Patients suffering anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures or rewards, particularly regarding food intake. Neuroimaging studies of AN patients reveal a neurobiological contribution to the disorder. The rodent Activity-Based Anorexia (ABA) model recapitulates human AN symptomology, including anhedonia. We will use this model to highlight the importance of reward pathways in maintenance of body weight within the context of AN. We hypothesize that increasing neuronal activity in reward circuits, predicted to underpin anhedonia in ABA, will prevent and even rescue ABA-associated weight loss.
Female rats (n=44; 6 weeks old) underwent bilateral stereotaxic injections of canine adenovirus-2-Cre (CAV2-Cre) into the nucleus accumbens (NAc) and activating DREADDs (AAV-hSyn-DIO-hM3D(Gq)-mCherry) into the ventral tegmental area (VTA). DREADDs reorient in the presence of retrogradely-transported Cre and intraperitoneal clozapine-n-oxide (CNO) administration causes mCherry-labelled cells to depolarise with temporal and anatomical specificity. ABA involves free access to running wheels and temporal food restriction (90 min/day), with daily intraperitoneal injections of CNO or saline (control) at the onset of food availability. For “prevention” experiments, CNO treatment commenced with the initiation of ABA, whereas for “rescue” experiments, CNO treatment was initiated following at least 15% baseline body weight loss.
CNO activation of DREADD-expressing VTA neurons was confirmed by colocalization of mCherry with elevated levels of Fos protein, a marker of neuronal activity. During prevention, CNO-mediated activation of this pathway increased food intake (t22=3.43, p=0.002) with a profound effect on survival [χ2(1)=9.95, p=0.002]. Additionally, CNO-mediated activation resulted in increased food anticipatory activity (FAA) which was positively correlated with subsequent food intake (r=.64, r2=.41, p<0.0001). Importantly during rescue, CNO-mediated excitation of this pathway increased survival [χ2(1)=3.97, p=0.046] with a small increase in food intake. These data highlight the importance of CNS reward pathways in feeding behaviour and sign-post possible therapeutic strategies for AN.