform public policy. In addition to relaying current thoughts on the topic from experts in the field, the article encourages continued efforts and communication between basic scientists and policy officials.