Jerry B. Richards - US grants

DESCRIPTION (Applicant's Abstract): The overall goal of this project is to develop a sensitive, precisely defined animal model of impulsive behavior. The model is based on the assumption that impulsive individuals are relatively insensitive to delayed and/or uncertain consequences (rewards and punishers). Devaluation of delayed and/or uncertain consequences causes impulsive individuals to be relatively more influenced by immediate certain consequences. The model measures sensitivity to consequences in terms of "discounted" value such that impulsive individuals discount the value of delayed and/or uncertain rewards and punishers more then nonimpulsive individuals. In the animal model the value of delayed and/or uncertain consequences is assessed quantitatively in rats. Eight experiments are proposed to asses the reliability and validity of the discounting procedure. In order to validate the model, manipulations which cause impulsive behaviors in humans will be tested. Thus, the effects of serotonin (5HT) lesions; and administration of amphetamine, ethanol and diazepam will be tested in all 8 experiments. Experiments 1 & 2 are control experiments which will assess the reliability of the procedure with different amounts of reward and punishment. It is predicted that 5HT lesions and drugs will not affect discounting in Experiments 1 & 2 because these experiments do not involve delay or uncertainty. Experiments 3 & 4 examine discounting of the value of rewarding and punishing consequences by delay. Experiments 5 & 6 examine discounting of rewarding and punishing consequences by uncertainty. Experiments 7 & 8 examine discounting of rewarding and punishing consequences by the combination of delay and uncertainty. It is predicted that 5HT lesions and amphetamine, ethanol, and diazepam will increase discounting in experiments 3, 4, 5, 6, 7, & 8. Establishing an animal model of impulsive human behavior will enable researchers to more systematically explore the neurochemical and pharmacological basis of impulsive behavior.

These studies are designed to advance our understanding of impulsive behavior and its relation to drug abuse by, i.) developing valid animal models of impulsive behavior and operationalizing different concepts of impulsivity, ii.) studying how both acute and chronic exposure to the drug of abuse methamphetamine (METH) affects impulsive behavior, iii.) studying the roles the neurotransmitter systems dopamine (DA) and serotonin (5HT) in impulsive behavior, and iv.) studying the roles of 5HT and DA in mediating the effects of METH on impulsive behavior. Impulsivity is a complex concept that refers to a range of different behaviors, and has been modeled in several laboratory procedures. However, few studies have assessed the relationships among the different measures. We will investigate 5 behavioral procedures that are thought to model important aspects of impulsive behavior in rats. Two of the tasks measure discounting, or preference for immediate vs delayed or certain vs uncertain positive consequences. A third task measures the animals' ability to wait for a delayed large reward when a small reward is available immediately. A fourth task measures "risk taking" by measuring preference for a safe small rewards vs risky large rewards which are sometimes followed by punishment. The final procedure measures the ability of the rat to stop (inhibit) an ongoing prepotent response. We plan to study the effects of both acute and chronic exposure to methamphetamine. We plan to investigate the role of serotonin and dopamine on impulsivity and on the effects of methamphetamine. This project is being conducted in parallel to a separate project using humans. The results of the rat and human studies will be compared to examine concordance between species in the behavioral processes, and to assess the validity of the rat models to human behavior. In sum, the proposed studies will advance our understanding of the behavioral and neural processes mediating impulsive behaviors, and of the effect of drugs of abuse on these behaviors.

