HS 014

Compulsive behavior is a debilitating clinical feature of many forms of neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive spectrum disorders, eating disorders, and autism. Although several studies link striatal dysfunction to compulsivity, the pathophysiology remains poorly understood. Here, we show that both constitutive and induced genetic deletion of the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striatal electrophysiologic impairments in synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores normal weight and metabolic features of MC4R-null mice, a model of human obesity. Our findings offer insights into the pathophysiology and treatment of both compulsive behavior and eating disorders.

OBJECTIVE: Intestinal overproduction of atherogenic chylomicron particles postprandially is an important component of diabetic dyslipidemia in insulin-resistant states. In addition to enhancing insulin secretion, peripheral glucagon-like peptide-1 (GLP-1) receptor stimulation has the added benefit of reducing this chylomicron overproduction in patients with type 2 diabetes mellitus. Given the presence of central GLP-1 receptors and GLP-1-producing neurons, we assessed whether central GLP-1 exerts an integral layer of neuronal control during the production of these potentially atherogenic particles.

Melanocortin receptor four (MC4R) is implicated in regulation of stress-related functions. We previously demonstrated that intranasal infusion of MC4R antagonist HS014, shortly before single prolonged stress (SPS) animal model of post-traumatic stress disorder, lessened the development of anxiety- and depression-like behavior depending on the dose. Here, we evaluated effects of HS014 on SPS-elicited changes in hypothalamic-pituitary-adrenal axis and expression of several genes of interest in mediobasal hypothalamus, hippocampus, and locus coeruleus. Rats were given intranasal infusion of HS014 (3.5 ng or 100 μg) and 30 min later subjected to SPS stressors. Short-term responses of HS014 rats in comparison with vehicle-treated, evident 30 min following SPS stressors, included smaller rise in plasma corticosterone (100 μg HS014), absence of induction of corticotrophin-releasing hormone mRNA in mediobasal hypothalamus and of mRNA for tyrosine hydroxylase and dopamine-β hydroxylase in locus coeruleus.

Although the role of alpha-melanocyte stimulating hormone (α-MSH) in alcohol seeking behaviour in rats has been demonstrated, the underlying mechanisms are not understood. Herein, we test the hypothesis that α-MSH might have a permissive effect in promoting the reward action of ethanol. Rats were implanted with cannulae targeted at the posterior ventral tegmental area (pVTA), because the site is sensitive to reinforcing effects of ethanol. These rats were trained to self-administer ethanol in standard two-lever (active/inactive) operant chamber test. Each active lever press resulted in self-administration of 100 nl of ethanol (100-300 mg%) containing solution. Over a period of 7 days, ethanol significantly increased the number of lever presses, which was considered as a measure of reward. Because ethanol at 200 mg% resulted in maximum number of lever presses (∼18-20 lever presses/30-minute session), the dose was employed in further studies.