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Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat

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Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat
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  Psychopharmacology (1988) 95: 395400 Psychopharmacology © Springer-Verlag 1988 Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat Jaime M. Monti, Marjorie Hawkins, H~ctor Jantos, Luisa D Angelo, and M6nica FernAndez Department of Pharmacology and Therapeutics, School of Medicine, Hospital de Clinicas P1, Montevideo, Uruguay Abstraet. The effects of the dopamine (DA) receptor ago- nists apomorphine, bromocriptine and pergolide were com- pared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.0252.0 mg/kg) and bro- mocriptine (0.25-6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05-0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferen- tially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects. The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of meso- limbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhibitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists. Key words: Sleep - Wakefulness - REM sleep - Apomor- phine - Bromocriptine - Pergolide - Haloperidol - Dopa- mine receptors The proposal that dopamine (DA) plays a neuroregulatory role in sleep and waking is supported by numerous pharma- cological studies; L-dopa and amphetamine produce arous- al while DA-receptor blockers, including chlorpromazine and haloperidol, produce enhanced slow wave sleep (SWS) and decreased REM sleep (REMS) (Altier et al. 1975; Monti 1979, 1982; Gillin 1981 ; Wauquier 1985). The available evidence favors the concept that dopamin- ergic mechanisms engage sleep-wake executive brain struc- tures. Accordingly, anatomical and biochemical studies have demonstrated the existence of dopaminergic ventral tegmental (AI0) projections to the locus coeruleus (LC), and an efferent pathway arising from the striatum connect- ing cell groups in the brain stem involved in EEG arousal Offprint requests to J.M. Monti via the pars reticulata (Hopkins and Niessen 1976; Simon et al. 1979; McRae-Degueurce and Milon 1983). A direct projection from medial dorsal substantia nigra to the dorsal raphe nucleus may constitute a modulatory input to raphe serotonergic structures related to the regulation of sleep behavior (Pasquier et al. 1977). Moreover, mesencephalic DA neurons in the ventral tegmental area give rise to an extensive neocortical DA innervation, and have been impli- cated in arousal behavior and locomotor activity (Carter and Pycock 1980; Thierry et al. 1984; Berger et al. 1985). In contrast to both 5-TH and NE neurons, the firing rates of the substantia nigra and ventral tegmental DA neu- rons are unchanged during waking (W), SWS and REMS (Trulson and Preussler 1984); it has been suggested that these neurons provide a tonic influence on structures in- volved in the modulation of sleep and wakefulness (Stein- felds et al. 1983). Two categories of DA receptors, D-1 and D-2, have been characterized by biochemical and pharmacological cri- teria. These receptors have been identified in the CNS on neuronal processes postsynaptic to DA axons. Presynaptic DA receptors that regulate the release of DA have been also demonstrated at central sites, and their pharmacologi- cal properties resemble those of the D-2 receptor (Stoof and Kebabian 1984; Kaiser and Jain 1985). Agonists and antagonists are now available which act selectively on D-1 or D-2 receptors. Relatively selective D-2 agonists include apomorphine, bromocriptine and pergolide, while haloperi- dol preferentially behaves as D-2 antagonist (Hyttel and Christensen 1983; Stoof and Kebabian 1984; Kaiser and Jain 1985). The present study quantifies the effects of the DA ago- nists apomorphine, bromocriptine and pergolide on sleep and wakefulness in the rat and compares them with the DA antagonist haloperidol. We also attempted to ascertain the importance of presynaptic DA receptors on sleep after low doses of apomorphine, bromocriptine or pergolide by haloperidol pretreatment at doses shown to act pref- erentially at presynaptic sites (Str6mbon 1977; Herrera- Marschitz and Ungerstedt 1984). Material and methods Male Wistar rats (School of Medicine Breeding Laborato- ries, Montevideo) weighing 350-400 g were implanted with Nichrome electrode (200 gm diameter) for chronic record- ing from frontal and occipital cortex and dorsal neck mus-  396 culature. The animals were maintained individually with ad lib food and water under controlled environmental con- ditions (12 h light: 12 h dark cycle). Fifteen days after sur- gery the animals were habituated to a dimly lit, soundproof chamber fitted