DESCRIPTION (provided by applicant): The primary objective of the proposed research is to adapt three procedures that we are currently using to measure impulsive behavior in rats to mice and to standardize these procedures in mice using parametric and pharmacological manipulations. The first task measures impulsivity in terms of the ability of animals to wait, using a differential schedule of low rate (DRL) schedule. This task requires the animal to wait between responses to earn a reward. The second behavioral procedure measures impulsivity by assessing the value of delayed rewards. This task measures how much the animals value delayed and/or probabilistic rewards using an Adjusting Amount (AdjAmt) procedure. The third procedure measures impulsivity in terms of the ability to stop (inhibit) an ongoing prepotent response. Greater impulsivity is indicated by slower stop reaction times. All three of these procedures have been used to characterize behavioral processes that may underlie impulsive behavior in both rats and humans. We plan to characterize performance on these tasks in two inbred strains of mice, which have been widely used as background strains for the development of transgenic models, and have been shown to exhibit pronounced differences in behavior. The effects of drugs will be tested in the two strains of mice and compared to results we have previously observed in rats in order to test cross species validity of the tasks. A major goal of the proposed studies is to establish and characterize these three test procedures in mice, so that the procedures can be used in future studies to identify the genetic basis of individual differences in performance and drug effects on impulsive behavior. The behavioral tasks to be developed in this project with mice are parallel to existing tasks used with humans and rats. Related studies are ongoing in other projects using humans and rats. The results of the mouse, rat and human studies will be compared to examine concordance in the behavioral processes and to assess the validity of the rat models to human behavior. The proposed studies with mice will allow us to extend our investigation to the genetic basis of impulsive behavior.

This project investigates "impulsivity" as a predisposing factor for drug abuse. Drug abuse researchers have extensively studied "reward-related" factors that facilitate drug-seeking behaviors, including both unconditioned and conditioned positive affective responses to drugs while ignoring "impulsivity-related" processes that normally inhibit or limit the use of drugs. We believe that processes related to impulsivity may be as important as reward processes in determining whether an individual will use drugs. One reason for the lack of attention to "impulsivity related" factors may be the lack of adequate laboratory models. The primary objective of the proposed research is to develop and use laboratory-based, behavioral measures of impulsivity to study the relationship between impulsive processes and drug abuse. Our own research as well as other recent findings indicates that "impulsivity" does not refer to a single process or trait. Instead, several distinct behavioral processes appear to underlie the broad category of "impulsive behaviors". One process that can result in impulsive behaviors is the preference for smaller, more immediate rewards over larger delayed rewards, and it is measured using the delay discounting task. A second process corresponds to the inability to inhibit (stop) a prepotent response. This is referred to as behavioral inhibition and is measured using the Stop Task. We have identified a new, third process, which relates to attention. Impairments in attention have not been studied extensively in relation to drug abuse;sustained attention is likely to be important for self-control, particularly during periods of abstinence from drug taking behaviors. The proposed project will use non-human laboratory models of impulsivity to determine the strength of association between cocaine self-administration and impulsivity as measured by delay discounting and sustained attention tasks. A self-administration (SA) procedure which includes acquisition of drug taking, escalation of drug intake, extinction of drug taking, and finally cue-induced reinstatement of drug taking, which models important features of human drug use will be used. We have previously accumulated promising data on these tasks, and the proposed studies will provide important information validating the role of specific types of impulsive behaviors in drug abuse. The proposed studies will provide important new information concerning putative animal models of impulsivity, and the ability of these models to predict cocaine self-administration.

