Rapid Tryptophan Depletion Plus a Serotonin 1A Agonist Competing Effects on Sleep in Healthy Men

Abstract

In the present study, we hypothesized that the REMsuppressing effects of 5-HT 1A receptor stimulation would counteract the REM-disinhibiting effects of rapid tryptophan depletion (RTD), and vice versa. We administered RTD plus ipsapirone (10 mg, p.o.) The rapid tryptophan depletion (RTD) paradigm (Young et al. 1985;Delgado et al. 1990) allows researchers to study the consequences of 5-HT system deactivation. In humans and animals, RTD has been shown to cause significant (but transient) reductions in the levels of tryptophan (TRP) in the blood, and to reduce the amount of 5-HT in the brain (for review, see Moore et al. 2000). RTD typically consists of a day's worth of a low-TRP diet, followed by ingestion of a TRP-free amino acid load, and RTD, but not the control TRP-containing condition, has been associated with myriad clinical and physiological effects. Relapse of depressive mood following RTD in recently remitted depressed patients has been reported (Delgado et al. 1990). In healthy subjects, mood responses as well as other behavioral measures have been somewhat inconsistent (Young et al. 1985;Barr et al. 1997).The sleep abnormalities often associated with depression are consistent with the notion of a pathophysiologic deficiency in serotonergic function in depression (Maes and Meltzer 1995). There is strong preclinical and clinical evidence that serotonin plays a role in suppressing REM sleep (McGinty and Harper 1976;Honda and Semba 1994;Luebke et al. 1992;Portas et al. 1996).RTD apparently disinhibits REM sleep measures in serotonin reuptake inhibitor (SRI)-treated patients in full remission ) and in healthy male control subjects ), using two different The Effects of REM Sleep of RTD plus Ipsapirone S41 strengths of RTD (100% and 25%). In SRI-treated patients, both RTD doses also reversed the reduced total sleep time and prolonged sleep latency observed at baseline. In normal males, both RTD doses significantly decreased REM latency compared with baseline, as well as significantly reduced total and free plasma TRP concentrations.Agonists at the 5-HT 1A receptor, such as ipsapirone, have been shown to inhibit REM sleep both in healthy subjects and in depressed patients (Gillin et al. 1994;Gillin et al. 1996;, and this effect presumably reflects predominantly post-synaptic receptor activity. In the present study, we examined the competing effects of 5-HT depletion and 5-HT stimulation on sleep. We predicted REM sleep measures with RTD plus placebo would be significantly enhanced compared with baseline as shown in previous studies with RTD alone, and that the combination of RTD and ipsapirone would produce REM measures with values intermediate between those obtained with either 5-HT manipulation alone. METHODS SubjectsTen healthy male subjects between the ages of 20 to 39 years (28.7 Ϯ 1.9, mean Ϯ SD) were recruited from the general public in the San Diego region through the UCSD Mental Health Clinical Research Center (MH-CRC). Eight Caucasian-Americans and two AfricanAmericans completed the study after givin...

Equivalent effects of acute tryptophan depletion on REM sleep in ecstasy users and controls

“…Previous studies have suggested that individuals with serotonergic abnormalities are more sensitive to ATD (e.g., Delgado 2006;Booij et al 2002;Moore et al 2001;Riedel et al 2002;Neumeister 2003;Neumeister et al 2006;Roiser et al 2006;Jans et al 2007). Positron emission tomography studies have found lower radioligand binding to the 5-HT transporter (a putative marker of cell integrity) in ecstasy users relative to controls (McCann et al 1998(McCann et al , 2005(McCann et al , 2008Buchert et al 2004;Thomasius et al 2006), although a recent study reported no such changes in a wellmatched sample of former users (Selvaraj et al 2009).…”

The use of sleep measures to compare a new 5HT1A agonist with buspirone in humans

“…Sleep studies of 5HT 1A agonists in healthy volunteers have reported REM suppression particularly in the first 3h of sleep (Ware et al, 1994;Gillin et al, 1994;Driver et al, 1995;Seifritz et al, 1996;Moore et al, 2001). These changes appear to be modest with buspirone and more marked with ipsapirone, although there have been no direct comparison studies.…”

Contribution of Sleep Physiology to Depressive Pathophysiology

“…Furthermore, some evidence even suggested opposite relationships and did not show intraindividual correlations between serotonergic REM suppression and cholinergic REM induction in depressed and healthy subjects ). In the same vein, the initially reported REM enhancing effects (Moore et al 1998) of serotonin depletion by means of a tryptophan-free amino acid challenge was not replicated in a second study carried out with virtually the same experimental parameters (Moore et al 2001).…”

“…For instance, REM sleep is suppressed following systemic 5-HT 1A agonists (Gillin et al 1994;Seifritz et al 1996) and promoted following cholinergic agonists (Sitaram et al 1976;Berger et al 1985;Gillin et al 1991b;. Muscarinic receptor antagonists, on the other hand, partially suppress REM sleep (Gillin et al 1991a), and the depletion of central serotonin enhances REM sleep Moore et al 1998Moore et al , 2001Voderholzer et al 1998). In depression, it was found that cho-S86 E. Seifritz et al N EUROPSYCHOPHARMACOLOGY 2001 -VOL .…”