Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OE dev mice) are reversed by decreasing function of the striatopallidal "no-go" pathway. To this end, we expressed the G ␣i -coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OE dev mice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization.Key words: calcium imaging; DREADD; indirect pathway; motivation; striatum IntroductionMotivation can be defined as the activation of goal-directed behavior. It involves a "directional" component, allowing subjects to efficiently select a behavior leading to optimal outcome, and an "activational" component that initiates and maintains the vigor and persistence of actions (Salamone, 1988;Simpson and Balsam, 2015). Different striatal subregions have been implicated in motivation, including the dorsomedial striatum (DMS) (Yin et State Psychiatric Institute. We thank Dr. Jonathan Javitch and members of the C.K. laboratory for thoughtful discussions on the data presented in the manuscript; and Dr. Rene Hen for sharing reagents and resources.The authors declare no competing financial interests. *P.D.B. and C.K. contributed equally to this manuscript. Significance StatementMotivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activat...

BackgroundA recent study examined the prevalence, clinical correlates, age trends, and stability of unhealthy weight control behaviors (UWCB; purging and diet pill use) in a nationally representative sample of Norwegian boys and girls. The purpose of this study was to provide similar, comparative analyses for a nationally representative sample of American youth.MethodsData were extracted from the restricted use data files of survey Waves I, II, and III of the National Longitudinal Study of Adolescent Health (Add Health), selecting all participants who at Wave I had provided information on age, sex, and UWCB. Using UWCB information, three groups were created (purging, diet pill use, and no recent UWCB “controls”) and compared on indicators of adverse health or mental health.ResultsGirls consistently were more likely than boys to report UWCB. UWCB were significantly associated with higher body mass index, self-perception of being overweight, low self-esteem, depression, and delinquency. Prevalence estimates for purging remained relatively constant across the three survey waves; in contrast, diet pill use was especially common at Wave III.ConclusionsAge trends, gender differences, and clinical correlates of change in the likelihood of UWCB between Waves I-III were all identified in analyses comparing purging and diet pill use in American adolescents. Females and older adolescents were specifically more likely to engage in pill use than purging, and individuals with increased weight dissatisfaction, a history of delinquent behaviors, more depression symptoms, or lower self-esteem were more likely to engage in an unhealthy weight control behavior over time. While the Norwegian study found that prevalence of purging was lower among young adult participants, our results suggested that there were no significant differences in prevalence between age groups.

BackgroundThere exists a dearth of prospective adolescent eating disorder studies with samples that are large enough to detect small or medium sized effects for risk factors, that are generalizable to the broader population, and that follow adolescents long enough to fully capture the period of development when the risk of eating disorder symptoms occurring is highest. As a result, the purpose of this study was to examine psychosocial risk factors for purging for weight control in a nationally representative sample of adolescents. Data were extracted from the restricted-use data sets of the National Longitudinal Study of Adolescent Health (Waves I-III), selecting females with valid demographic and purging information (N = 5,670).ResultsThe prevalence of purging was 0.88% at Wave II and 0.56% at Wave III. In multivariable multinomial logistic regressions, purging at Wave II was predicted by parental poverty and low levels of self-esteem at Wave I; purging at Wave III was predicted by body mass index and the frequency of delinquent behaviors at Wave I.ConclusionsIndividuals with high body mass index, individuals with low self-esteem, and individuals in families experiencing economic hardship appear specifically at risk for the development of purging behaviors in later years and may benefit from more targeted prevention efforts.

The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [11C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [11C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance.

Shen et al. Synaptic Inhibition Increases at Puberty to impairments in synaptic plasticity. These results may have relevance for the changes in cognitive function reported during early adolescence.