NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.4 345 Effects of Catecholamine Depletion on Alertness and Mood in Rested and Sleep Deprived Normal Volunteers Una D. McCann, M.D., David M. Penetar, Ph.D., Yavin Shaham, Ph.D., DruidR. Thorne, Ph.D., Helen C. Sing, B.S., Maria L. Thomas, B.A., ,. Christian Gillin, M.D., and Gregory Belenky, M.D. Alpha·methyl-para-tyrosine (AMPT), a tyrosine In contrast, although combined treatment with AMPT kydroxylase inhibitor, was used to evaluate the and sleep deprivation led to large increases in negative ylrysiologic role of central nervous system catecholamines mood, neither treatment alone produced consistent mood • modulating alertness and mood. Forty healthy males changes. These findings are consistent with the view that 1m randomized to one of four conditions: AMPT in a sleep deprivation is associated with decreased functional sed condition; AMPT plus 40.5 hours of total sleep catecholamine neurotransmission. Furthermore, mood Itprivation; placebo plus sleep deprivation; or placebo in effects following sleep deprivation plus AMPT suggest • rrsted condition. Repeated measures of alertness and that catecholamines may be involved in mood changes mxl rroealed that treatment with AMPT or sleep during sleep deprivation. £Neuropsychopharmacology. Itprir1(ltion increased sleepiness, and combined treatment 8:345-356, 1993J "muced greater sleepiness than either treatment alone. DY WORDS: Sleep deprivation; Alertness; Mood; The restorative actions of amphetamine are thought to CIltcholamines; Monoamines be secondary to functional increases in catecholamine neurotransrnission (Glowinski et al. 1966). Conversely, Thereis considerable pharmacologic evidence that cen­ drugs that decrease catecholamine activity also influ­ Ira!n ervous system (CNS) catecholamines are impor­ ence arousal. In general, drugs that inhibit noradrener­ tant modulators of arousal in man. For example, gic or dopaminergic activity increase daytime sleepi­ llimulants such as amphetamine effectively reverse ness. For example, a variety of catecholamine receptor decrements in alertness and cognitive performance as­ blockers cause sedation, fatigue, and sleepiness (Betts IlCiatedwith sleep deprivation (Weiss and Laties 1962). 1981) and decrease sleep latency times (Nicholson and Pascoe 1990). From the Department of Behavioral Biology; Walter Reed Army Further evidence for catecholaminergic involve­ .atuteofResearch (UDM, DMP, DRT, HCS, MLT, GB), Washing­ ment in arousal stems from clinical observations made .... DC; Section on Anxiety and Affective Disorders, Biological Plydtiatry Branch (UDM), National Institute of Mental Health, in a variety of patient populations treated with alpha­ SiIionallnstitutes of Health, Bethesda, Maryland; Department of methyl-para-tyrosine (AMPT); AMPTis a selective cat­ PIydlology, Concordia University (YS), Montreal, Quebec, Canada; echolamine synthesis inhibitor that can be utilized to alDepartmentof Psychiatry, University of California,and Psychiatry SInn,San Diego V.A. Medical Center (JCG), San Diego, California. determine the involvement of catecholamines in be­ Addresscorrespondence to: Una D. McCann, Section on Anxiety havior (Nagatsu et al. 1964; Spector et al. 1965). In pa­ alAffectiveDisorders, National Institute of Mental Health, Building tient populations, AMPT has been noted to produce II. Room 35·239, 9000 Rockville Pike, Bethesda, Maryland 20892. RtreivedJuly 1, 1992; revised October 28, 1992; accepted November sedation early in the course of treatment (Engelman et 111992. a1. 1968; Jonsson et a1. 1971; Ahlenius et al. 1973; Pabbshed 1993 by Elsevier Science Publishing Co., Inc. 0893-133X/93/$0.00 346 U. D. McCann et a1. NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.4 Pozuelo 1976; Nasrallah et al. 1977}. In addition, it has tained, subjects completed a Beck Depression Inven· been noted that discontinuation of AMPT treatment is tory ([BOI] Beck et al. 1961) and underwent a thorough associated with insomnia and decreased total sleep physical and laboratory examination, including an elec· (Bunney et al. 1971, 1977). This observed rebound in­ trocardiogram, psychiatric screening, SMA-20, thyroid somnia has been postulated to be secondary to an in­ function tests, hepatitis screen, human immunoden· crease in catecholaminergic activity. Further evidence ciency virus testing, complete blood count, urinalysis, for catecholaminergic involvement in the sleep-wake and urine drug screen for drugs of abuse. Exclusion cycle has been reviewed elsewhere (Mendelson 1987). criteria included self-reported past or present major In addition to their importance in sleep, there iscon­ medical or psychiatric illness, positive urine drug siderable pharmacologic evidence that brain catechol­ screens, a