The melanocortin melanocyte-stimulating hormone/adrenocorticotropin(4-10) decreases body fat in humans.

The control of body fat is a prominent factor in human health. Animal studies have indicated a homeostatic central nervous system regulation of body fat with particular involvement of the melanocortin receptor pathway. This study provides evidence for a similar role for melanocortins in the long-term control of fat stores in humans. Thirty-six normal weight humans were assigned to one of three experimental groups. After a 4-week baseline, one group was treated with MSH/ACTH(4-10) (MSH/ACTH(4-10)) representing the core sequence of all melanocortins. Another group received desacetyl-alphaMSH, a selective agonist of the brain melanocortin-4 receptor, which shares the 4-10 sequence with MSH/ACTH(4-10). The third group received placebo. Treatments were given intranasally twice daily for 6 weeks, at equimolar doses (MSH/ACTH(4-10), 0.5 mg; desacetyl-alphaMSH, 0.84 mg). Body weight, body composition, and plasma hormone concentrations were measured before and after treatment. MSH/ACTH(4-10) reduced body fat, on the average, by 1.68 kg (P < 0.05) and body weight by 0.79 kg (P < 0.001). Concurrently, plasma leptin levels were decreased by 24% (P < 0.02), and insulin levels were decreased by 20% (P< 0.05) after MSH/ACTH(4-10). Changes after desacetyl-alphaMSH remained nonsignificant. The finding of reduced body adiposity after MSH/ACTH(4-10) confirms and extends to the human the findings of animal models indicating an essential role of the hypothalamic melanocortin system in body weight control.

Signs of sexual behaviour are not increased after subchronic treatment with LHRH in young men.

Apart from its action as gonadotropin releasing factor, luteinizing hormone-releasing hormone (LHRH) is a potent regulator of sexual behaviour in animals. The present study aimed to assess a similar role of LHRH for sexuality in humans. In a double-blind placebo-controlled and randomized study, effects of human LHRH after acute (400 microg) and subchronic (800 microg/day over 2 weeks) intranasal administration were evaluated in 20 young and healthy men. Sexual desire and activity was assessed by a diary, ratings of women's attractiveness, a modified version of the Stroop colour naming task and a short term memory task. Effects on sexuality were contrasted with those on eating motivation and general neurocognitive functioning, the latter being assessed in addition by tasks of divergent thinking and a motor perseveration test. None of the measures of sexual desire and activity indicated any effect of LHRH, neither after acute nor after subchronic treatment. Unexpectedly, the diary indicated a significant increase in 'food intake' towards the end of the 14-day LHRH treatment. Enhanced colour naming performance on the Stroop task (independently of whether sex, food or neutral stimuli were used) in conjunction with an increased motor perseveration after LHRH points to a general effect on cognitive function towards stronger focussing of cortical processing. While overall the data show discrete central nervous changes after LHRH, a particular influence on sexuality after acute or subchronic intranasal administration in healthy men was not detected.

Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology?

Given the tremendous number of neuropeptides, which are synthesized in the central nervous system, the brain can be viewed as one of the most prominent endocrine organs. Elucidation of the functions of these peptides is hampered by the facts that after intravenous administration access to brain receptors is prevented or impaired by the blood-brain barrier. Here, we provide evidence that intranasal administration can be a way to circumvent the blood-brain barrier. Selected experiments will be reported indicating that peptides after intranasal administration in humans can specifically alter a great variety of brain functions. For vasopressin, we demonstrated improving effects of long-term intranasal treatment on sleep in elderly people. Insulin showed improving effects of short-term memory functions. For adrenocorticotropin/melanocyte stimulating hormone, ACTH/MSH-(4-10), a twofold action was isolated: The melanocortin fragment diminished selective attention and, with subchronic administration, reduced body fat. These results could provide the basis for developing a new, specific, and "soft" neuropharmacology.

Brain potentials and attention after acute and subchronic intranasal administration ofACTH 4-10 and desacetyl-alpha-MSH in humans.

Neuropeptides related to adrenocorticotropin (ACTH) are potent regulators of neurobehavioral functions. In humans, ACTH and its behaviorally active fragment ACTH 4-10 have been consistently found to diminish event-related brain potential (ERP) signs of focussing attention. This study aimed at (1) evaluating effects of ACTH 4-10 on ERP indicators of attention in healthy controls after intranasal administration of the peptide. This route of administration has been proposed to provide a more direct access to the brain than the intravenous administration of the peptide, (2) comparing acute effects and effects of a subchronic treatment with ACTH 4-10, and (3) comparing effects of ACTH 4-10 with those of desacetyl-alpha-MSH (corresponding to ACTH 1-13 amide) which like ACTH 4-10 binds to subgroups of the melanocortin receptor family. Double-blind placebo-controlled experiments were completed in 54 healthy young subjects. ERPs were recorded while the subject performed an auditory selective attention task. Moreover, a modified Stroop interference test including motivational (food, sex) and nonmotivational words was performed. Acute intranasal administration of ACTH 4-10 (1 mg) reduced the processing negativity (PN) of the ERP over frontal and central cortical areas (p < 0.05) indicating diminished focussing of attention. Moreover, on this condition subjects were more prone to interference on the Stroop task especially with motivational words (p < 0.05). Subchronic administration of ACTH 4-10 (1 mg/day over 6 weeks) did not affect PN and Stroop performance. Acute intranasal administration of desacetyl-alpha-MSH at equimolar doses (1.68 mg) also remained ineffective. However, some measures of Stroop performance appeared to improve after subchronic desacetyl-alpha-MSH treatment. Results confirm an acute decrease in focussing of attention after ACTH 4-10. These effects of intranasal administration are likely to reflect a direct action of the peptide on respective brain functions. Moreover, they were specific to ACTH 4-10 and were not obtained after equimolar doses of desacetyl-alpha-MSH, thus excluding a mediation via the known melanocortin receptors.

