Introduction

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"Sleep homeostasis" refers to the increased drive to sleep after periods of extended wakefulness. In rats and humans, this sleep drive is manifested by increased sleep bout length, time spent in NREM, EEG delta power during NREM sleep, as well as decreased latency to sleep onset (for reviews, see Bonnett, 1994; Borbely, 1994). Sleep drive increases proportionally as a function of prior wakefulness and dissipates exponentially with subsequent sleep (Borbely and Neuhaus, 1979; Dijk et al., 1987, 1990; Tobler and Borbely, 1986). At present, the central mechanisms responsible for mediating compensatory sleep are poorly understood. Natural waking, which is actively facilitated by the circadian timekeeping system (Edgar et al., 1993), opposes homeostatic sleep drive at particular times of day (Dijk and Czeisler, 1994, 1995; Edgar et al., 1993; Edgar, 1994), and depends on the activity of ascending monoaminergic projections (Jones et al., 1973; Steriade and Hobson, 1976). Robust compensatory sleep responses are produced after wakefulness induced by psychomotor stimulants such as amphetamine, methamphetamine and methylphenidate (Caldwell and Caldwell, 1997; Edgar and Seidel, 1997; Leith and Barrett, 1976; Touret et al., 1995); such compounds dose-dependently increase dopaminergic, noradrenergic and serotonergic neurotransmission (Cho, 1993; Kuczenski, 1983; Kuczenski and Segal, 1997), but their wake-promoting effects are thought to be mediated primarily by postsynaptic dopamine receptor stimulation (Nishino and Mignot, 1997).

More selective modulation of a specific monoaminergic transmitter system can be achieved by administration of selective autoreceptor antagonists (Chesselet, 1984; Langer, 1981). For example, the DAAs (+)AJ76 and (+)UH232 enhance dopamine neurotransmission, primarily by blocking presynaptic D2 and/or D3 dopamine synthesis and/or release-modulating receptors (Gainetdinov et al., 1994; Gifford and Johnson, 1993; Rayevsky et al., 1995; Waters et al., 1993). The more recently developed DAA ()DS121 is more active at release-controlling dopamine autoreceptors than (+)AJ76 and (+)UH232 (Sonesson et al., 1993, 1994). To date, only one study has examined the wake-promoting effects of DAAs. Svensson et al. (1987) found that both (+)AJ76 and (+)UH232 produce dose-dependent increases in waking. However, it is not known whether the waking induced by DAAs elicits compensatory sleep responses analogous to those seen after psychostimulants (Edgar and Seidel, 1997) or sleep deprivation (Tobler and Borbely, 1986). In the present study we examined the acute effects of ()DS121 on sleep/wake, locomotor activity and body temperature parameters and subsequent compensatory sleep responses in the rat.

	Methods

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Animal surgery. Adult male Wistar rats (300-500 g at time of surgery, Charles River Laboratories, Wilmington, MA) were anesthetized with Nembutal (60 mg/kg i.p.) and surgically prepared with a cranial implant that permitted chronic EEG and EMG recording (Edgar et al., 1991). The cranial implant consisted of four stainless steel screws for EEG recording (two frontal at + 3.9 mm AP and ± 2.0 mm ML from bregma, two occipital at 6.4 mm AP and ± 5.5 ML from bregma). EMG was monitored by two Teflon-coated stainless steel wires positioned under the nuchal trapezoid muscles. All leads were soldered to a miniature connector before surgery and gas sterilized. The implant assembly was affixed to the skull with a combination of cyanoacrylate and dental acrylic. Body temperature and LMA were monitored via miniature transmitters (Minimitter, Sunriver, OR) surgically placed in the abdomen. A minimum of 3 weeks was allowed for postsurgical recovery.

Recording environment. Rats were housed individually within specially modified Nalgene microisolator cages equipped with a commutator and filter-top riser, as described previously (Seidel et al., 1995). Each cage was located within separate ventilated compartments of a stainless steel cabinet. Animals had ad libitum access to food and water, and were kept in a 24-h (LD 12:12) light-dark cycle throughout the study using 4-watt fluorescent bulbs 5 cm from the cage (32-35 lux inside the cage). Animals were undisturbed for 3 days before and after drug treatment.

