Could dopamine agonists aid in drug development for anorexia nervosa?

Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways

Cocaine Addiction as a Homeostatic Reinforcement Learning Disorder

Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction

The Nucleus Accumbens Core Dopamine D1 and Glutamate AMPA/NMDA Receptors Play a Transient Role in the Performance of Pavlovian Approach Behavior

The role of the nucleus accumbens core (NAc core) continues to be redefined with newly acquired data on neurochemical mechanisms mediating the learning and performance of behavior. Previous empirical data showed that dopamine transmission at the D1 receptor (D1R) plays a transient role in the expression of learned Pavlovian approach behavior. Here we show that, prior to overtraining, dopamine activity at D1Rs specifically within the NAc core is critical for the performance of approach behavior elicited by the recently-acquired reward-paired cue. Blockade of D1Rs in the NAc core, but not the dorsomedial striatum or NAc shell, disrupted approach responses during early training; however, the dependence of Pavlovian approach on D1R transmission declined throughout training. Upon blockade of NAc core D1Rs during extended training, the expression of Pavlovian approach responses remained intact. Given these findings we next explored whether a) neuronal activity within the core of accumbens still mediates cued approach during the late training stages in the absence of D1R transmission by relying on glutamatergic transmission or b) whether mediation of the cued approach becomes independent of the NAc core itself, i.e., shifts to another substrate. We blocked AMPA/NMDA receptors in the NAc core during early versus extended training and showed that loss of neuronal activation in the NAc core only disrupted expression of conditioned stimulus-elicited responses during early training. Our results indicate that NAc core activity is not necessary for the expression of well-acquired approach

A Neurocomputational Model of the Functional Role of Dopamine in Stimulus-Response Task Learning and Performance

Thesis (Ph.D.) - Indiana University, Psychology, 2009The neuromodulatory neurotransmitter dopamine (DA) plays a complex, but central role in the learning and performance of stimulus-response (S-R) behaviors. Studies have implicated DA's role in reward-driven learning and also its role in setting the overall level of vigor or frequency of response. Here, a neurocomputational model is developed which models DA's influence on a set of brain regions believed to be involved in the learning and execution of S-R tasks, including frontal cortex, basal ganglia, and cingulate cortex. An `actor' component of the model is trained, using `babble' (random behavior selection) and `critic' (rewarding and punishing) components of the model, to perform acceptance/rejection responses upon presentation of color stimuli in the context of recently presented auditory tones. The model behaves like an autonomous organism learning (and relearning) through `trial-and-error'. The focus of the study, the impact of hypo- and hyper-normal DA activity on this model, is investigated by three different dopaminergic pathways--two striatal and one prefrontal cortical--being manipulated independently during the learning and performance of the color response task. Hypo-DA conditions, analogous to Parkinsonism, cause slowing and reduction of frequency of learned responses, and, at extremes, degrade the learning (either initial or reversal) of the task. Hyper-DA conditions, analogous to psychostimulant effects, cause more rapid response times, but also can lead to perseveration of incorrect learning of response on the task. The presence of these effects often depends on which DA-ergic pathway is manipulated, however, which has implications for interpretation of the pharmacological experimental data. The proposed model embodies an integrative theory of dopamine function which suggests that the base rate of DA cell activity encodes the overall `activity-oriented motivation' of the organism, with hunger and/or expectation of reward driving both response vigor and tendency to generate an explorative `babble' response. This more `tonic' feature of DA functionality coexists naturally with the more extensively-studied `phasic' reward-learning features. The model may provide better insights on the role of DA system dysfunction in the cognitive and motivational symptoms of disorders such as Parkinsonism, psychostimulant abuse, ADHD, OCD, and schizophrenia, accounting for deficits in both learning and performance of tasks

Reductions in Mesolimbic Dopamine Signaling and Aversion: Implications for Relapse and Learned Avoidance

The ability to adjust behavior appropriately following an aversive experience is essential for survival, yet variability in this process contributes to a wide range of disorders, including drug addiction. It is clear that proper approach and avoidance is regulated, in part, by the activity of the mesolimbic dopamine system. While the importance of this system as a critical modulator of reward learning has been extensively characterized, its involvement in directing aversion-related behaviors and learning is still poorly understood. Recent studies have revealed that aversive stimuli and their predictors cause rapid reductions in nucleus accumbens (NAc) dopamine concentrations. Furthermore, a normally appetitive stimulus that is made aversive through association with cocaine also decreases dopamine, and the magnitude of the expressed aversion predicts drug-taking. However, whether the presentation of a drug cue that reduces dopamine, and evokes a negative affective state, can motivate relapse is unknown. Here we demonstrate that the presentation of an aversive drug cue both reduces dopamine and causes cocaine-seeking. This finding is provocative because drug seeking in reinstatement designs is typically associated with increased dopamine signaling. Using a combination of fast scan cyclic voltammetry (FSCV) and in vivo electrophysiology we subsequently show that the presence of an aversive drug cue abolishes the dopaminergic encoding of other drug cues and alters NAc neuronal activity patterns. Importantly, a subpopulation of neurons that subsequently encode aspects of drug-seeking behavior increase their baseline firing rates during this aversive experience. We then examine the mechanistic regulation of dopamine signaling by aversive stimuli under more natural conditions. Using FSCV and site-specific behavioral pharmacology we demonstrate that blockade of ventral tegmental area kappa opioid receptors attenuates aversion-induced reductions in dopamine, and prevents proper avoidance learning caused by punishment. By maintaining D2 receptor occupancy within the NAc during punishment, we demonstrate the requirement of aversion-induced reductions in dopamine for aversive learning. Together, these studies inform an evolving model of striatal physiology. Our findings emphasize a role for both increases and decreases in dopamine signaling that modulate behavior by promoting the stimulus-specific activity of distinct striatal output pathways. The continued interrogation of this model may offer novel targets for therapeutic development aimed at treating neurodegenerative disease and drug addiction

