Circadian modulation of the ryanodine receptor type 2 in the SCN of rodents.

We examined the temporal modulation of intracellular calcium release channels in the suprachiasmatic nucleus (SCN). We found a circadian rhythm in [3H]ryanodine binding that was specific to the SCN. The peak in the rhythm occurred at CT 7 and was due to an increase in Bmax, which correlated well with immunoblots showing an increase in RyR-2 expression in the SCN. Double immunohistochemical studies showed that RyR-2 was expressed exclusively in neurons. Ryanodine and caffeine applied around CT 7-9 advanced the clock phase in a hamster brain slice preparation. No rhythm of IP3R was seen in any of the brain areas studied. Our results indicate that RyR-2 exhibits an endogenous rhythm, which influences the intracellular calcium dynamics and thus modulates SCN activity.

Neuronal subpopulations in the suprachiasmatic nuclei based on their response to retinal and intergeniculate leaflet stimulation.

In order to characterize how suprachiasmatic nuclei (SCN) neurons integrate its visual inputs, extracellular responses from SCN and adjacent hypothalamic neurons were recorded after stimulation of either the retina, the intergeniculate leaflet (IGL) or both simultaneously. Individual stimulation of either structure elicited excitatory or inhibitory responses in 36% of SCN and 20% of non-SCN neurons. Three subpopulations of SCN neurons were found, the first two responding exclusively either to the retina or the IGL, and the third responding to both the retina and the IGL. Simultaneous stimulation of the retina and the IGL induced a change in the firing pattern of some SCN neurons, which suggests modulatory regulation of SCN neuronal activity by synaptic interactions between its visual inputs.

Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.

Effects of biperiden on sleep at baseline and after 72 h of REM sleep deprivation in the cat.

We examined the effects of the muscarinic M1 antagonist biperiden in cats. In the first experiment a dose-response analysis was performed with intraventricular injection (IV ventricle) of biperiden. In the second experiment after REM sleep deprivation cats were injected with either biperiden (0.1 mg/kg) or saline. Biperiden produced a reduction in REM sleep percentage and an increase in REM sleep latency with these high doses. The 0.1 mg/kg biperiden dose, which did not suppress REM sleep at baseline, did reduce the REM sleep rebound. The present study suggests a modulatory role of biperiden on REM sleep regulatory processes. The fact that an effect of biperiden is noted only at the high doses suggests that at these doses the drug is influencing non-M1 receptors. Changes in the sensitivity of these receptors as a result of REM sleep deprivation might explain why a dose of biperiden will reduce REM sleep rebound, while being ineffective in suppressing REM sleep at baseline.

Rapid eye movement (REM) sleep increases by auditory stimulation reverted with biperiden administration in normal volunteers.

Auditory stimulation during REM sleep increases REM sleep time. The purpose of the present work was to determine if the selective muscarinic M-1 antagonist biperiden could modify the effect of the auditory stimulation on REM sleep. Twelve healthy volunteers were divided into placebo and biperiden groups. All the volunteers were studied under sleep laboratory conditions as follows: one acclimatization night, one baseline night, four nights with auditory stimulation either with placebo or biperiden, and two follow-up nights. Biperiden (4 mg) or placebo in identical capsules was administered 1 hour before beginning the sleep recordings. REM sleep time and REM density in the placebo group were increased relative to baseline by auditory stimulation. Biperiden blocked the REM time increase over the three treatment nights and suppressed the REM density increase over all four treatment nights. Biperiden also increased the latency compared to the placebo group. The present findings suggest that M-1 mechanisms are related to REM sleep regulation.

Effects of auditory stimulation during rapid eye movement sleep in healthy volunteers and depressed patients.

Auditory and somesthesic forms of stimulation have substantially increased rapid eye movement (REM) sleep in cats. We investigated whether auditory stimulation, applied during REM sleep or outside REM sleep, would have similar effects in normal volunteers. We also administered auditory stimulation to depressed patients during REM sleep. Subjects were studied during 1 acclimatization night, 2 baseline nights, 4 consecutive nights with auditory stimulation, and 1 followup night without auditory stimulation. Normal volunteers were randomly divided into Group R, which received auditory stimulation during each REM sleep episode, and Group NR, which received auditory stimulation at the end of each REM sleep episode. Depressed patients (Group D) received auditory stimulation during each REM sleep period. Only Group R showed increased REM sleep time during the nights of auditory stimulation and throughout the followup night. This group also increased their sleep efficiency. Group NR showed reduced sleep efficiency due to an increase in both the duration and frequency of awakenings. Group D did not show increased REM sleep time, but did show shortened REM sleep episodes, increased REM sleep frequency, and increased duration of awakenings. Group D did not show clinical changes.

Biperiden administration in normal sleep and after rapid eye movement sleep deprivation in healthy volunteers.

Twenty-six healthy volunteers were randomly assigned to one of four groups. Groups Bip-4 and Bip-6, each with six subjects, received 4 and 6 mg of biperiden, respectively, and were studied on acclimatization, baseline, biperiden, and follow-up nights. Group REM-P (n = 7) and Group REM-Bip (n = 7) were studied on acclimatization, baseline, six nights of REM sleep deprivation, and one recovery (treatment) night with either placebo (group REM-P) or biperiden (group REM-Bip), and one follow-up night. Biperiden 4 and 6 mg increased REM sleep latency and biperiden 6 mg reduced REM sleep time. On the recovery night following REM sleep deprivation Group REM-P and REM-Bip showed an increase in sleep continuity. REM sleep time in the REM-P group was increased during the recovery (treatment) night (REM sleep recovery), while the REM-Bip group did not show a significant REM sleep increase during recovery (treatment) night. It was not until the follow-up night that REM sleep increased in the REM-Bip group.

Effects of physostigmine infusion on healthy volunteers deprived of rapid eye movement sleep.

Rapid eye movement sleep (REMS) deprivation is believed to alter the sensitivity of various neurotransmitter systems. In the present article, we studied 20 healthy volunteers divided into three groups. Group A attended the sleep laboratory for three nights: acclimatization, a baseline night, and one night of physostigmine infusion. Group B attended for eight nights; acclimatization, baseline, four nights of REMS deprivation, and two recovery nights. With the exception of the first recovery night, when group C volunteers were administered physostigmine, group C's schedule was identical to group B's. The infusions received by group A and C were composed of 1.0 mg of physostigmine, dissolved in 100 ml of saline solution. These were administered 5 min after sleep onset and thereafter every hour, except when the subjects were either awake or in REMS. All of the subjects receiving the cholinomimetic infusion were given a peripheral anticholinergic. Group A experienced a great number of awakenings with a decrease in REMS percentage. Group B recovery occurred over two nights, with an increase in the average length of REMS. Group C exhibited maximum REMS rebound on the first recovery night with an increased number of REMS episodes, as well as significant reductions in the first REMS latency. Our findings suggest that physostigmine alters REMS rebound following REMS deprivation.