Automated monitoring. Sleep/wake parameters were monitored using "SCORE", a microcomputer-based sleep/wake and physiological data collection system. Details regarding the design and performance of this system are described elsewhere (Edgar et al., 1991; van Gelder et al., 1991). EEG was amplified 10,000 times (EEG bandpass, 1-30 Hz, 6 dB per octave) and digitized at 100 Hz. EMG was amplified similarly (bandpass, 10-100 Hz) and integrated (root mean square, 0-5 V output; Barrows RDI-8, Palo Alto, CA). Tb and nonspecific LMA were monitored by telemetry. Drinking activity was detected when animals contacted the watering spout. All variables were monitored continuously and simultaneously. Arousal states were classified on-line as NREM sleep, REM sleep or theta-dominated wake every 10 sec with use of EEG feature extraction and pattern-matching algorithms. The classification algorithm used individually taught EEG arousal-state templates plus EMG criteria to differentiate REM sleep from theta-dominated wakefulness, plus behavior-dependent contextual rules (e.g., if the animal was drinking, it was awake). Drinking and LMA were recorded as discrete events every 10 sec; Tb was recorded every 60 sec. LMA and Tb were detected by a telemetry receiver (Data Sciences, St. Paul, MN) located beneath the cage. Telemetry measures (LMA and Tb) were not part of the sleep-wake scoring algorithm; thus sleep-scoring and telemetry were independent measures.

Drug administration and study design. ()DS121 (courtesy of The Upjohn Company, Kalamazoo, MI) was dissolved in sterile 0.25% methylcellulose and injected i.p. in a volume of 1 ml/kg at CT-05 (5 h after lights-on). Doses given were 0.5, 1, 5 and 10 mg/kg or vehicle control. Separate groups of animals received 5 mg/kg ()DS121 or vehicle at CT-18 (6 h after lights-off), or were subjected to sleep deprivation (see below). In all cases animals were assigned randomly to parallel treatment groups. Sample sizes (n) were between 8 and 14 per active treatment group, and n = 20 for vehicle control groups.

Sleep deprivation. To determine whether drug-induced wakefulness produces compensatory sleep responses analogous to sleep deprivation, a separate group of rats was maintained awake for 4 h starting at CT-5 (n = 10). Sleep deprivation was achieved by introducing novel stimuli such as toys, paper and other objects into the cage, or if necessary, making gentle contact with the animal. Stimuli were only applied when animals attempted to sleep, as defined by visual observation and confirmed by real-time computer scoring. Four hours of sleep deprivation was found empirically to produce the same net amount of waking as 10 mg/kg ()DS121. Animals were undisturbed for 30 h before and after sleep deprivation.

Data analysis and statistics. The principle variables recorded were percent per hour of NREM, REM, total sleep time (defined as minutes per hour of NREM + REM) and WAKE, ASBL and MSBL (in minutes), AWBL and MWBL (in minutes), counts per hour of LMA, LMAI (defined as LMA counts per min of wakefulness; see Edgar et al., 1997; Edgar and Seidel, 1997), counts per hour of DRINK and average Tb deviation from the 24 h baseline mean. Sleep and wake bout length, LMA, DRINK and Tb parameters were averaged across post-treatment hours 1 to 4 (designated treatment effect) and hours 5 to 10 (designated recovery) for each treatment group, as well as for the corresponding values during the 24-h pretreatment period (designated baseline) (see tables 1 and 2). Differences between post-treatment drug group and vehicle were compared by one-way ANOVA. In the presence of a significant main effect, Dunnett's contrasts ( = 0.05) assessed differences between the active treatment group and vehicle controls.

	Results

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Acute effects on sleep/wake and physiological parameters. All analyses were performed relative to base line and contrasted with vehicle controls. Figures 1 and 2 show the normal circadian oscillations in NREM, REM, LMA and Tb and the effects of a 5 mg/kg dose of ()DS121 at CT-5 or CT-18, respectively, on these parameters. ()DS121 (5 mg/kg) induced a decrease in NREM and REM sleep as well as an increase in LMA and Tb immediately after administration at CT-5. With the exception of REM sleep, which exhibited delayed compensatory sleep responses (see below), these parameters returned to normal circadian patterns by 12 h post-treatment. CT-18 administration of the same dose produced a decrease in NREM sleep as well as an increase in Tb, but the increase in LMA did not exceed vehicle control levels. Under baseline conditions (e.g., 24 h before treatment at CT-5), rats exhibited relatively high levels of NREM and REM sleep and low levels of LMA and Tb, commensurate with nocturnal sleep/wake behavior. Thus, treatment at CT-5 with 5 mg/kg ()DS121 produced more robust effects on these variables than during the animals' circadian active phase at CT-18. Also, in contrast to CT-5, these variables returned to normal circadian patterns by 6 h post-CT-18-treatment, with delayed compensatory REM sleep responses again being an exception.