Dopamine overdose hypothesis: Evidence and clinical implications

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinson's disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review, we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted‐U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor, as supported by multimodal neuroimaging studies. A patient's individual genotype will determine the relative baseline position on this inverted‐U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable, inverted‐U dose‐response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities. © 2013 International Parkinson and Movement Disorder SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102168/1/mds25687.pd

Learning and reversal in the sub-cortical limbic system: a computational model

The basal ganglia are a group of nuclei that signal to and from the cerebral cortex. They play an important role in cognition and in the initiation and regulation of normal motor activity. A range of characteristic motor diseases such as Parkinson's and Huntington's have been associated with the degeneration and lesioning of the dopaminergic neurons that target these regions. The study of dopaminergic activity has numerous benefits from understanding how and what effects neurodegenerative diseases have on behavior to determining how the brain responds and adapts to rewards. The study is also useful in understanding what motivates agents to select actions and do the things that they do. The striatum is a major input structure of the basal ganglia and is a target structure of dopaminergic neurons which originate from the mid brain. These dopaminergic neurons release dopamine which is known to exert modulatory influences on the striatal projections. Action selection and control are involved in the dorsal regions of the striatum while the dopaminergic projections to the ventral striatum are involved in reward based learning and motivation. There are many computational models of the dorsolateral striatum and the basal ganglia nuclei which have been proposed as neural substrates for prediction, control and action selection. However, there are relatively few models which aim to describe the role of the ventral striatal nucleus accumbens and its core and shell sub divisions in motivation and reward related learning. This thesis presents a systems level computational model of the sub-cortical nuclei of the limbic system which focusses in particular, on the nucleus accumbens shell and core circuitry. It is proposed that the nucleus accumbens core plays a role in enabling reward driven motor behaviour by acquiring stimulus-response associations which are used to invigorate responding. The nucleus accumbens shell mediates the facilitation of highly rewarding behaviours as well as behavioural switching. In this model, learning is achieved by implementing isotropic sequence order learning and a third factor (ISO-3) that triggers learning at relevant moments. This third factor is modelled by phasic dopaminergic activity which enables long term potentiation to occur during the acquisition of stimulus-reward associations. When a stimulus no longer predicts reward, tonic dopaminergic activity is generated. This enables long term depression. Weak depression has been simulated in the core so that stimulus-response associations which are used to enable instrumental response are not rapidly abolished. However, comparatively strong depression is implemented in the shell so that information about the reward is quickly updated. The shell influences the facilitation of highly rewarding behaviours enabled by the core through a shell-ventral pallido-medio dorsal pathway. This pathway functions as a feed-forward switching mechanism and enables behavioural flexibility. The model presented here, is capable of acquiring associations between stimuli and rewards and simulating reversal learning. In contrast to earlier work, the reversal is modelled by the attenuation of the previously learned behaviour. This allows for the reinstatement of behaviour to recur quickly as observed in animals. The model will be tested in both open- and closed-loop experiments and compared against animal experiments

Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity.

BACKGROUND: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. METHODS: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. RESULTS: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. CONCLUSIONS: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders

From genes to behavior: placing cognitive models in the context of biological pathways.

Connecting neural mechanisms of behavior to their underlying molecular and genetic substrates has important scientific and clinical implications. However, despite rapid growth in our knowledge of the functions and computational properties of neural circuitry underlying behavior in a number of important domains, there has been much less progress in extending this understanding to their molecular and genetic substrates, even in an age marked by exploding availability of genomic data. Here we describe recent advances in analytical strategies that aim to overcome two important challenges associated with studying the complex relationship between genes and behavior: (i) reducing distal behavioral phenotypes to a set of molecular, physiological, and neural processes that render them closer to the actions of genetic forces, and (ii) striking a balance between the competing demands of discovery and interpretability when dealing with genomic data containing up to millions of markers. Our proposed approach involves linking, on one hand, models of neural computations and circuits hypothesized to underlie behavior, and on the other hand, the set of the genes carrying out biochemical processes related to the functioning of these neural systems. In particular, we focus on the specific example of value-based decision-making, and discuss how such a combination allows researchers to leverage existing biological knowledge at both neural and genetic levels to advance our understanding of the neurogenetic mechanisms underlying behavior