Long term blocking of GABA-A receptor in locus coeruleus by bilateral microinfusion of picrotoxin reduced rapid eye movement sleep and increased brain Na-K ATPase activity in freely moving normally behaving Rats

Abstract

Isolated studies showed that norepinephrinergic REM-OFF neurons are active throughout except during rapid eye movement (REM) sleep when they are inhibited possibly by GABA. Similarly, independent studies have also reported that during REM sleep deprivation those REM-OFF neurons continue firing, that there is increased norepinephrine (NE) in the brain and that increased levels of NE increases the Na-K ATPase activity in the brain. However, it was not known if all those changes were directly related to REM sleep deprivation, what could be the mechanism for such changes and their patho-physiological significance. To confirm the same, based on the reports, mostly from our group, it was hypothesised that GABA antagonist in the locus coeruleus (LC) should at least significantly reduce REM sleep and simultaneously increase Na-K ATPase activity in the brain. To confirm the proposed hypothesis, picrotoxin, a GABA-A receptor antagonist, was bilaterally microinjected every 6 h for 36 h into the LC of freely moving normally behaving rats and the effects on electrophysiological signals signifying sleep-wakefulness and on brain synaptosome Na-K ATPase activity were estimated. The microinjection was done with the help of a remote control pump without handling or disturbing the rats. The findings that REM sleep was significantly reduced and there was associated increase in Na-K ATPase activity confirmed our hypothesis. The results also support our modified (GABA-mediated) model of neural connections in the LC for the regulation of REM sleep. Also, this is probably the first report to simulate REM sleep deprivation using receptor antagonist.