The effect of dopamine agonists on adaptive and aberrant salience in Parkinson's disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinson's disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus-reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus-reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus-reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward

Desire and Dread from the Nucleus Accumbens: Cortical Glutamate and Subcortical GABA Differentially Generate Motivation and Hedonic Impact in the Rat

Background: GABAergic signals to the nucleus accumbens (NAc) shell arise from predominantly subcortical sources whereas glutamatergic signals arise mainly from cortical-related sources. Here we contrasted GABAergic and glutamatergic generation of hedonics versus motivation processes, as a proxy for comparing subcortical and cortical controls of emotion. Local disruptions of either signals in medial shell of NAc generate intense motivated behaviors corresponding to desire and/or dread, along a rostrocaudal gradient. GABA or glutamate disruptions in rostral shell generate appetitive motivation whereas disruptions in caudal shell elicit fearful motivation. However, GABA and glutamate signals in NAc differ in important ways, despite the similarity of their rostrocaudal motivation gradients. Methodology/Principal Findings: Microinjections of a GABAA agonist (muscimol), or of a glutamate AMPA antagonist (DNQX) in medial shell of rats were assessed for generation of hedonic ‘‘liking’ ’ or ‘‘disliking’ ’ by measuring orofacial affective reactions to sucrose-quinine taste. Motivation generation was independently assessed measuring effects on eating versus natural defensive behaviors. For GABAergic microinjections, we found that the desire-dread motivation gradient was mirrored by an equivalent hedonic gradient that amplified affective taste ‘‘liking’ ’ (at rostral sites) versus ‘‘disliking’ ’ (at caudal sites). However, manipulation of glutamatergic signals completely failed to alter pleasure-displeasure reactions to sensory hedonic impact, despite producing a strong rostrocaudal gradient of motivation

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression