Abstract
Eating disorders such as anorexia typically emerge during adolescence, are characterized by engagement in compulsive and detrimental behaviors, and are often comorbid with neuropsychiatric disorders and drug abuse. No effective treatments exist. Moreover, anorexia lacks adolescent animal models, contributing to a poor understanding of underlying age-specific neurophysiological disruptions. To evaluate the contribution of dopaminergic signaling to the emergence of anorexia-related behaviors during the vulnerable adolescent period, we applied an established adult activity-based anorexia (ABA) paradigm (food restriction plus unlimited exercise access for 4 to 5 days) to adult and adolescent rats of both sexes. At the end of the paradigm, measures of plasma volume, blood hormone levels, dopamine transporter (DAT) expression and function, acute cocaine-induced locomotion, and brain water weight were taken. Adolescents were dramatically more affected by the ABA paradigm than adults in all measures. In vivo chronoamperometry and cocaine locomotor responses revealed sex-specific changes in adolescent DAT function after ABA that were independent of DAT expression differences. Hematocrit, insulin, ghrelin, and corticosterone levels did not resemble shifts typically observed in patients with anorexia, though decreases in leptin levels aligned with human reports. These findings are the first to suggest that food restriction in conjunction with excessive exercise sex-dependently and age-specifically modulate DAT functional plasticity during adolescence. The adolescent vulnerability to this relatively short manipulation, combined with blood measures, evidence need for an optimized age-appropriate ABA paradigm with greater face and predictive validity for the study of the pathophysiology and treatment of anorexia.SIGNIFICANCE STATEMENTAdolescent rats exhibit a distinctive, sex-specific plasticity in dopamine transporter function and cocaine response after food restriction and exercise access; this plasticity is both absent in adults and not attributable to changes in dopamine transporter expression levels. These novel findings may help explain sex differences in vulnerability to eating disorders and drug abuse during adolescence.
Highlights
Eating disorders afflict $3% of individuals in developed countries, and disproportionately impact females over males by more than double (Smink et al, 2014; Keski-Rahkonen and Mustelin, 2016)
Relative to same-sex cage control (CC), circulating leptin and corticosterone were reduced in adolescent female activity-based anorexia (ABA) and food restricted control (FC) groups, and adolescent female FCs exhibited reduced ghrelin and increased insulin postprandial
Only leptin levels were reduced compared to CCs in ABA animals and FCs
Summary
Eating disorders afflict $3% of individuals in developed countries, and disproportionately impact females over males by more than double (Smink et al, 2014; Keski-Rahkonen and Mustelin, 2016). These disorders, which include anorexia nervosa (AN), bulimia nervosa, and binge-eating disorder, most often emerge during adolescence (Herpertz-Dahlmann, 2015). AN and bulimia nervosa, are characterized by drastic changes in eating and/or activity behaviors that, when sufficiently rewarding to the individual’s desired outcome (e.g., dramatic weight loss), can lead to compulsive engagement in such behavior despite severe deterioration in health or lifestyle. DA pathophysiology is suspected to underlie, at least in part, adolescent-onset eating disorders (Barry and Klawans, 1976; Golden and Shenker, 1994; Frank et al, 2005; Frieling et al, 2010; Scherag et al, 2010; Kaye et al, 2013)
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