ABSTRACT
Ghrelin, a peptide hormone produced by the stomach, is the endogenous ligand for the Growth Hormone Secretagogue Receptor (GHSR). Ghrelin acts on the GHSR to increase food intake, appetitive behaviors, and adiposity. Recently, a rat model with a null mutation to the GHSR gene (FHH-GHSR(m1/Mcwi)) was generated and used in behavioral studies, but the basic metabolic phenotype of this strain as well as that of the background strain (Fawn Hooded Hypertensive, FHH) has not been characterized in detail. Here we compared male FHH-GHSR(m1/Mcwi) rats with their wild-type littermates (FHH-WT) in a number of metabolic parameters. In the 24h of recovery following an acute overnight fast, FHH-GHSR(m1/Mcwi) rats consumed less food than FHH-WT animals, and relative to their body weights, adult FHH-GHSR(m1/Mcwi) rats consumed fewer calories when placed on a high-fat diet. Despite this, FHH-GHSR(m1/Mcwi) rats did not show a difference in diet-induced obesity or weight gain. Fasted FHH-GHSR(m1/Mcwi) rats exhibited increased Agouti-Related Peptide (AgRP) and Neuropeptide Y (NPY) expression in the Arcuate Nucleus (ARC), indicative of altered central regulation of feeding and energy balance. FHH-GHSR(m1/Mcwi) rats exhibited lower levels of home cage locomotor behavior over the entire light/dark cycle, and reduced levels of food anticipatory activity when placed on a restricted feeding schedule. Finally, FHH-GHSR(m1/Mcwi) rats consumed less of a palatable dessert (cookie dough) given after the completion of the scheduled meal. Altogether, our data show that rats lacking a functional GHSR tend to eat less than their wild-type counterparts in the face of acute fasts, chronic high-fat diet exposure, and exposure to a palatable dessert, despite not showing differences in body weight and glucose homeostasis that are characteristic of GHSR null mice. These data indicate that many, but not all responses to GHSR ablation are conserved between rats and mice. The FHH-GHSR(m1/Mcwi) rat thus represents a novel and useful model for studying GHSR function in rats.
Subject(s)
Diet, High-Fat , Eating/genetics , Feeding Behavior/physiology , Ghrelin/metabolism , Mutation/genetics , Receptors, Ghrelin/metabolism , Agouti-Related Protein/metabolism , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Body Weight/genetics , Diet, High-Fat/methods , Disease Models, Animal , Fasting/physiology , Gene Expression Regulation/genetics , Glucose Tolerance Test , Humans , Locomotion/genetics , Male , Neuropeptide Y/metabolism , Obesity/etiology , Obesity/genetics , Rats , Rats, Transgenic , Receptors, Ghrelin/geneticsABSTRACT
Ghrelin is an orexigenic hormone produced by the stomach that acts on growth hormone secretagogue receptors (GHSRs) both peripherally and centrally. The presence of GHSRs in the ventral tegmental area (VTA) suggests that ghrelin signaling at this level may increase the incentive value of palatable foods as well as other natural and artificial rewards. The present investigation sought to determine if ghrelin plays a role in relapse to such foods following a period of abstinence. To achieve this, thirty-six male Long Evans rats were trained to press a lever to obtain a high fat chocolate food reward on a fixed ratio schedule of 1. Following an extinction period during which lever presses were not reinforced, rats were implanted with a cannula connected to a minipump that continuously delivered ghrelin, a GHSR antagonist ([d-Lys-3]-GHRP-6), or saline in the VTA for 14days. One week later, food reward-associated cues, food reward priming, and an overnight fast were used to induce reinstatement of the lever pressing response. Our results indicate that intra-VTA ghrelin enhances cue-induced reinstatement of responses for palatable food pellets. To the extent that the reinstatement paradigm is considered a valid model of relapse in humans, this suggests that ghrelin signaling facilitates relapse to preferred foods in response to food cues through GHSR signaling in the VTA.
Subject(s)
Conditioning, Operant/physiology , Cues , Food , Ghrelin/metabolism , Receptors, Ghrelin/metabolism , Reward , Ventral Tegmental Area/metabolism , Animals , Conditioning, Operant/drug effects , Ghrelin/administration & dosage , Male , Rats , Rats, Long-Evans , Receptors, Ghrelin/antagonists & inhibitors , Ventral Tegmental Area/drug effectsABSTRACT
Rat strains selectively bred to be seizure-prone (Fast) versus seizure-resistant (Slow) show differing levels of anxiety, with Slow rats displaying relatively enhanced anxiety-like behaviors to aversive stimuli. Ample data has suggested that highly anxious rodents exhibit reduced avidity for sucrose and greater startle responses than rodents with relatively low anxiety levels. Thus, it was hypothesized that the Slow rats would have lower appetitive (sucrose consumption) and greater defensive (startle response) behaviors than Fast rats. Results confirmed that Slow rats consumed significantly less sucrose and exhibited greater acoustic startle responses than Fast rats. Startle response magnitude was not associated with water consumption, food consumption or body weight but was negatively correlated with sucrose consumption. These observations attest to the link between sucrose avidity and startle reactivity and further reveal that genetic selection for amygdala excitability lead to strain differences in appetitive and defensive behaviors. Thus, Fast and Slow rats may be two unique strains with which to further elucidate the genetic and neurobiological mechanisms underlying appetitive and defensive behaviors and their relation to anxiety and seizure sensitivity.
Subject(s)
Food Preferences/physiology , Genetic Predisposition to Disease , Reflex, Startle/genetics , Seizures/genetics , Sucrose , Acoustic Stimulation , Analysis of Variance , Animals , Behavior, Animal/physiology , Rats , Seizures/physiopathology , Species SpecificityABSTRACT
The creation of seizure-prone (Fast) and seizure-resistant (Slow) rat strains via selective breeding implies genetic control of relative seizure vulnerability, yet ample data also advocates an environmental contribution. To investigate potential environmental underpinnings to the differential seizure sensitivities in these strains, the authors compared amygdala kindling profiles in adult male Fast and Slow rats raised by (a) their own mother, (b) a foster mother from the same strain, or (c) a foster mother from the opposing strain. Ultimately, strain-specific kindling profiles were not normalized by cross-fostering. Instead, both strains became more seizure-prone regardless of maternal affiliation (i.e., cross-fostered groups from both strains kindled faster than uncrossed controls). Interhemispheric seizure spread was also facilitated in cross-fostered Slow rat groups and was associated with increased commissural cross-sectional areas, giving them a Fast-like profile. It is important to note, however, that all Fast groups remained significantly more seizure-prone than Slow groups, suggesting that although the postnatal environment strongly influenced seizure disposition in both strains, it did not wholly account for their relative dispositions. Investigation into mechanisms fundamental to cross-fostering-induced seizure facilitation should help prevent postnatal worsening of pathology in already seizure-prone individuals.