with slip-rings and cable connectors and were then administered either a control solution or the drug to be tested. Electrographic activity of each 50-s epoch was analyzed and assigned to the following categories based on the wave- form: W [characterized by low voltage fast waves in frontal cortex, a mixed theta rhythm (4-7 Hz) in occipital cortex and relatively high EMG activity]; light sleep (LS, high voltage slow cortical waves interrupted by low voltage fast EEG activity); SWS (continuous high amplitude slow fron- tal and occipital waves combined with a reduced EMG) or REMS (low voltage fast frontal waves, a regular theta rhythm in the occipital cortex and a silent EMG except for occasional myoclonic twitchings). In addition, SWS and REMS latencies were determined. The speed of the paper drive was 3 mm/s and a time constant of 0.04 was used in the EEG recordings. During the first set of experi- ments we studied the effects of apomorphine hydrochlo- ride (Sandoz) 0.025-2.0mg/kg, bromocriptine (Sandoz) 0.25-6.0 mg/kg, pergolide mesylate (Lilly) 0.05-0.5 mg/kg and haloperidol (Janssen) 0.020-0.160 mg/kg as base. In the second set of experiments, 0.025 mg/kg apomorphine, 0.5 mg/kg bromocriptine or 0.05 mg/kg pergolide was in- jected into animals pretreated with haloperidol 0.020 mg/ kg. Twenty minutes after the injection of haloperidol the animals received the corresponding doses of the DA ago- nists. Bromocriptine and haloperidol were dissolved in a small volume of glacial acetic acid diluted with distilled water and adjusted to pH 5.5-6.0. Apomorphine was dis- solved in distilled water containing ascorbic acid (2 mg/ml). During control sessions the rats were given the correspond- ing volume of control solution. All injections were given intraperitoneally in a final volume of 1 ml/kg body weight and recording started 10 min after the last injection. A bal- anced order of drug and control recordings was used, and two rats receiving the same treatment were simultaneously recorded. At least 5 days were allowed to elapse between experiments to avoid long-lasting and rebound effects on sleep. All data were tested for homogeneity of variances using Bartlett's test before testing the null hypothesis. One-way analysis of variance was used for statistical comparison of three or more samples, with multiple post hoc comparisons performed by the Scheff6 test. In those instances when ho- mogeneity of variance could not be established, the nonpar- ametric Kruskal-Wallis test was applied and multiple com- parisons effected in a fashion paralleling the Newman- Keuls test by using rank sums instead of means (Zar 1974). Results Quantitation of 1 h sessions after apomorphine showed bi- phasic effects on sleep and wakefulness. The lower doses (0.025-0.050 mg/kg) of the DA agonist decreased W and sleep latencies and increased SWS and REMS, while the larger doses (l.0-2.0mg/kg) induced opposite effects (Fig. 1, Table 1). Haloperidol prevented the decrease of W and of SWS latency and the increase of SWS and REMS produced by apomorphine 0.025 mg/kg (Fig. 2, Table 1). Min 6 55 5o 45 4 35 3 25 2o 15 lO 5 o O~ °1 w i J,;.~ i' <> <> Io LS SWS REMS Fig. 1. The effect of apomorphine IP on wakefulness (W), light sleep (LS), slow wave sleep SWS) and REM sleep REMS) during l-h sessions. Ordinate: mean amount in min of behavioral stage according to EEG criteria. All values are the means_+ SEM. Six animals were in each experimental group. Dose in mg/kg. Com- pared with control values (W and SWS): *P<0.05; **P<0.005 (Scheff~ test). Compared with control values (REMS): *~=0.05 (Newman-Keuls test). • Control; [] APO 0.025; [] APO 0.050; [] APO 1.0;[[]APO 2.0 Min 45 40 35 3O 20 ii~ii i~it ~:::::::::t 10 iili l iEii ~il @ a__l W LS SWS REMS Fig. 2. Effects of haloperidol pretreatment on apomorphine-in- duced changes of sleep and wakefulness during 1-h sessions. Com- pared with control values: *P<0.05; **P<0.02; ***P<0.0I (Scheff6 test). • Control; [] APO 0.025; [] HAL 0.020 + APO 0.025 As can be seen from Fig. 3, W was significantly de- creased during the first 3 h following treatment with 0.5 or 2.0 mg/kg bromocriptine. The amount of time spent in LS and SWS showed slight but consistent increments. Fur- thermore, administration of the 6.0 mg/kg dose resulted in an increase of W and decrease of SWS, although signifi- cance was not attained. Treatment with bromocriptine also produced biphasic effects on REMS. Accordingly, REMS  Table 1. Effects of apomorphine on sleep latencies SWS latency REMS latency Control 18.1+ 3.3 65.4+_ 5.6 Apomorphine 0.025 0.050 1.0 2.0 Haloperidol 0.02 Haloperidol 0.02 + Apomorphine 0.025 5.4± 2.6 b 28.1± 3.7 ~ 7.6± 4.0 54.4±13.2 56.9± 9.8 b 175.6±28.5 c 54.3±14.6" 148.3±49.4 10.3± 3.5 69.0±26.4 9.7± 3.5 37.5± 7.6" All