Central infusion of the melanocortin receptor antagonist agouti-related peptide (AgRP(83-132)) prevents cachexia-related symptoms induced by radiation and colon-26 tumors in mice.

Cachexia is a clinical wasting syndrome that occurs in multiple disease states, and is associated with anorexia and a progressive loss of body fat and lean mass. The development of new therapeutics for this disorder is needed due to poor efficacy and multiple side effects of current therapies. The pivotal role played by the central melanocortin system in regulating body weight has made this an attractive target for novel cachexia therapies. The mixed melanocortin receptor antagonist AgRP is an endogenous peptide that induces hyperphagia. Here, we used AgRP(83-132) to investigate the ability of melanocortin antagonism to protect against clinical features of cachexia in two distinct animal models. In an acute model, food intake and body weight gain were reduced in mice exposed to radiation (300 RAD), and delivery of AgRP(83-132) into the lateral cerebral ventricle prevented these effects. In a chronic tumor cachexia model, adult mice were injected subcutaneously with a cell line derived from murine colon-26 adenocarcinoma. Typical of cachexia, tumor-bearing mice progressively reduced body weight and food intake, and gained significantly less muscle mass than controls. Administration of AgRP(83-132) into the lateral ventricles significantly increased body weight and food intake, and changes in muscle mass were similar to the tumor-free control mice. These findings support the idea that antagonism of the central melanocortin system can reduce the negative impact of cachexia and radiation therapy.

Central administration of peptide and small molecule MC4 receptor antagonists induce hyperphagia in mice and attenuate cytokine-induced anorexia.

We investigated the effect of melanocortin 4 receptor (MC4) antagonists on food intake in mice. Food intake during the light phase was significantly increased by ICV administration of mixed MC3/MC4 antagonists (AgRP and SHU9119) or MC4 selective antagonist peptide [(Cyclo (1-5)[Suc-D-Nal-Arg-Trp-Lys]NH2] (MBP10) and the small molecule antagonists THP and NBI-30. Both mixed and selective antagonists significantly reversed anorexia induced by ICV administration of the MC4 agonist (c (1-6) HfRWK-NH2) and the cytokine IL-1beta. These findings provide pharmacological evidence that the MC4 receptor mediates the effects of melanocortin agonists and antagonists on food intake in mice, and support the idea that selective small molecule MC4 antagonists may be useful as therapeutics for cachexia.

The role of taste in the recovery from specific nutrient deficiencies in rats.

Humans and animals have an impressive ability to use behavioral means to recover from nutritional deficits. Under some conditions, recovery ray be manifest in the form of a specific appetite for the missing nutrient. This review will discuss how the gustatory system is used by the rat to aid in the recovery from deficiencies of sodium, vitamin B, and individual essential amino acids. While it is likely that a deficient rat will use all available cues to guide intake of a limited nutrient, the role of taste can be partitioned out using techniques that measure immediate behavioral responses to brief exposures of taste stimuli and/or by measuring responsiveness before and after nerve transection. Taste can be used to identify stimuli in the environment as well as serve to motivate intake in terms of producing a particular affective reaction. Compensatory alterations in these aspects of the gustatory system are considered for three types of deficiencies. For learned appetites the utility of conditioning paradigms is presented as a potential means to gain a further understanding of behavioral recovery from specific micronutrient deficiencies.

Long-term effects on feeding and body weight after stimulation of forebrain or hindbrain CRH receptors with urocortin.

Research on the contribution of CRH receptor stimulation to energy homeostasis has focused on forebrain substrates. In this study, we explored the effects of caudal brainstem administration of the CRH receptor agonist, urocortin, on food intake and body weight, and on plasma glucose and corticosterone (CORT) in non-deprived rats. Urocortin (0, 0.3, 1, 3 microg) delivered, respectively, to the fourth and lateral ventricles yielded substantial suppression of food intake measured 2, 4 and 24 h later. A significant but more modest anorexia was observed between 24 and 48 h after injection. Intake responses did not differ between the injection sites, but body weight loss measured 24 h after lateral-i.c.v. injection was substantially greater than that after fourth-i.c.v. injection. Fourth-i.c.v. urocortin administration (3 microg) produced substantial elevations in plasma glucose and CORT that were not distinguishable in magnitude and duration from responses to lateral-i.c.v. delivery. Unilateral microinjection of urocortin into the dorsal vagal complex significantly reduced 24-h food intake at a dose (0.1 microg) that was subthreshold for the response to ventricular administration, suggesting that fourth-i.c.v. effects are mediated in part by stimulation of CRH receptors in this region of the caudal brainstem. The results indicate that similar effects can be obtained from stimulation of anatomically disparate populations of CRH receptors, and that interactions between forebrain and hindbrain structures should be considered in the evaluation of CRH contributions to food intake and body weight control.