View larger version (26K): [in this window] [in a new window]   Fig. 1.   NREM, REM, LMA and Tb circadian rhythms before and after treatment at CT-5 with ()DS121 (5 mg/kg i.p.) (solid line, n = 10 or 11) or methylcellulose vehicle (dotted line, n = 20). The injection at CT-5 is denoted by the triangle on the x-axis. The four variables are plotted as mean ± S.E.M. across a 2.5-day period, and light/dark bars along the x-axis indicate lights on/off. Note that during hours 1 to 4 post-treatment NREM and REM are decreased relative to vehicle controls, and during hours 5 to 10 post-treatment these variables are increased, which indicates compensatory sleep responses. Conversely, both LMA and Tb are increased during hours 1 to 4 post-treatment followed by distinct periods of hypolocomotion and decreased body temperature during hours 5 to 10 post-treatment relative to vehicle controls.

View larger version (25K): [in this window] [in a new window]   Fig. 2.   NREM, REM, LMA and Tb circadian rhythms before and after treatment at CT-18 with ()DS121 (5 mg/kg i.p.) (solid line, n = 13 or 14) or methylcellulose vehicle (dotted line, n = 20). The injection at CT-18 is denoted by a triangle on the x-axis. Data are plotted as in figure 1. Note the lack of significant effects on LMA and Tb, and the delayed compensatory REM sleep response beginning approximately 12 h after treatment.

View this table: [in this window] [in a new window]   TABLE 1 Dose-response analysis of ()DS121 at CT-05 on sleep/wake architecture and physiological parametersa

View this table: [in this window] [in a new window]   TABLE 2 ()DS121 (5 mg/kg) effects on sleep/wake architecture and physiological parameters at CT-18a

View larger version (31K): [in this window] [in a new window]   Fig. 3.   Wake-promoting profile of ()DS121 during the initial 4-h post-treatment. Data are plotted as mean ± S.E.M. (upper panel) Treatment of animals at CT-5 with 5 mg/kg (open circles, n = 11) or 10 mg/kg (solid triangles, n = 13) () DS121 or vehicle (solid circles, n = 20). (lower panel) Treatment at CT-18 with 5 mg/kg ()DS121 (open circles, n = 13) or methylcellulose vehicle (solid circles, n = 20). Note decline to vehicle waking levels by 3 to 4 h post-treatment. Hour 0 indicates the 1-h period immediately preceding treatment.

View larger version (34K): [in this window] [in a new window]   Fig. 4.   Maximum wake (A) and sleep (B) bout length per hour after treatment at CT-5 with 10 mg/kg () DS121 (solid line, n = 13) or methylcellulose vehicle (dotted line, n = 20). Injection at CT-5 is represented by a black triangle on the x-axis. Data are plotted as in figure 1.

Compensatory sleep and physiological responses to drug-induced waking. Wakefulness induced by ()DS121 resulted in immediate compensatory sleep responses that were proportional to the duration of drug-induced wakefulness. In figure 1, this immediate compensatory sleep response was evidenced as a robust increase in NREM sleep that exceeded normal circadian levels during the 5- to 10-h post-CT-5-treatment interval. Compensatory sleep also was evidenced by a marked increase in REM sleep relative to vehicle-treated animals in the 8- to 12-h interval after treatment at CT-5 (fig. 1) and the 12- to 18-h interval after treatment at CT-18 (fig. 2).

