Research reportHuman sleep EEG following the 5-HT1A antagonist pindolol: possible disinhibition of raphe neuron activity
Introduction
The profile of the β1/2-blocker pindolol includes antagonism at 5-hydroxytryptamine (5-HT)1A/1B receptors [30]. In laboratory animals, pindolol inhibits the suppression of post-synaptic 5-HT release elicited by 5-HT1A agonists [51], and enhances post-synaptic 5-HT release elicited by selective serotonin reuptake inhibitors 7, 17, 28. Because 5-HT neurons in the midbrain raphe nuclei are inhibited by 5-HT1A receptors located on their soma and dendrites, these effects are most likely mediated through blockade of these autoreceptors. Pindolol has attracted major attention in recent years because of reports that it may hasten the antidepressant efficacy of selective serotonin reuptake inhibitors 2, 10. Converging evidence, from preclinical work, suggests that the underlying mechanisms include (possibly selective) blockade of the autoinhibitory action of somatodendritic 5-HT1A receptors [3].
The sleep electroencephalogram (EEG) may be utilized as a pharmacodynamic assay in humans. Rapid-eye-movement (REM) sleep, presumptively, is controlled by two neuronal groups in the brainstem, REM-on and REM-off cells. Increased activity of cholinergic/cholinoceptive REM-on cells in the pedunculopontine/laterodorsal tegmental (PPT/LDT) nuclei is believed to initiate and maintain REM sleep [31]. Activity of monoaminergic REM-off cells projecting to REM-on zones 22, 29, on the other hand, is reduced prior to and during REM sleep, including firing of serotonergic neurons in the dorsal raphe nucleus [38]and of norepinephrinergic neurons in the locus coeruleus [5]. Located post-synaptically on pontine REM-on cells, activated 5-HT1A receptors lead to hyperpolarization 34, 35, and, presumptively, are involved in the inhibitory control of REM sleep [48]. This may explain why systemically administered 5-HT1A agonists inhibit REM sleep in animals 40, 45, 54and humans 18, 24, 25. Consistent with the self-inhibition of 5-HT neurons through somatodendritic 5-HT1A receptor activation in the dorsal raphe [52]and the inhibitory effects of serotonergic activity on REM sleep, perfusion of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the dorsal raphe nucleus produces, concomitant with a decrease in extracellular 5-HT, an enhancement of REM sleep [44].
In addition, power spectra alterations in the EEG during non-REM sleep may be utilized for pharmacodynamic characterization of serotonergic compounds. For instance, consistent evidence suggests that antagonists at 5-HT2 receptors increase slow-wave sleep (reviewed in [19]) and produce an EEG power spectrum that is characterized by a (rather unique) bimodal enhancement of activity in the δ/θ-frequency range in rats [13]and in humans [16]. Serotonin1A and 2 receptors appear to exert complementary interactions. Hyperpolarizations mediated by post-synaptic 5-HT1A receptors modulate the effects of depolarizing 5-HT2 receptors with which they are colocalized on the same cells in various brain regions [1]. We have recently shown in humans that the systemic application of the 5-HT1A agonist ipsapirone produced an EEG power spectrum during non-REM sleep that was almost identical to that found following a 5-HT2 antagonist [49]. This effect, we suggested, resulted from activation of pre-synaptic 5-HT1A receptors in the raphe nuclei – leading to an inhibition of 5-HT neuron firing and, consequently [50], to a decrease of serotonin release at projection sites – and/or activation of post-synaptic 5-HT1A receptors producing heterologous inhibition of 5-HT2 receptors.
Previous studies in humans have found a suppression of REM sleep and a decrease in sleep continuity after either a 1-week [32]or a single administration of pindolol [18]. However, while the first study described chronic effects of pindolol, the latter study provided only preliminary non-standardized data from EEG records. The present study was carried out to analyze dose-dependent effects of pindolol on REM sleep and on the non-REM sleep EEG power spectrum. In an attempt to disentangle the β-adrenergic properties of pindolol from its 5-HT-ergic properties, we also studied the effects of the selective β1-adrenoceptor antagonist betaxolol which is devoid of serotonergic affinity [30].
Section snippets
Subjects
Twelve healthy male subjects (mean±S.D. age 30.8±7.7, range 24–45 years) were enrolled. Written informed consent was obtained following approval by the internal review board of the University of California, San Diego. The standard screening protocol entailed extensive physical and psychiatric examinations, and laboratory work-ups, as described previously [25].
Protocol
The first 2 nights of sleep recordings in the laboratory served to habituate the subjects to the experimental conditions and to exclude
Sleep architecture and continuity
The results of the visual scoring of the sleep EEG records are summarized in Table 1 and Fig. 1. Significant F ratios were obtained for sleep latency (time between lights out and occurrence of stage 2 or REM sleep), total sleep time, sleep efficiency (total sleep time/time in bed, in %), wake-time after sleep onset, duration of stage 2 sleep, REM latency, REM sleep duration, and REM density (visually estimated measure of ocular activity during REM sleep, scored on a scale of 0–4/30-s epoch, but
Discussion
The main findings of the present study are that pindolol suppressed REM sleep in a dose-related fashion, and, on a descriptive level, produced at the higher dose an attenuation of EEG spectral power in portions of the δ, θ, and α frequencies. No such changes were found following betaxolol administration. No peripheral effects of either pindolol or betaxolol were observed. Because of pindolol's mixed serotonergic/adrenergic profile, the results will be discussed separately for each system.
Acknowledgements
Research was supported by Swiss National Science Foundation, Ciba-Geigy-Jubiläums Stiftung, Janggen Pöhn Stiftung, Freiwillige Akademische Gesellschaft Basel, Wilhelm Doerenkamp Stiftung, Lundbeck Schweiz (to E.S.), UCSD GCRC (Dr. M. Ziegler, MOI RR00827), NIMH Nos. 30914, 18394, 18399, and 38738, and Department of Veterans Affairs (to J.C.G.). We thank D. Greenfield, A. Schlosser and the other members of the UCSD MHCRC and the sleep laboratory for their invaluable contributions, and P.L.
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