Time course and pattern of compensatory ingestive behavioral adjustments to lysine deficiency in rats.

We and others have demonstrated that rats deficient in an essential amino acid (EAA) will consume sufficient quantities of the lacking nutrient to produce repletion when it is made available in solution. In the current series of experiments, we made rats deficient in lysine (LYS) by limiting the level of this EAA in the diet. We then examined licking behavior during approximately 23-h two-bottle intake tests over 4 consecutive days. In three separate experiments, rats were presented with the following: 1) 0.1 mol/L LYS and water, 2) 0.2 mol/L threonine (THR) and water and 3) 0.1 mol/L LYS and 0.2 mol/L THR. Lysine-deficient (LYS-DEF) rats drink significantly more LYS than did nondepleted controls (CON) when this amino acid was available. Meal pattern analysis revealed that the enhanced intake of LYS occurred as a function of a greater number of ingestive bouts, not changes in bout size. A cumulative analysis of LYS intake between CON and LYS-DEF rats revealed that a potentiation of intake developed within 30 min of sampling the solution when LYS and water were available and within 90 min when LYS and THR were the contrasting choices. In conclusion, increased LYS intake in the deficient rats occurs relatively rapidly and appears to be at least somewhat specific. Moreover, LYS deficiency does not seem to enhance the palatability of the limiting amino acid as judged by behaviors such as lick rate and bout size. Instead, LYS-DEF rats relieve the deficiency by increasing the number of drinking episodes initiated.

Essential amino acid deficiency enhances long-term intake but not short-term licking of the required nutrient.

Rats can adjust their nutrient intake in response to nutritional deficiency. This phenomenon has been described extensively for sodium deficiency, whereas other nutrient deficiencies have not been explored thoroughly. Essential amino acid (EAA) deficiency represents a relevant model to describe adaptive changes in behavior resulting from deficiency. The purpose of these experiments was to examine more closely the behavioral responses that occur as a result of lysine (LYS) and threonine (THR) deficiency. Licking to LYS, THR, glycine and distilled water during 10-s trials was measured in control (CON) and EAA-deficient rats. Licking tests were conducted both before and after 23-h intake tests. Although EAA-deficient rats did not show increased licking to the deficient EAA in any of the brief-access tests, in all cases, they did initiate significantly more overall trials than did CON. The EAA-deficient rats also had elevated intake of the deficient EAA in long-duration tests. These findings suggest that LYS or THR deficiency does not emulate the behavioral properties of sodium deficiency in that it does not result in enhanced immediate licking responses to the limiting EAA in brief-access tests. Nevertheless, an appetite is expressed to the relevant EAA in a long-term intake test.

Glossopharyngeal nerve transection reduces quinine avoidance in rats not given presurgical stimulus exposure.

Behavioral studies on the effects of bilateral glossopharyngeal nerve (GL) transection on quinine responsiveness have yielded mixed results. These differences may be explained by the presence or absence of presurgical exposure with the tastant. In the present experiment we measured unconditioned licking to quinine in rats that had no exposure to quinine before surgery. Rats were water deprived and trained to lick water during 10 s trials in an automated gustometer. Next, they were divided into groups that received either GL transection or sham surgery (CON). Following recovery, the water-deprived rats were presented with seven concentrations of quinine hydrochloride (0.003-3 mM) and distilled water. The number of licks to each tastant was averaged over three days of testing. Rats with GL transection licked significantly more to the higher concentrations of quinine relative to CON rats, resulting in a 0.44 log10 unit shift in the quinine concentration-response curve. These results when considered with prior work suggest that experience before nerve transection may have a small protective effect on taste-guided behavioral responsiveness to quinine in rats.

Chorda tympani transection and selective desalivation differentially disrupt two-lever salt discrimination performance in rats.

Water-restricted rats were trained to press 1 of 2 levers if a sampled stimulus was NaCl and the other lever if the stimulus was KCl (0.05, 0.1, or 0.2 M). Responses were reinforced with water. After training, the average rate of correct responses was 90%. Performance was unchanged following sham surgery. Chorda tympani (CT) transection reduced average discrimination performance to 67.7% correct, and extirpation of the sublingual and submaxillary salivary glands reduced average performance to 80% correct. Although selective desalivation moderately reduced discriminability, a disrupted salivary environment does not explain the effects of CT transection. More likely, the discrimination deficit in CT-transected rats reflects a loss of critical taste input conveyed by the CT about salts.

Sucrose vs. maltose taste discrimination by rats depends on the input of the seventh cranial nerve.

