The effects of the dopamine D2/3 agonist quinpirole on incentive value and palatability-based choice in a rodent model of attention-deficit/hyperactivity disorder.

RATIONALE: Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD. OBJECTIVES: To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains. METHODS: Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01-0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls. RESULTS: All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability. CONCLUSIONS: These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD.

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

The neurobehavioral mechanisms of motivational control in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) poses debilitating impairments in the neurobehavioral systems governing reward-related processes-key to the control of motivated behaviors. Individuals with ADHD may rely on a motivational control system that favors cue-driven habits-rooted in the posterior putamen-over caudate and prefrontal cortex-driven goal-directed behaviors. We examined the neurobehavioral correlates of motivational control in ADHD. Twenty-five adults with ADHD and 25 neurotypicals underwent fMRI while training on two stimulus-response-outcome associations. A devaluation procedure followed, whereby they were selectively satiated on one of the snack outcomes, decreasing its value. A subsequent extinction test determined outcome-sensitivity (i.e., whether responses towards devalued snack diminished). Despite behavioral similarities, the ADHD group displayed a distinct neural signature marked by enhanced posterior putamen activation as a function of training. This region also displayed diminished functional connectivity with the dorsal anterior cingulate cortex, which is associated with top-down control. Our whole-brain analysis yielded ADHD-specific posterior putamen and opercular/insular cortex activity over the course of training-regions associated with stimulus-sensitivity and maladaptively rigid behaviors, respectively. Neural comparisons also identified hyper-recruitment of the hippocampus in the ADHD group. These results highlight corticostriatal discrepancies in ADHD, possibly serving as a biomarker of the disorder.

The Relationship Between Social Communication and Social Functioning in Pediatric TBI: A Pilot Study.

Objective: Social communication presents a significant difficulty for children with traumatic brain injury (TBI). Although several measures are used to examine social communication, there is no gold-standard assessment tool. The present pilot study examined the ability of the Social Communication Disorders Checklist (SCDC) to detect social communication difficulties in pediatric TBI. Further, we examined the relationship between social communication and social functioning as assessed by parental ratings of behavior and objective measures of social cognition. Methods: Sixteen children with pediatric TBI and 20 age, education and sex matched healthy controls (HCs) participated. All participants participated in a neuropsychological evaluation and parents filled out questionnaires. Parents rated their children's social communication abilities using the SCDC, as well as the Behavior Assessment System for Children, Second Edition (BASC-2). The pediatric subjects completed a task of social cognition, specifically Theory of Mind (ToM). Results: The pediatric TBI group had significantly lower scores on the SCDC compared to the HCs (p = 0.001). In the pediatric group, SCDC scores correlated significantly with scores on the BASC-2, as well as performance on the ToM task, indicating that children with lower parent-rated social communication abilities also had lower scores on the objective measure of social cognition. Conclusions: These data provide preliminary evidence that children with TBI have difficulties with social communication, as evidenced by lower scores on the SCDC, and that SCDC scores correlate with subjective and objective measures of social cognition and behavior in pediatric TBI.

Dopaminergic Modulation of Goal-Directed Behavior in a Rodent Model of Attention-Deficit/Hyperactivity Disorder.

Aside from its clinical symptoms of inattention, impulsivity and hyperactivity, patients with Attention/Deficit-Hyperactivity Disorder (ADHD) display reward and motivational impairments. These impairments may reflect a deficit in action control, that is, an inability to flexibly adapt behavior to changing consequences. We previously showed that spontaneously hypertensive rats (SHR), an inbred rodent model of ADHD, show impairments in goal-directed action control, and instead are predominated by habits. In this study, we examined the effects of specific dopamine receptor sub-type (D1 and D2) agonists and antagonists on goal-directed behavior in SHR and the normotensive inbred control strain Wistar-Kyoto (WKY) rats. Rats acquired an instrumental response for different-flavored food rewards. A selective-satiety outcome devaluation procedure followed by a choice test in extinction revealed outcome-insensitive habitual behavior in SHR rats. Outcome-sensitive goal-directed behavior was restored in SHR rats following injection prior to the choice test of the dopamine D2 receptor agonist Quinpirole or dopamine D1 receptor antagonist SCH23390, whereas WKY rats showed habitual responding following exposure to these drugs. This novel finding indicates that the core behavioral deficit in ADHD might not be a consequence of dopamine hypofunction, but rather is due to a misbalance between activation of dopamine D1 and D2 receptor pathways that govern action control.

Neural Correlates of Outcome Anticipation in Multiple Sclerosis.

Outcome anticipation is not only a mental preparation for upcoming consequences, but also an essential component of learning and decision-making. Thus, anticipation of consequences is a key process in everyday functioning. The striatum and the ventromedial prefrontal cortex are among the key regions that have been shown to be involved in outcome anticipation. However, while structural abnormalities of these regions as well as altered decision-making have been noted in individuals with multiple sclerosis (MS), neural correlates of outcome anticipation have not been explored in this population. Thus, we examined the neural correlates of outcome anticipation in MS by analyzing brain activation in individuals with MS while they performed a modified version of a card-guessing task. Seventeen MS and 13 healthy controls performed the task while functional magnetic resonance imaging (fMRI) was obtained. To achieve maximal anticipatory response and prevent the possibility of differential performance on the task, participants were presented with monetary rewards only on 50% of the trials. While replicating previous evidence of structural abnormalities of the striatum in MS, our results further showed that individuals with MS exhibited greater activation in the putamen, right hippocampus, and posterior cingulate cortex during outcome anticipation compared to healthy controls. Furthermore, even though there was no strategy that participants could learn in order to predict outcomes, 76% of participants with MS indicated that they used strategies while performing the task. We thus propose that the increased neural activation observed in MS during outcome anticipation might be explained by a failure in recognizing the lack of regularity in the task structure that could result in using strategies to perform the task.

The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD.

Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD) have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75-P105] Spontaneously Hypertensive Rats (SHR; ADHD rat model) and Wistar-Kyoto rats (WKY), the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action-outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate (MPH), a commonly used ADHD medication, on goal-directed behavior, we injected rats with either MPH or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, MPH administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how MPH acts differently on SHR and WKY animals to restore or impair this behavior, respectively.

Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants.

One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject's relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky's (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not "normal" when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs.

Depression impairs learning, whereas the selective serotonin reuptake inhibitor, paroxetine, impairs generalization in patients with major depressive disorder.

To better understand how medication status and task demands affect cognition in major depressive disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the selective serotonin reuptake inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures is critical for generalization.