Cumulative changes in NREM, REM and WAKE. Dose-dependent comparison of long-term compensatory sleep responses after drug-induced wakefulness is complicated by the fact that both the magnitude (i.e., minutes per hour of waking) and the duration of drug action (i.e., total time the drug increases waking) can vary independently with dose. The pharmacodynamic profile of drug-induced waking and the course of subsequent recovery sleep can be quantified precisely for each treatment, however, by plotting a running sum of the difference from the corresponding hour during baseline 24 h earlier for each hour post-treatment ("sleep deficit" analysis) (Edgar et al., 1997; Edgar and Seidel, 1997). Figure 5 shows the group mean arousal state accumulation profiles for NREM, REM and WAKE after 5 and 10 mg/kg ()DS121 and methylcellulose vehicle administered at CT-5. Arousal state accumulation profiles for vehicle and 5 mg/kg treatment at CT-18 are shown in figure 6. The greatest amount of drug-induced sleep loss (e.g., negative-most value for cumulated NREM or REM) or accumulated wake, the time to reach such "peak" values (computed from the group mean profiles in fig. 5), and cumulative measures of each arousal state 24-h post-treatment, are shown in table 3. When given at CT-5, ()DS121 rapidly reduced NREM and REM sleep (evidenced by the negative slopes for NREM and REM during the first 4 h in fig. 5), but the time course of these effects differed as a function of the variable measured and as a function of drug dose. For example, 6 and 7 h after treatment with 5 and 10 mg/kg of ()DS121, the maximum deficit was reached after 3 and 4 h for NREM but after 6 and 7 h for REM, respectively. After treatment with either higher dose, there was an intense NREM compensatory sleep response (positive slope in the NREM accumulation plots) that preceded compensatory REM sleep (see also fig. 1 for comparison). Recovery of 50% of REM sleep lost to drug-induced waking was observed 6 to 7 h after recovery of 50% of NREM sleep lost (see fig. 5). Waking induced by vehicle treatment also showed NREM recovery preceding REM recovery, although the absolute magnitude of this effect is small. By 24 h post-treatment, animals had recovered approximately 100% of NREM and 65% of REM suppressed by 5 mg/kg of ()DS121 at CT-5. In contrast, animals recovered only 65% of both NREM and REM 24 h after 10 mg/kg at CT-5.

View larger version (33K): [in this window] [in a new window]   Fig. 5.   Total cumulated change in minutes of NREM (upper panel), REM (middle panel) and WAKE (lower panel) relative to baseline 24 h earlier after treatment at CT-5 with 5 mg/kg () DS121 (, n = 11), 10 mg/kg ()DS121 (, n = 13) or methylcellulose vehicle (, n = 20). Data are plotted as mean ± S.E.M. for 30 h post-treatment. For NREM and REM, a negative slope indicates cumulative sleep loss whereas a positive slope indicates compensatory sleep response, and vice versa for WAKE. Note the recovery of virtually all sleep lost because of waking at 5 mg/kg, and approximate 65% recovery at 10 mg/kg.

View larger version (29K): [in this window] [in a new window]   Fig. 6.   Total cumulated change in minutes of NREM (upper panel), REM (middle panel) and WAKE (lower panel) relative to baseline 24 h earlier after treatment at CT-18 with 5 mg/kg () DS121 (, n = 13) or methylcellulose vehicle (, n = 20). Data are plotted as in figure 5. Note the recovery of virtually all sleep lost because of drug-induced waking.

View this table: [in this window] [in a new window]   TABLE 3 ()DS121 effect on cumulated changes in NREM, REM and WAKE time (based on individual values of maximum wake-promoting duration)

View larger version (43K): [in this window] [in a new window]   Fig. 7.   Duration of wakefulness (A) and compensatory NREM sleep responses (B) as a function of ()DS121 dose and total accumulated wakefulness.

Comparison with sleep deprivation. To determine whether the partial NREM sleep recovery observed 24 h post-treatment with 10 mg/kg ()DS121 reflected the normal course of sleep homeostasis, or was a function of drug treatment, untreated rats were sleep deprived (see "Methods") for 4 h beginning at CT-5. This sleep deprivation procedure produced a NREM deficit very similar to 10 mg/kg ()DS121, but the long-term course of NREM recovery sleep differed markedly (see fig. 8). The sleep-deprived rats exhibited a more rapid NREM recovery than the drug-treated rats. The NREM deficit imposed by sleep deprivation (102.5 ± 7.9 min) was recovered completely (100%) within 10 h after the end of sleep deprivation. NREM recovery after sleep deprivation was significantly greater (t-test, P < .005) than the maximum NREM sleep recovered (65%) 24 h after treatment with ()DS121 (fig. 8).

