title: Selective alterations of the first NREM sleep cycle in humans by a dopamine D1 receptor antagonist (NNC-687).
abstract: This paper details the first study of the effects of dopamine D1 receptor antagonism on the regulation of human sleep EEG (electroencephalogram). The investigational drug NNC-687 (NNC 01-0687/CEE 03-310) was administered to 20 healthy young men in doses of 5, 10, and 15 mg in a double blinded, placebo controlled, crossover design. In rats, dopamine D1 receptor antagonism can produce large increases in the amounts of both rapid eye-movement (REM) and non-rapid eye-movement (NREM) sleep. In this study, drug effects were most prominent in the first NREM period. D1 antagonism markedly reduced the peak-amplitude of delta EEG waves but increased their instantaneous frequency as well as enhancing the total number, incidence, and burst-duration of sleep spindles. The length of the first NREM period was increased up to 47% over baseline. Despite these large increases in NREM sleep time, the amount of delta EEG power accumulated over the first NREM period was conserved at baseline levels. We note that the sleep-EEG profile of D1 antagonism is very similar to that of GABAA (gamma-aminobutyric acid) receptor modulators and suggest that D1 antagonism may alter the properties of the neuronal networks which generate delta and spindle, and K-complex EEG waveforms through the upstream modulation of GABAA receptor activity.
authors.affiliation: Göteborg University, Institute of Clinical Neuroscience, Section of Clinical Neurophysiology, Blå Stråket 7, vån 3, SU/Sahlgrenska University Hospital, SE 413 45 Göteborg, Sweden. derek.eder@neuroscience.gu.se
authors.forename: Derek N
authors.initials: DN
authors.lastname: Eder
authors.forename: Milan
authors.initials: M
authors.lastname: Zdravkovic
authors.forename: Gordon
authors.initials: G
authors.lastname: Wildschiødtz
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D018592:Cross-Over Studies; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D006801:Humans; D008297:Male; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012016:Reference Values; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D012894:Sleep Stages / Q000187:drug effects
chemical_list: D001552:Benzazepines; D001572:Benzofurans; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; C077122:5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol; D004298:Dopamine