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) fam ily are most potent modulators of cognitive function. Their neurobehavioral activity is principally encoded in the 4-10 fragment of the ACTH/MMSH mole cule; in humans, it has been shown to pertain primarily to functions of att entive stimulus/response processing. The aims of this study were (1) to exa mine the effects of ACTH 4-10 on event-related brain potentials (ERPs) and behavioral indicators of stimulus encoding within the working memory; (2) t o compare the effects after a single dose and after prolonged treatment wit h ACTH 4-10; and (3) to compare the effects of ACTH 4-10 with those of desa cetyl-alpha-MSH (i.e., ACTH 1-13 amide), which, like ACTH 4-10, binds to th e known brain melanocortin receptors (MC-Rs) but with distinctly higher aff inity. Double-blind, placebo-controlled experiments were performed in 60 he althy control subjects. The authors monitored ERPs and reaction times while these subjects performed an auditory vigilance task ("oddball"). Recall wa s tested on a verbal short-term memory task including different word catego ries (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 e nhanced the positive slow wave in ERPs to target stimuli of the vigilance t ask (p < 0.05), but left classic P3 unaffected. Moreover, single-dose and p rolonged 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 rec all of neutral words (p < 0.05). Equimolar doses of desacetyl-alpha-MSH did not influence ERPs, neither after a single dose nor after prolonged treatm ent. Similar to ACTH 4-10, desacetyl-alpha-MSH increased the error rate dur ing vigilance and acutely impaired the recall of neutral words. The increas e in ERP slow-wave positivity, in conjunction with behavioral impairments a fter treatment with ACTH 4-10, complemented previous results of inferior fo cusing of attention and a less concise structure of thought after administr ation of ACTH 4-10. The changes indicated an impairment in differential pro cessing of relevant versus irrelevant contents within the working memory, a nd, in this regard, might mimic aspects of psychopathologic disturbances of attention and thought processes. Their persistence after prolonged treatme nt with ACTH 4-10 suggests an activation of mechanisms subserving the conso lidation of the peptide's effects. The poor efficacy of desacetyl-alpha-MSH suggests that the known MC-Rs may be irrelevant for mediating cognitive ef fects of this neuropeptide family.