View larger version (28K): [in this window] [in a new window]   Fig. 8.   Total cumulated change in minutes of NREM relative to baseline 24 h earlier after treatment at CT-5 with 10 mg/kg ()DS121 (, n = 13) or 4 h sleep deprivation (, n = 10). Data are plotted as in figure 5. Note the recovery of virtually all sleep lost in the sleep deprivation group, and only partial recovery in the ()DS121-treated group.

	Discussion

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Dopaminergics exert a powerful influence on the arousal state by their actions on monoaminergic projections in the brain (Holman, 1994; Ongini and Longo, 1989). Psychostimulants such as methamphetamine and d-amphetamine increase dopaminergic and noradrenergic transmission by facilitating neurotransmitter release, inhibiting neurotransmitter reuptake and inhibiting the degradative enzyme monoamine oxidase (Cho, 1993; Holman, 1994; Kuczenski, 1983). However, the wakefulness-promoting effects of psychomotor stimulants are thought to be associated primarily with dopaminergic rather than noradrenergic neurotransmission (Nishino and Mignot, 1997). These compounds also elicit strong compensatory sleep responses that are proportional to the amount of drug-induced waking (Edgar and Seidel, 1997). In the present study, ()DS121, a substituted 3-phenylpiperidine that preferentially antagonizes presynaptic D2 and D3 dopamine autoreceptors (Sonesson et al., 1993, 1994), produced a dose-dependent increase in wakefulness and robust compensatory hypersomnolence akin to that reported for methamphetamine (Edgar and Seidel, 1997) and d-amphetamine (Touret et al., 1995), consistent with our working hypothesis that dopaminomimetic-induced wakefulness engages homeostatic compensatory sleep responses.

The wake-promoting effects of ()DS121 at CT-5 (i.e., rest phase) and CT-18 (i.e., activity phase) were consistent with the actions of other DAAs such as (+)AJ76 and (+)UH232 (Svensson et al., 1987). These compounds are thought to increase wakefulness through blockade of presynaptic inhibitory autoreceptors on dopaminergic terminals (Svennson et al., 1986; Sonesson et al., 1993, 1994) resulting in increased levels of extracellular dopamine (Gainetdinov et al., 1994; Gifford and Johnson, 1993; Rayevsky et al., 1995; Waters et al., 1993). Conversely, stimulation of presynaptic dopamine autoreceptors by 3-PPP or low doses of apomorphine has been reported to produce sedation and increased REM sleep time (Corsini et al., 1977; Hjorth, 1983; Kafi de St. Hilaire et al., 1985; Mereu et al., 1979).

Treatment effects at CT-5 vs. CT-18. The threshold wake-promoting efficacy for ()DS121 at CT-5 was 1 mg/kg, at which dose all variables except wake time (i.e., sleep and wake bout lengths, LMA, Tb) were not affected significantly. Thus, EEG wakefulness can be a very sensitive measure of dopaminomimetic drug action. At higher doses (5 and 10 mg/kg), ()DS121 at CT-5 dose-relatedly increased both wake bout parameters (AWBL and MWBL), which indicates that this compound not only increased wakefulness, but also consolidated wakefulness. A comparison of 5 mg/kg doses at CT-5 and CT-18 revealed that ()DS121 can potently suppress NREM and REM sleep at both times of day. Indeed, the pharmacodynamic profile of ()DS121 (i.e., percent wake per hour post-treatment) was very similar at each CT, which suggests that there was little interaction between drug efficacy and the circadian time-keeping system. However, the total wake time induced at CT-18 was less than at CT-5. As a nocturnal species, rats are typically awake approximately 70% time during the lights-off phase of the circadian cycle (Edgar et al., 1991; Edgar, 1994, 1996). Drug "ceiling effects" on sleep-wakefulness therefore limit the net increase in wakefulness as a function of time of day. Similar issues come to bear when contrasting LMA and Tb as a function of treatment time of day. Large increases in LMA and Tb were seen in response to 5 mg/kg ()DS121 at CT-5. At CT-18, similar levels of LMA and Tb were observed, but were not markedly different from the usual levels (e.g., as in vehicle group or during baseline 24 h earlier). This circadian variation in LMA response to treatment is consistent with previous reports of circadian variation in locomotor responses to psychostimulants and other dopaminomimetics (Gaytan et al., 1996; Martin-Iverson and Iversen, 1989; Nagayama et al., 1978; Urba-Holmgren et al., 1977), as well as circadian variations in dopamine receptor number (Kafka et al., 1983; Wirz-Justice, 1984).

