PT  - JOURNAL ARTICLE
AU  - T. Lee Gilman
AU  - W Anthony Owens
AU  - Christina M George
AU  - Lauren Metzel
AU  - Melissa Vitela
AU  - Livia Ferreira
AU  - Melodi A Bowman
AU  - Georgianna G Gould
AU  - Glenn M Toney
AU  - Lynette C Daws
TI  - Age- and sex-specific plasticity in dopamine transporter function revealed by food restriction and exercise in a rat activity-based anorexia paradigm
AID  - 10.1124/jpet.119.260794
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.260794
4099  - http://jpet.aspetjournals.org/content/early/2019/09/03/jpet.119.260794.short
4100  - http://jpet.aspetjournals.org/content/early/2019/09/03/jpet.119.260794.full
AB  - 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. Yet 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 4-5 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 study of the pathophysiology and treatment of anorexia.SIGNIFICANCE STATEMENT Adolescent rats exhibit a distinctive, sex-specific plasticity in dopamine transporter function and cocaine response after food restriction and exercise access that 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.