DESCRIPTION (provided by applicant): The primary objective of the proposed research is to develop a rodent model of self administration (SA) in which drug consumption has delayed negative consequences. Self administration procedures in which the animals make responses that are reinforced by IV drug injections are widely used and are perhaps the most convincing non-human animal models of drug abuse. Non-human animal SA models, however, may not model important aspects of human drug SA. In humans, impulsivity is considered an important component of drug abuse because individuals take drugs despite the knowledge of negative (often delayed) outcomes associated with drug use. In contrast, standard laboratory animal models of SA have no explicit negative outcomes associated with the SA of the drug. Because there are currently no SA models that incorporate negative consequences, the impact of negative outcomes is not generally incorporated into current ideas about the underlying behavioral and neurobiological mechanisms mediating drug abuse. The goal of the Experiment 1 of this application is to determine a dose of cocaine and an amount of water that have equivalent reinforcing efficacy. In this application reinforcing efficacy is measured using progressive ratio schedules of reinforcement. In progressive ratio schedules, reinforcement efficacy is operationally defined as the break point (BP) which indicates the maximum number of responses an animal will make on a progressive ratio schedule of reinforcement for a given reinforcer. Determination of a dose of cocaine and an amount of water that have equivalent efficacy will insure that cocaine and water reinforcers of equivalent reinforcing efficacy are used In Experiments 2 and 3. Experiment 2 will determine if immediate shock has different effects on the reinforcing efficacy of drug and natural reinforcers using the progressive ratio schedule of reinforcement. Building upon Experiments 1 and 2, Experiment 3 will determine the effects of delaying the shock on the reinforcing efficacy of the cocaine/shock and water/shock reinforcers. These studies will advance to our understanding of drug abuse by determining if punishment or delays to punishment have similar (or dissimilar) effects on drug (cocaine) and natural (water) reinforcers of equivalent reinforcing efficacy. These results will help to determine if a "punished" SA model is a valuable tool with which to investigate the behavioral and cognitive regulation of drug abuse by negative consequences. PUBLIC HEALTH RELEVANCE: The primary objective of the proposed research is to develop a rodent model of self administration (SA) in which drug consumption has delayed negative consequences. There is little doubt that non-human animal SA procedures model important aspects of drug taking in humans;however in some respects the typical application of this model in the laboratory does not model important aspects of drug consumption by human addicts. According to the Diagnostic and Statistical Manual of Mental Disorders (APA, 1994) an important characteristics of human drug addiction is continued drug intake despite harmful consequences. However, current non human animal models of drug abuse do not address this important issue. Consequently, the impact of negative outcomes is not generally incorporated into current ideas about the underlying behavioral and neurobiological mechanisms mediating drug abuse. We believe that drug abuse in humans is a function of two separate processes, "rewarding" positive affective responses to the drug and "impulsivity-related" factors, or influences that normally inhibit or limit the use of drugs. Development of a non human SA model that incorporates negative consequences will enhance research into "impulsivity-related factors" that are necessary for drug abstinence.

Project summary/Abstract (Project 3) The primary goal of the project is to find genetic variants underlying the individual differences in animal models of psychological traits often related to drug abuse, including sensation seeking, social approach, inattention, and impulsivity. In the current funding period (Year 5 began 3 months ago) we have almost reached our goal of phenotyping 1,600 heterogenous stock (HS) rats. We have estimated the SNP heritability of all the behavioral traits and confirmed that they are within a range suitable for genome-wide association (GWAS); indeed they are among the highest observed for any behavior studied by this center. By using genetic correlation, we have estimated shared genetic influences between our measures and those studied in Project 2 (Socially acquired nicotine self-administration). While our study is still ongoing, we have already identified many genome-wide significant associations. Several of the quantitative trait loci (QTL) associated with our phenotypes contain only a few genes. This extremely accurate mapping is a key feature of the HS population and will facilitate identification of the causal gene within each locus. In some cases, the list of candidate genes can be further narrowed by an overlapping gene expression QTL. Both human GWAS and our recently completed GWAS of several physiological traits (n~3,200) have shown that increasing sample size results in an exponential increase in genome-wide significant hits. Based on the success of our phenotyping pipeline during the previous funding period, we are proposing to phenotype an additional 1,600 male and female HS rats on these five behavioral tasks. Our proposed studies are arranged as follows: In Aim 1. we will phenotype 1,600 HS rats provided by Core B (HS breeding core) on all five behavior tests. Each year we will study 400 rats (200M and 200F). Phenotyping will be conducted using existing protocols so that the entire dataset of 3,200 rats can be analyzed together. In Aim 2, we will analyze the vast amount of behavior data (over 100 measures per rat) and prepare them for GWAS. After rigorous quality checking of these data, we will submit them to Core A (Administrative Core) to be entered into a database and subsequently used for GWAS by Core C (genotyping, RNA-Seq, and GWAS). In Aim 3, we will conduct genetic correlation, phenome-wide association, and meta- analysis using traits obtained from different cohort of animals. We are in an unique position of being able to study the shared and unique genetic influences between three behavior models of impulsivity. We will also use these methods to examine the shared genetic factors between the psychological traits we study and the drug- related traits studied by Project 1 (cocaine), Project 2 (nicotine) and other affiliated U01s (cocaine, oxycodone).