Enhanced selective attention after low-dose administration of the benzodiazepine antagonist flumazenil.

Although recognized for their sedative properties, benzodiazepines are also known to impair sustained and selective attention. Flumazenil at low doses may act to antagonize benzodiazepine-induced effects. This study examined whether low doses of flumazenil would improve event-related brain potential (ERP) indicators of selective attention and induce feelings of activation and anxiety in healthy men. Data from 11 men (24-30 years) who received intravenous flumazenil (0.2 mg, plus 0.3 mg 30 minutes later) and placebo were analyzed according to a double-blind crossover design. ERPs were recorded while subjects performed an auditory selective attention task. Mismatch negativity (MMN), processing negativity (PN), and the P3 component were extracted from the ERP as markers of preattentive mismatch processing, selective attention, and stimulus processing within working memory, respectively. Counting accuracy and performance on a letter cancellation test were used as behavioral indicators of attention. Mood was assessed by an adjective checklist and the State-Trait Anxiety Inventory. Flumazenil significantly increased PN over frontocortical areas, indicating improved selective attention (p < 0.05). Increases in the P3 amplitude and MMN after drug treatment remained nonsignificant. Subjects felt more activated and extraverted after flumazenil treatment than after placebo (p < 0.05). Anxiety was not increased. The findings of this study confirm the concept that flumazenil administered at a low dose in humans exerts effects opposite to those of benzodiazepines.

Event-related brain potentials and working memory function in healthy humans after single-dose and prolonged intranasal administration of adrenocorticotropin 4-10 and desacetyl-alpha-melanocyte stimulating hormone.

Neuropeptides of the adrenocorticotropin/melanocorticotropin (ACTH/MSH) family are most potent modulators of cognitive function. Their neurobehavioral activity is principally encoded in the 4-10 fragment of the ACTH/MSH molecule; in humans, it has been shown to pertain primarily to functions of attentive stimulus/response processing. The aims of this study were (1) to examine the effects of ACTH 4-10 on event-related brain potentials (ERPs) and behavioral indicators of stimulus encoding within the working memory; (2) to compare the effects after a single dose and after prolonged treatment with ACTH 4-10; and (3) to compare the effects of ACTH 4-10 with those of desacetyl-alpha-MSH (i.e., ACTH 1-13 amide), which, like ACTH 4-10, binds to the known brain melanocortin receptors (MC-Rs) but with distinctly higher affinity. Double-blind, placebo-controlled experiments were performed in 60 healthy control subjects. The authors monitored ERPs and reaction times while these subjects performed an auditory vigilance task ("oddball"). Recall was tested on a verbal short-term memory task including different word categories (neutral, rare, food, sex). After a single (1 mg) as well as prolonged intranasal administration (1 mg/day over a period of 6 weeks), ACTH 4-10 enhanced the positive slow wave in ERPs to target stimuli of the vigilance task (p < 0.05), but left classic P3 unaffected. Moreover, single-dose and prolonged administration of ACTH 4-10 increased the rate of false responses during vigilance (p < 0.01). In the short term, ACTH 4-10 also impaired recall of neutral words (p < 0.05). Equimolar doses of desacetyl-alpha-MSH did not influence ERPs, neither after a single dose nor after prolonged treatment. Similar to ACTH 4-10, desacetyl-alpha-MSH increased the error rate during vigilance and acutely impaired the recall of neutral words. The increase in ERP slow-wave positivity, in conjunction with behavioral impairments after treatment with ACTH 4-10, complemented previous results of inferior focusing of attention and a less concise structure of thought after administration of ACTH 4-10. The changes indicated an impairment in differential processing of relevant versus irrelevant contents within the working memory, and, in this regard, might mimic aspects of psychopathologic disturbances of attention and thought processes. Their persistence after prolonged treatment with ACTH 4-10 suggests an activation of mechanisms subserving the consolidation of the peptide's effects. The poor efficacy of desacetyl-alpha-MSH suggests that the known MC-Rs may be irrelevant for mediating cognitive effects of this neuropeptide family.