Behavioral hyperactivity. The wake-promoting effects of low-dose ()DS121 (1 mg/kg) at CT-5 or a moderate dose (5 mg/kg) at CT-18 were not accompanied by significant increases in LMA or LMAI relative to vehicle controls. These observations are consistent with a preliminary report that low-dose treatment with the selective dopamine reuptake inhibitor GBR 12909 increases waking without producing disproportionate motor activity (Edgar et al., 1995b). In contrast, classic psychostimulants produce hyperactivity at all doses that also produce waking (Edgar and Seidel, 1997; Wise, 1988). Thus, it seems that modest enhancement of dopamine transmission can promote wakefulness without extrapyramidal motor side effects.

Duration of drug action: cohort vs. individual effects. Dose comparisons of compensatory sleep responses in stimulant-treated rats are inherently complicated because low-dose effects of stimulants are of shorter duration than higher doses; thus fixed interval analysis can be problematic. In the present study we used two alternative approaches to estimate the duration of the primary wake-promoting effect of ()DS121, and in turn, to detect compensatory sleep responses in the hours after the initial waking effect peaked. Each approach revealed strengths and weaknesses. In the first approach ("variable-interval" analysis), mean arousal state accumulation profiles (see "Methods") were used to define the duration of initial drug action on WAKE, NREM and REM, and the beginning of the respective arousal state recovery periods. This technique yielded an average pharmacodynamic profile of drug interaction with clear compensatory sleep, including estimates of net recovery sleep many hours after treatment. With this approach the net wake-promoting effect was dose-related; however, the duration of wake-promoting action of ()DS121 only was not precisely dose-related (see t_max in table 3). In contrast, when the duration of wake-promoting action was determined first for individual animals (defined as the initial continuous duration that wakefulness exceeded the corresponding baseline 24 h earlier, computed in hourly blocks) and then averaged, there was a straightforward relation between dose, duration of wake-promoting action and increase in accumulated wakefulness (see fig. 7). The difference in results from these two approaches is likely caused by the "cohort effect" of the former technique; that is, averaging inherently smoothes data. In particular, when wake-duration estimates are computed by the group mean wake accumulation profile, the variance in individual animals makes it probable that drug-induced waking in some animals overlaps and is averaged together with compensatory sleep responses in other animals. Unfortunately, drug duration estimates from individual rats can be methodologically difficult because the individual accumulation profiles are not as smooth as the group mean profile, making it difficult to define objectively the true maxima/minima in some individual profiles. This latter approach is complicated further at threshold doses, wherein some animals respond and others do not. In the present study, nonresponders were not excluded from the analysis.

Indices of sleep homeostasis. Relatively few studies have analyzed the compensatory sleep responses after stimulant-induced waking. Homeostatic sleep responses can be divided into two phases: an initial recovery phase usually characterized by intense hypersomnolence (i.e., increases in NREM sleep time and sleep bout lengths) such as immediately follows sleep deprivation, and a less intense but elevated level in manifest sleep tendency that may last several hours thereafter. Although some laboratories have focused on spectral correlates of EEG activity during compensatory sleep as an index of sleep homeostasis (Borbely, 1994; Borbely and Neuhaus, 1979; Dijk et al., 1987, 1990), the present study used NREM bout lengths and NREM sleep time as principal markers of the compensatory sleep responses. In rats, NREM bout lengths correlate closely with EEG delta power in NREM episodes after sleep deprivation (Edgar, 1996). It is our experience that some drugs can induce subtle shifts in EEG frequency that alter EEG power assessments without altering NREM sleep bout lengths. This phenomenon was noted previously in the assessment of benzodiazepine hypnotic action, in which drugs like triazolam can increase nocturnal sleep efficiency (and therefore improve subsequent daytime alertness), yet significantly reduce EEG delta power in NREM sleep (Johnson et al., 1983). Thus, EEG delta power can be a less reliable index of compensatory sleep than measures of sleep continuity, the latter of which strongly correlates with sleep quality (Roehrs et al., 1994).