Acute Stress Exposure Alters Food-Related Brain Monoaminergic Profiles in a Rat Model of Anorexia

Abstract

Background Adverse life experiences are a major risk factor for anorexia nervosa (AN). Eating-provoked anxiousness associated with AN is postulated to be due to food-related exaggerated serotonin activity in the brain and imbalances of monoamine neurotransmitters. Objectives Using a rodent model of stress-induced hypophagia, we investigated if stress exposure augments food-related serotonin turnover and imbalances in measures of brain serotonin and dopamine activity in manners consistent with anxiousness toward food and restricted eating. Methods Adult male F344 rats were conditioned to associate an audio cue with daily food over 2 weeks, after which half of the rats were exposed to a single episode of tail shocks (stress) or left undisturbed (nonstressed). All rats were killed 48 h later, during a control period, the food-associated cue, or a period of food access. Serotonin, dopamine, and norepinephrine, as well as metabolite concentrations, were assessed across brain regions comprising reward, emotion, and feeding circuits relevant to AN in acutely stressed and nonstressed rats using HPLC. Statistical significance level was 5%. Results Stress-induced rat hypophagia paralleled an augmented serotonin turnover in response to the food-associated cue in the hypothalamus and hippocampus, as well as food access in the hypothalamus and cortical areas (all P < 0.05). Stress exposure increased the ratio of serotonin to dopamine metabolites across several brain areas, but the magnitude of this imbalance was further augmented during the food-associated cue and food access in the brainstem, hippocampus, and cortical areas (all P < 0.05). Finally, stress lowered norepinephrine concentrations by 18% in the hypothalamus (P < 0.05). Conclusions The observed stress-induced changes to monoamine profiles in rats could have key implications for physiological states that contribute to restricted eating and may hold relevance for the development of AN precipitated by adverse life experiences.

An evaluation of the rat intestinal monoamine biogeography days following exposure to acute stress

“…Rats in the Pre-Food group ( n = 9 Unstressed, n = 9 Stressed) were sampled after a 12 h period fasting. The Pre-Food group was designed to observe intestinal neurochemical responses to stress without the presence of food in the GI tract, to minimize possible confounds in neurochemical data that could occur due to stress-induced reductions in eating ( Reed et al, 2021 ). Rats in the Post-Food group ( n = 9 Unstressed, n = 8 Stressed) were sampled 30 min after food access.…”

“…Cages (consisting of 2-3 rats) were randomly assigned to receive uncontrollable tail shocks (Stress) or remained in their home cages (Unstressed). The tail shock paradigm followed our previous publications (Clark et al, 2014(Clark et al, , 2015Reed et al, 2021). Briefly, the procedure took place in a room adjacent to the room they were housed.…”

“…For instance, gut microbiota have been shown to regulate 5-HT and DA levels in various manners, including, but not limited to, influencing host tryptophan metabolism, as well as 5-HT and DA metabolism (Yano et al, 2015;Moya-Pérez et al, 2017;Li et al, 2019b;Kaur et al, 2019;Kwon et al, 2019;Kennedy and Chang, 2020). Yet still, stress-related differences of localized monoaminergic activities across intestinal regions may have implications for the etiology of GI distress symptoms, including those that have been reported in rats following immediately to days following exposure to unpredictable tail shocks (Weiss, 1970;Abbott et al, 1984;Garrick et al, 1989;Morrow and Garrick, 1997;Mika et al, 2017;Reed et al, 2021). Evidence indicates that sufficiently elevated 5-HT and lowered DA activity in the gut can promote inflammatory responses, thereby increasing intestinal motility and heightening visceral sensitivity (Galvin, 1992;Mawe et al, 2013;Galligan et al, 2013;Dong et al, 2017;Kwon et al, 2019;Alvarado and Ciroba., 2020;Steinsvik et al, 2020;Kurnik-Łucka et al, 2021).…”

“…Moreover, the unpredictable tail shock paradigm has been argued to be a promising model for understanding the biological underpinnings of GI dysfunction that are common with PTSD ( Stam et al, 1997 ). Indeed, rats display several symptoms consistent with GI dysfunction following exposure to this stressor, including abnormal gastral contractility and mucosal injury ( Weiss, 1968 ; Abbott et al, 1984 ; Garrick et al, 1989 ; Tsuda et al, 2013 ), alterations to the microbiome ( Thompson et al, 2020 ), evidence of increased intestinal permeability ( Maslanik et al, 2012 ), persistent hypophagia ( Reed et al, 2021 ), as well as suppressed colonic contractility and increased fecal output that is watery in consistency ( Morrow and Garrick, 1997 ). However, despite these observations, little work has been completed investigating the possible intestinal physiological underpinnings of GI distress using this model.…”

Hypothalamic TRH Mediates Anorectic Effects of Serotonin in Rats

“…Importantly, there is a high expression of 5HT 1 , 5HT 2 , 5HT 6 receptors in the PVN ( Marvin et al, 2010 ; Garfield et al, 2014 ; Lauffer et al, 2016 ), and the anorectic effects of the serotonergic pathway result by activating 5HT 1 and 5HT 2 receptors ( Bagdy, 1996 ; Doslikova et al, 2013 ), or by the antagonism of 5HT 6 ( Woolley et al, 2001 ). Furthermore, food deprivation-induced hungry animals show reduced 5HT concentration in their brain ( Haleem, 2009 ), whereas those with anorexia present high c-fos expression in different areas including the PVN that is blocked with 5HT antagonists (LPS-induced anorectic rats; Kopf et al, 2010 ), a serotonergic hyperinnervation (anx/anx mice; Jahng et al, 1998 ), or an enhanced 5HT turnover (stress-induced anorectic rats; Reed et al, 2021 ) in the hypothalamus.…”