title: Sleep homeostasis and depression: studies with the rat clomipramine model of depression.
abstract: Neonatal treatment of rat pups with clomipramine (CLI) has been shown to cause long-lasting and persistent depression-related behaviors and changes in sleep architecture and in brain-derived neurotrophic factor (BDNF) signaling in adult animals, producing an animal model of depression. However, the molecular mechanisms which mediate these effects of early-life CLI treatment on adult animals remain largely unknown. In order to characterize these further, we investigated in neonatally CLI-treated rats the sleep architecture as well as the extracellular and cellular levels of sleep regulators (nitric oxide, adenosine) and BDNF, respectively, in the basal forebrain (BF), i.e. the brain area which is implicated in sleep and depression. We found that CLI-treated rats exhibited a disturbed sleep architecture (REM sleep fragmentation was increased and NREM periods preceding REM were shorter) and reduced levels of BDNF and adenosine in the BF, whereas the levels of nitric oxide were elevated. Next, we examined sleep deprivation (SD)-induced homeostatic responses on sleep regulation and brain BDNF levels in CLI-treated rats. Compared to control rats, 3h of SD induced a smaller increase in the amount of NREM sleep during sleep recovery. At the molecular level, the normal homeostatic response was dissociated: the rise in the adenosine level was not accompanied by a rise in the nitric oxide concentration. Moreover, while BF BDNF levels decreased during SD in control rats, such a decline was not observed in CLI rats. Taken together, neonatal CLI treatment produces long-lasting functional changes in the sleep architecture and sleep regulation in adult rats, accompanied by dysregulated BDNF signaling in the BF.
authors.affiliation: Institute of Biomedicine, Department of Physiology, University of Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland. sergey.saveljev@gmail.com
authors.forename: S A
authors.initials: SA
authors.lastname: Savelyev
authors.forename: T
authors.initials: T
authors.lastname: Rantamäki
authors.forename: K-M
authors.initials: KM
authors.lastname: Rytkönen
authors.forename: E
authors.initials: E
authors.lastname: Castren
authors.forename: T
authors.initials: T
authors.lastname: Porkka-Heiskanen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002997:Clomipramine / Q000494:pharmacology*; D003866:Depressive Disorder / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016548:Prosencephalon / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012895:Sleep, REM / Q000187:drug effects* / Q000502:physiology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002997:Clomipramine