Although rats treat the taste of sucrose and maltose as perceptually similar, they nonetheless appear to be able to distinguish between the two sugars, as suggested from prior work examining the cross-generalization of conditioned taste aversions. This study explictly tested whether rats could behaviorally discriminate sucrose from maltose and examined the relative importance of the gustatory input of the seventh and ninth cranial nerves in maintaining such performance. Water-restricted rats were presurgically trained in a conditioned avoidance task to suppress licking to sucrose or maltose and to maintain licking to the other sugar. Concentration (0.05, 0.1, 0.2, and 0.4 M) was varied to make intensity an irrelevant cue. Stimuli were randomly presented in 5-s trials during 50-min sessions. Bilateral transection of the chorda tympani nerve (CT) or the glossopharyngeal nerve or sham surgery did not disrupt discrimination performance. In contrast, combined transection of the CT and greater superficial petrosal nerve, which collectively removes the taste input of the seventh cranial nerve, caused severe impairments in sugar discriminability. In these rats, performance was more disturbed at the lower concentrations. These findings confirm that rats can discriminate sucrose from maltose and that this capability relies heavily on the taste input of the seventh cranial nerve. Although the input of the ninth cranial nerve is unnecessary, it may help sustain partial competence in this task, especially at high concentrations, in the combined absence of the CT and greater superficial petrosal nerve.

Chorda tympani nerve transection disrupts taste aversion learning to potassium chloride, but not sodium chloride.

In Experiment 1, rats with chorda tympani nerve transection (CTX) acquired a LiCl-conditioned taste aversion to 0.1 M NaCl at the same rate as controls. After 3 conditioning trials, the aversion generalized to 0.03 and 0.3 M NaCl, but did not generalize to KCI (0.03, 0.1, and 0.3 M), in either the sham or CTX group. In Experiment 2, the sham group, but not the CTX group, formed an aversion to 0.1 M KCI after 1 trial. The CTX rats did form a moderate aversion after 2 conditioning trials. Following the 3rd trial, the CTX group did not suppress licking to 0.03 or 0.3 M KCI or any concentration of NaCl in relation to controls. Although there is strong evidence that CTX affects NaCl taste perception, these findings indicate that, under certain conditions, rats can nonetheless distinguish NaCl from KCI after such neurotomy. Moreover, CTX appears to have a substantial effect on the perceived intensity of KCl.

Amiloride is an ineffective conditioned stimulus in taste aversion learning.

The present study demonstrated that 100 microM amiloride serves as an ineffective conditioned taste stimulus in a taste aversion paradigm. Even if amiloride has a detectable taste, it's unlikely that its behavioral effects in salt mixture experiments are due to its inherent taste quality.

Salt discriminability is related to number of regenerated taste buds after chorda tympani nerve section in rats.

Transection of the chorda tympani nerve (CTX) impairs taste-guided discrimination of NaCl from KCl in rats. We wanted to determine whether this discrimination recovers after chorda tympani regeneration. Experiment 1 showed that few taste buds regenerated 14 days after CTX, whereas substantial regeneration occurred 42 days after surgery. Experiment 2 demonstrated that rats trained before CTX could clearly discriminate the two salts when tested starting 49 days after surgery, whereas rats tested starting 8 days after surgery were severely impaired in this task. Rats tested starting 28 days after CTX were unimpaired, moderately impaired, or severely impaired on the discrimination task. Overall, discrimination performance was significantly related to the number of regenerated taste buds. Unilaterally transected rats tested shortly after surgery were nearly as competent as controls. These results indicate that rats can recover the ability to discriminate NaCl from KCl after regeneration of anterior tongue taste buds.

Glossopharyngeal nerve transection does not compromise the specificity of taste-guided sodium appetite in rats.

The chorda tympani nerve (CT) has been shown to be critical in the sodium-specific drinking behavior of sodium-depleted rats, but the role of other gustatory nerves and the contribution of the major salivary glands remain to be elucidated. In this study, rats received either bilateral section of the CT (CTX) or the glossopharyngeal nerve (GLX), extirpation of the sublingual and submaxillary salivary glands (DSAL), or sham surgery. After recovery, rats were sodium depleted with furosemide and tested for their licking responses to 0.05 and 0.3 M NaCl, KCl, CaCl2, and NH4Cl, as well as distilled water in an automated gustometer. Rats that received GLX maintained a specific sodium appetite comparable to controls despite denervation of approximately 64% of the taste buds. In contrast, compared with control rats, CTX and DSAL rats had altered response profiles, showing much smaller differences in licking to NaCl relative to the other stimuli. This was accompanied by a substantially lower lick rate in DSAL rats, raising the possibility that general licking impairments contributed to the decreased NaCl responsiveness in these rats. These findings imply that the CT, but not the glossopharyngeal nerve, is necessary for the maintenance of normal sodium-specific, taste-guided behavior under sodium deplete conditions.