score of 10 or greater on the BDI, regular amines are involved in the regulation of mood (Schild­ tobacco use, ingestion of more than three cups of coffee kraut 1965; Bunney and Davis 1965; Greenspan et al. (or the equivalent) per day, or atypical sleeping patterns 1969; Iqbal et al. 1989; Schildkraut et al. 1973a, 1973b; (including unusually delayed or advanced sleep phases, Goodwin and Post 1975), although the relationship be­ history of insomnia or hypersomnia, or habitual sleep tween sleep and mood is complex. For example, major hours not occurring between 2000and 1000hours). Fol· depression is associated with objective electroen­ lowing completion of screening procedures, subjects cephalographic sleep abnormalities (Kupfer and Thase were randomlyassigned to one of four treatment con· 1983; Gillin 1983), and manic patients typicallyhave de­ ditions: 1) treatment with AMPT in a rested state creased sleep, particularly during the period when they (AMPT/R); 2) treatment with AMPT plus sleep depri· switch into mania (Bunney et al. 1972). Further suggest­ vation (AMPTISD); 3) treatment with placebo plus sleep ing a link between the regulation of mood and arousal deprivation (P/SD); or 4) treatment with placebo ina is the observation that the majority of depressed pa­ rested state (P/R). A schematic time line of study proce­ tients exhibit symptomatic improvement following one dures is depicted in Figure 1. night of total sleep deprivation (Vogel et al. 1975). The mechanism by which sleep deprivation improves mood Drug Administration in depressed individuals remains unclear, but may in­ volve catecholamines (Siegel and Rogawski 1988; Hart­ Drugs were administered in a double-blind fashion, mann and Schildkraut 1973; Schildkraut et al. 1973b; with subjects from both drug conditions included in Post et al. 1976; Mogilnicka et al. 1986). each study run, beginning at 1430 hours on treatment Despite the growing clinical interest in the relation­ day 1 (TD1). Subsequent doses were administered at ship between sleep and mood, few studies have 1830 and 2330 hours on TD1, and at 0730, 1330, 1830, reported on the effects of one night of sleep depriva­ and 2330 hours on treatment day 2 (TD2). Each of the tion on mood in healthy populations (Gerneret al. 1979; seven doses contained 750 mg AMPT (or lactose pia· Gillberg and Akerstedt 1981), and of these, results have cebo), for a total of 5.25 g AMPT over a 33-hour period. varied. Moreover, no study that has investigated the Previous studies have shown that this regimen depletes effect of sleep deprivation on mood in normal volun­ cerebrospinal fluid catecholamines by 68% to 77%af· teers has used a rested control group. The purpose of ter 24 hours (Brodie et al. 1971). Subjects treated with this study was twofold: frrst, to systematically evalu­ AMPT in the present study had signiflcantelevations ate the effects of sleep deprivation on self-reported in serum prolactin concentrations on day 2, indicating mood in healthy volunteers; and second, to use AMPT depletion of eNS catecholamines at the level of the as a pharmacologic probe for assessing the role of cate­ cholamine neurotransmitters in changes of alertness Tlme Unefor AMPT study mood associated with sleep deprivation. The pres­ and 0700 ent study was performed as part of a larger research Sleep· Deprivation project investigating the role of catecholamines in alert­ ness, sleep, performance, and mood. Adaptation Baseline Treatment T,elltment Recovery Night Night Day t Day 2 Day METHODS Subjects Forty healthy men with a mean age of 25 years (range Figure 1. Generalized time line for study procedures. Fol· 21 to 36) were recruited through advertisements in lo­ lowing adaptation and baseline sleep nights, subjects were cal newspapers. After an initial telephone screen, in­ sleep deprived for 40.5 hours (treatment days 1 and 2). Our· terested volunteers came to the laboratory for a more ing the sleep-deprivation period, subjects received seven detailed evaluation. After informed consent was ob- doses of AMPT (750 mg/dose) or placebo. �OPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.4 AMPT and Sleep Deprivation in Normal Volunteers 347 Ipothalamus(McCann et al. 1992). Subjects received Alertness and Mood Measures 6eirla st dose of AMPT immediately before recovery Simultaneous measures of alertness and mood were *ep.at the end of the sleep-deprivation period. taken during the two sleep-deprivation and drug­ treatment days (TD1 and TD2) and the day following recovery sleep (recovery day). Measurements included IerpDeprivation a pencil and paper VAS designed to measure global PI!viouslydescribed methods for sleep-deprivation and vigor and affect (Monk 1989), and a computerized ver­ paformance assessment were used, with minor mod­ sion of the Prohle