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  • The Growth Hormone Secretagogue Receptor GHSR also

    2021-09-26

    The Growth Hormone Secretagogue Receptor (GHSR), also known as the ghrelin receptor, is a G protein-coupled receptor (GPCR) expressed widely throughout the body and brain, with particular enrichment in Roxithromycin regions concerned with homeostatic and motivational function such as the hypothalamus, hippocampus, as well as in a number of midbrain and brainstem nuclei [25], [26]. In addition to its role as a receptor for active ghrelin, GHSR also participates in receptor dimers with numerous other GPCRs including those for dopamine (D1R, D2R), serotonin (5-HT2C) and the melanocortin-3 receptor (MC3R) [27], [28], [29], [30]. In the arcuate nucleus of the hypothalamus (ARC), GHSR is expressed in neurons that co-express the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP), and both peripheral and central ghrelin administration activates these neurons, leading to upregulation of these neuropeptides [31], [32]. Ghrelin inhibits the activity of pro-opiomelanocortin (POMC) neurons, though this is likely an indirect trans-synaptic effect since POMC neurons do not generally express GHSR [33], [31]. Leptin and ghrelin have opposing effects on food intake and body weight, but in most hypothalamic nuclei, with the notable exception of the AgRP/NPY neurons of the ARC, the leptin receptor (ObRb) and GHSR are not co-localized [34]. Knowledge of ghrelin's physiological and behavioral effects has been advanced in large part by the use of knockout mouse models. The gene coding for ghrelin itself can be knocked out, leading to a complete absence of circulating ghrelin [35], as can GOAT, leading to a specific lack of acylated ghrelin [15]. Mice lacking GHSR (GHSR−/−) have also been well-studied, showing mild hypophagia, resistance to diet-induced obesity, and resistance to diet-induced metabolic dysfunctions such as impaired glucose tolerance and insulin sensitivity [36], [37]. Moreover, GHSR−/− mice show reduced food intake when placed on a restricted feeding schedule [7], reduced anticipatory behavior to scheduled meals [24], and preferential use of fat as an energy substrate under conditions of stress [11]. Importantly, these phenotypic effects are quite subtle and often reveal themselves only under the appropriate dietary, energetic, or behavioral challenges. Though many advances in the ghrelin literature are owed to transgenic mouse models, there are some experimental situations, particularly those involving complex surgical procedures or behavioral tasks, to which rats are better suited. A GHSR knockout rat model based on the Fawn Hooded Hypertensive (FHH) inbred background strain was recently generated at the Medical College of Wisconsin using N-ethyl-N-nitrosourea (ENU)-induced mutagenesis (FHH-GHSRm1/Mcwi) [38]. These rats resist the effects of exogenous ghrelin on gastrointestinal motility and food intake [39], [40], as well as the locomotor sensitizing effect of chronic cocaine exposure [40]. Young (2–4months) FHH-GHSRm1/Mcwi rats have reduced dendritic spine density and fewer doublecortin immunopositive neurons in the dentate gyrus relative to their wild-type counterparts, and in old age (5–8months) knockouts go on to exhibit reduced performance in a food-motivated radial arm maze task [41]. Although this strain has been used to good effect in several studies so far, its body weight, food intake, and metabolic phenotype have not yet been evaluated in detail. The effect of this GHSR mutation on the consumption of normal and palatable food, for example, is an important consideration not only in studies of metabolism, but also in cognitive, motivational, and behavioral Roxithromycin experiments in which food is used as a reinforcer. There are many such models that are already well-adapted to using rats as an experimental organism, and the usefulness and validity of the FHH-GHSRm1/Mcwi rat in these will be greatly enhanced if its commensurability with the GHSR−/− mouse is better understood, since this mouse is the basis for much of the pre-existing knowledge of ghrelin function. Therefore, in order to better understand the phenotype of this rat, we evaluated a number of metabolic, neurobiological, and behavioral traits that are well-established phenotypic markers of GHSR−/− mice.