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.

Effects of serotonin 1A or 1B receptor agonists on social aggression in male and female Syrian hamsters.

Numerous studies have demonstrated that activation of serotonin 5-HT1A or 5-HT1B receptor decreases aggression in male mammals. To determine whether female mammals also show decreased aggression in response to 5-HT1A or 5-HT1B activation, we assessed the effects of the serotonin receptor agonists 8-OH-DPAT (5-HT1A) and CGS-12066A (5-HT1B) on aggression in female Syrian hamsters. Female Syrian hamsters were tested for interfemale aggression 2 days before and 15 min after receiving intracerebroventricular infusions of 8-OH-DPAT (5, 10, 20 microg) or CGS-12066A (5, 10, 20 microg). Neither drug affected aggression as measured by the latency and frequency of attacks or uprights, although the highest dose of 8-OH-DPAT increased general activity. For male hamsters, intraventricular infusions of 10 microg of 8-OH-DPAT essentially eliminated aggression, whereas 5 microg of 8-OH-DPAT or 20 microg of CGS-12066A were without effect. Systemic treatment with 8-OH-DPAT (1 mg/kg body weight) did reduce aggression in females, although there was an attendant increase in symptoms of nonspecific serotonergic activity. There were no behavioral effects of systemic CGS-12066A (4 mg/kg body weight) on female hamsters. These results indicate that there may be sex differences in the neurochemical regulation of aggression and point to a need for more studies directed at this issue.

Dopamine receptor antagonists attenuate conditioned place preference following sexual behavior in female Syrian hamsters.

We assessed the effects of the dopamine D2 receptor antagonists, sulpiride and raclopride, on conditioned place preference produced by sexual behavior in female Syrian hamsters. Female hamsters treated with sulpiride or raclopride showed high levels of sexual behavior (lordosis) that were equivalent to control females receiving vehicle injections. The degree of place preference conditioning for sulpiride-treated females was marginally reduced, whereas females treated with raclopride showed no evidence of conditioning. These results indicate that conditioned place preference is a useful means for probing the appetitive components of female sexual behavior, and that dopamine D2 receptors are involved in this appetitive process.

-Fos expression in female hamster brain following sexual and aggressive behaviors.

The goal of these experiments was to use c-Fos immunocytochemistry to determine areas of the female hamster brain that are active during lordosis and aggression. Ovariectomized hamsters were given (i) estradiol and progesterone, plus a lordosis test, (ii) estradiol and progesterone, but no lordosis test, (iii) oil, plus an aggressive behavior test, or (iv) oil, but no behavior test. Results showed that following lordosis, there was increased c-Fos expression in the medial bed nucleus of the stria terminalis, medial accumbens, medial preoptic nucleus, paraventricular nucleus and medial amygdala. Following a single aggression test, c-Fos was significantly increased only within the medial amygdala. There was no effect of lordosis or aggression on c-Fos expression within the lateral or central ventromedial hypothalamus, suprachiasmatic nucleus or dorsal midbrain central gray. In a second experiment, ovariectomized female hamsters were given (i) repeated aggressive experience, (ii) a single aggression test or (iii) no aggression test. Because some females were not aggressive towards males, they became a separate group post hoc. The number of cells expressing c-Fos was higher in the medial preoptic nucleus and medial amygdala of females given a single aggressive test and in non-aggressive females vs control females. Females given prior aggressive experience showed higher c-Fos expression only in the medial preoptic nucleus. These results demonstrate that increased neural activation in several forebrain nuclei is seen after sexual or aggressive behaviors in female hamsters. However, because the pattern of c-Fos staining in the non-aggressive females was similar to the pattern in aggressive females, this questions previous conclusions regarding the behavioral specificity of these effects and suggests instead that such activation is common to social interactions in general.

Conditioned place preference in female hamsters following aggressive or sexual encounters.

Prior studies have demonstrated the utility of conditioned place preference procedures for examining the motivational or rewarding properties of behavior. The purpose of this experiment was to assess whether female Syrian hamsters would show evidence of conditioned place preference for aggression or sexual behaviors. Weekly conditioning sessions were conducted for three groups of female hamsters for 5 weeks. One group of female hamsters engaged in sexual activity with a male hamster in the gray compartment of a place preference apparatus. A second group of females experienced aggressive interactions with a male when placed together also in the gray compartment. Females in each of these conditioning groups were placed alone in the white compartment within 1 h of the behavioral interactions. A control group of hormone-treated females was placed alone in both compartments of the apparatus. Following the conditioning sessions, all females were given free access to the conditioning apparatus. Females with prior sexual or aggressive experience spent significantly more time in the gray compartment than they did before conditioning. Control females did not show any significant change in their preference for either compartment of the apparatus. The results suggest that female hamsters prefer an environment associated with the prior rewarding properties of sexual or aggressive interactions.