Robert A. Wheeler - US grants

Previous research has indicated that selected strains can be used as a tool for the study of the neural mechanisms responsible for reward comparison processes. In particular, Lewis rats have a greater avidity for drugs of abuse which serves to override responsiveness for natural rewards, while the drug non-preferring Fischer rats ramain impervious to these reward comparison processes. Thus, we hypothesize that the differences in the molecular characteristics between Lewis and Fischer rats mediate the difference in responding for a saccharin CS following taste-drug pairings. The proposed studies will test this hypothesis by employing behavioral, lesion, and molecular techniques to examine the generality of the phenomenon (Specific Aim I), the nature of the difference in responding between the Lewis and Fischer rats (Specific Aim II), and the role of specific neural substrates in mediating this difference (Specific Aim III).

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The nucleus accumbens (NAc) is an important neural structure involved in mediating the reinforcing actions of natural rewards as well as drugs of abuse, such as cocaine. Indeed, individual populations of NAc cells selectively encode for cocaine or natural rewards. However, experiences with powerful rewards impact behavioral reactions to lesser rewards and ultimately, natural rewards are devalued as they are compared to drugs of abuse. In fact, dysfunctional reward comparison behavior is a sufficient criterion for the diagnosis of Substance Abuse as defined by the DSM-IV, and one of the criteria for the diagnosis of Substance Dependence. Unfortunately, the neural foundation of the pathological interaction of drugs of abuse and natural rewards remains unclear. The PI will investigate these interactions in real time using electrophysiological and electrochemical recordings in the NAc that allow for measurements of cell firing and DA release for the natural reward that predicts access to the drug of abuse as well as for the drug reward itself. These studies will shed light on the neural substrate of reward comparison. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The development of negative emotional states as a result of chronic drug use has a profound impact on substance abuse disorder and has yet to be comprehensively modeled. This award will provide the basis for the refinement of such a model to be used in conjunction with state of the art neural electrochemical and electrophysiological measurement techniques to probe the influence of negative affect on drug seeking. This training will provide the PI a unique skill set and understanding of the manner by which drugs of abuse alter and usurp the neural circuitry evolved to process the motivational and hedonic properties of natural rewards. Specific Aim 1 will determine if rapid dopamine release in the nucleus accumbens (NAc) core and shell is similarly altered by rewarding and aversive taste stimuli as well a for a natural reward in situations in which it predicts cocaine versus when it does not. The results will broaden our understanding of the role of dopamine in associative learning and hedonic processing. We have shown that a cocaine-predictive taste cue induces a negative affective state that is linked to increased early-session drug taking. This aversive state may be akin to a cue-induced withdrawal state. Specific Aim 2 will test this hypothesis by examining the influence of the negative affective state on responding for intracranial self-stimulation (ICSS). The results of this study will demonstrate whether ICSS thresholds are elevated after the presentation of the cocaine predictive taste, consistent with a cue-induced withdrawal state. Specific Aim 3 will determine if distinct subregions of the NAc selectively process associative, versus hedonic aspects of the learned aversion to the cocaine-associated cue that promotes drug seeking. In Specific Aim 4, two experiments will probe the breadth of this phenomenon and the control this negative affective state exerts on drug seeking. The results of these studies will demonstrate whether non-gustatory, drug-predictive cues also elicit a negative affective state that retards extinction responding and promotes relapse. Together these experiments will rigorously test the role of negative affect on drug seeking in rats while providing training in electrochemical and behavioral techniques under the guidance of experts in their respective fields. PUBLIC HEALTH REVELANCE: The findings of these studies will shape our view and treatment of substance abuse disorders. A negative emotional state is associated with drug seeking and relapse in human addicts. The PI will investigate the motivational properties and neural underpinnings of this state that promotes drug seeking. Such investigations could lead to new pharmacotherapies aimed at disrupting the motivation to seek cocaine.

DESCRIPTION (provided by applicant): An insidious aspect of addiction is that afflicted individuals are at risk of relapse even after extended periods of abstinence. Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may set the stage for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. This proposal seeks to elucidate the mechanisms by which stress, through increases in glucocorticoid hormones, influences relapse vulnerability. We have previously shown that treatment of rodents with stress levels of glucocorticoids does not lead to reinstatement of drug-seeking behavior, but potentiates reinstatement in response to a dose of cocaine that, by itself, is not sufficient to trigger relapse. In parallel to its behavioral effect, corticosterone pretreatment also potentiates the effects of low-dose cocaine on extracellular dopamine concentration in the nucleus accumbens, suggesting that glucocorticoids may potentiate drug seeking by enhancing dopaminergic neurotransmission in this critical reward-processing brain region. We are examining the role of organic cation transporter 3, a high-capacity dopamine transporter that is acutely and directly inhibited by glucocorticoids, in mediating the effects of glucocorticoids on dopaminergic neurotransmission, cocaine relapse, and motivated behavior in rodents. Because of a lack of pharmacologically specific inhibitors for OCT3, we are using two different genetic approaches to test the hypothesis that corticosterone potentiates cocaine-induced dopaminergic neurotransmission and drug-seeking behavior by inhibiting OCT3-mediated clearance of dopamine in the nucleus accumbens. In the first aim, we will determine the impact of corticosterone-induced inhibition of dopamine clearance in the nucleus accumbens on dopamine signaling and drug relapse by using in vivo microdialysis and fast-scan cyclic voltammetry to measure dopamine concentration and clearance in cocaine-seeking animals. In the second aim, we will determine the role of OCT3 in the behavioral and neurochemical effects of corticosterone by examining corticosterone effects on drug-seeking behavior and nucleus accumbens dopamine signaling in animals genetically modified to lack OCT3 expression either globally or specifically in the nucleus accumbens. In the third aim, we will test the hypothesis that corticosterone-induced decreases in dopamine clearance modulate reward sensitivity and natural reward processing. These findings will thoroughly characterize a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake and motivated behavior in general.

DESCRIPTION (provided by applicant): Aversive environmental events (e.g. loss of employment, fight with spouse, etc.) influence the daily lives of all people by altering their emotional states, decision making, and motivated behavior. For individuals with substance abuse disorders who are attempting to remain abstinent, these unfortunate events are clinically relevent, as they are frequently cited as a principle cause of relapse. In order to develop strategies to protect against this important determinant of relapse, it is essential to thoroughly characterize mechanisms by which aversive stimuli influence affective and motivational neural circuitry. To that end, several decades of research have identified the nucleus accumbens as a critical limbic motor interface, heavily regulated by dopamine, where affective and associative reward information directly influence behavioral output. Unfortunately, the manner by which aversive stimuli regulate dopamine signaling remains poorly understood, with several studies producing conflicting results. These discrepant results reflect both parametric experimental constraints and the inability of traditional measures to resolve the role of dopamine with sufficient spatial and temporal precision. This proposal details several experiments that will combine optogentic, electrophysiological, and electrochemical approaches in behaving animals that have a history of cocaine self-administration to clarify the causal relationship between negative affect-inducing aversive environmental events, decreased dopamine signaling, and drug seeking. Simultaneously, these experiments will directly test the sufficiency of decreased dopamine signaling in modulating nucleus accumbens' electrophysiological activity, hedonic responses, and drug seeking. The studies will determine if site-specific modulation of these discrete circuits reverses negative affective responses and prevents drug seeking. Specific Aim 1 will determine the causal role of aversive stimuli in promoting cocaine-seeking and simultanously characterize the precise role of dopamine signaling in each stage of the process: from the experience of the aversive stimulus to the transition to the cocaine-seeking state. Specific Aim 2 will determine if the decreased dopamine signaling observed following the presentation of cocaine-predictive stimuli is sufficient to cause drug seeking, and if this effect can be blocked by regulating dopamine. Specific Aim 3 will determine the discrete influence of dopamine on the encoding of reward and aversion-related behaviors by nucleus accumbens neurons. Together, the results of the proposed studies will provide unprecedented insight into the mechanism by which aversive stimuli alter the affective state of the animal, dopamine signaling, and drug seeking. The goal is to identify an aversion-sensitive motivational pathway that can be manipulated to protect abstinent substance abusers from a principle cause of relapse.

PROJECT SUMMARY Aversive environmental events influence the daily lives of all people by altering their emotional states, decision making, and motivated behavior. For individuals with substance abuse disorders who are attempting to remain abstinent, these unfortunate events are clinically relevent, as they are frequently cited as a principle cause of relapse. In order to develop strategies to protect against this important determinant of relapse, it is essential to characterize the mechanisms through which aversive stimuli influence motivational neural circuitry. To this end, several decades of research have identified the nucleus accumbens (NAc) as a critical limbic/motor interface, heavily regulated by dopamine, where affective and associative reward information directly influence behavioral output. Unfortunately, the manner by which aversive stimuli regulate dopamine signaling remains poorly understood, with several studies producing conflicting results. We have identified an aversion signal, initiated by aversion-induced reductions in dopamine concentration, that is associated with increased striatal activity and drug seeking. The objective of this proposal is to determine how aversive stimuli regulate NAc dopamine signaling and the mechanisms through which reductions in dopamine alter neuronal activity in the NAc to shape behavior. To accomplish this objective, the proposal brings together a multi-disciplinary team that will use in vivo fast scan cyclic voltammetry, in vivo electrophysiology, and ex vivo slice electrophysiology to examine the independent contributions of reduced dopamine signaling and increased striatal activity to a panel of aversion- related behaviors, including drug seeking, and both reward and punishment sensitivity. In Aim 1 we will test the hypothesis that aversive stimuli, via reductions in NAc dopamine activate a subpopulation of aversion-responsive D2-like receptor-expressing NAc neurons to produce aversion-related behavioral responses. In Aim 2 we test the hypothesis that aversive stimuli increase corticotropin releasing factor (CRF) in the ventral tegmental area (VTA) and reduce dopamine in the NAc through a CRFR1- and GABAB receptor-dependent regulation of Girk channels on VTA DA neurons that project to the NAc shell. In Aim 3 we will examine upstream pathways that mediate the effects of aversive stimuli on NAc dopamine and behavior and will test the hypothesis that a beta adrenergic receptor-regulated pathway from the ventral bed nucleus of the stria terminalis to the VTA represents one such pathway. Understanding how aversive stimuli alter NAc dopamine signaling and how such alterations encode behavior has implications for understanding and treating a range of stress-related neuropsychiatric conditions including addiction and depression.