values are the means +_ SEM (min). Six animals were in each experimental group. Drugs were given by IP route. Doses in mg/kg. Compared with control values : P<0.05; b P<0.02; P<0.01 (Scheff~ test) Table 2. Effects of bromocriptine on sleep latencies SWS latency REMS latency Control 18.2±3.9 59.7± 8.4 Bromocriptine 0,25 0,5 2,0 6,0 Haloperidol 0.02 Haloperidol 0.02 + Bromocriptine 0.5 397 12.8±3.1 77.2±22.4 8.2±2.6 b 51.7± 9.0 5.3±2.9 b 57.0±14.2 7.5±2.2 a 253.8±60.0 c 10.0±3.5 69.0±26.4 7.7±0.8 b 60.7±14.5 All values are the means__ SEM (rain). Six animals were in each experimental group. Drugs were given by IP route. Doses in mg/kg. Compared with control values: a P<0.05; b P<0.02; c p < 0.01 (Scheff6 test) Min 12 11 1 9 8 7 6 5 4 3 2 1 o I w LS SWS REMS Fig. 3. Effects of bromocriptine IP on W, LS, SWS and REMS during 3-h sessions. Six animals were in each experimental group. Dose in mg/kg. Compared with control values: *P < 0.02 (Scheff~ test). • Control; [] BROM 0.25; [] BROM 0.5; [] BROM 2.0; [] BROM 6.0 Min 120 110 100 90 80 70 60 50 40 30 20 10 0 W _L i iiil :i:::):: i i) ii LS SWS ¢, REMS Fig. 4. Effects of haloperidol pretreatment on bromocriptine-in- duced changes of sleep and wakefulness during 3-h sessions. Com- pared with control values: *P<0.01 (Scheff6 test). • Control; [] BROM 0.5; [] HAL 0.020; [] HAL 0.020+BROM 0.5 was increased after 0.5 mg/kg and decreased after 6.0 rag/ kg. Slow wave sleep latencies were markedly decreased after administration of 0.25-6.0 mg/kg bromocriptine. In con- trast, the 6.0 mg/kg dose increased REMS latency (Ta- ble 2). As shown in Fig. 4, haloperidol prevented the in- crease of REMS produced by bromocriptine. However, W decrease was only partly antagonized. The decrease in SWS latency was not prevented in rats pretreated with haloperi- dol (Table 2). Figure 5 shows that following pergolide 0.05 mg/kg SWS was significantly increased and REMS decreased dur- ing the first 2 h of recording session. Waking decrement did not attain significance (P<0.1). Larger doses (0.1-0.5mg/kg) increased W and decreased SWS and REMS in a dose-dependent manner. Slow wave sleep la- tency was markedly decreased after the injection of 0.05-0.1 mg/kg pergolide, while the 0.5 mg/kg dose pro- duced an opposite effect. The latencies to REMS occurrence showed a significant increment at the 0.1-0.5 mg/kg doses (Table 3). Pretreatment with haloperidol failed to prevent REMS supression while SWS increase was effectively antag- onized (Fig. 6). Haloperidol did not prevent the decrease in SWS latency (Table 3). Haloperidol tended also to induce biphasic effects on sleep and W during the first 3 h of the recording session. Accordingly, the 0.020 mg/kg dose moderately increased W,  398 Min 1o0 90 80 70 60 50 40 30 20 10 0 Fig. 5. Effects of pergolide IP on W, LS, SWS and REMS during 2-h sessions. Six animals were in each experimental group. Dose in mg/kg. Compared with control values (W and SWS): *P < 0.02; **P<0.01 (Scheff6 test). Compared with control values (REMS): *~=0.02 (Newman-Keuls test). • Control; [] PERG 0.05; [] PERG 0.1; [] PERG 0.25;[] PERG 0.5 Min ~> 90 o ¢, ~ 80 ° 70 3_ 60 2 40 L i [ 3o liliiii O O 0 ":::~::~ W kS SWS P, MS W kS SWS REMS Fig. 6. Effects of haloperidol pretreatment on pergolide-induced changes of sleep and wakefulness during 2-h sessions. Compared with control values: *P< 0.05 (Scheff6 test). • Control; [] PERG 0.05; [] HAL 0.02; [] HAL 0.02+PERG 0.05 TaMe 3. Effects of pergolide on sleep latencies SWS latency REMS latency Control 16.7_+ 4.1 46.7_ 6.8 Pergolide 0.05 1.5± 1.1 ¢ 63.8_+ 6.8 0.1 4.5_+ 3.5 a 163.0_+ 49.4 b 0.25 18.5_+ 7.6 279.8 ± 36.1 d 0.5 45.8___ 16.2 a 317.8_+29.3 Haloperidol 0.02 12.0__+ 5.1 36.3-+ 4.3 Haloperidol 0.02 + Pergolide 0.05 1.8-+ 0.3 c 71.7_+ 10.7 All values are the means ± SEM (min). Six animals were in each experimental group. Drugs were given by IP route. Doses in mg/kg. Compared with control values : a P<0.05; b P<0.02; P<0.01; d P<0.001 (Scheff+ test) in 120 110 100 90 .80 70 60 50 40 30 20 10 0 I , - iiiii i ::-';i W LS SWS REMS Fig. 7. Effects of haloperidol IP on W, LS, SWS and REMS during 3-h sessions. Seven animals were in each experimental group. Dose in mg/kg. Compared with control values: **P < 0.02 (Scheff6 test). • Control; [] HAL 0.020; [] HAL 0.040; [] HAL 0.080; []HAL 0.160 while the increased remained 0.160 mg/kg dose significantly decreased W and SWS (Fig. 7). On the other hand, sleep latencies almost unchanged. Discussion Apomorphine induced biphasic effects on sleep and W in rats. Low doses increased SWS and REMS, while large doses increased W. There were concomitant changes in the onset of these sleep states. Pretreatment with haloperidol at a dose which produced only a small alteration of the sleep-wake cycle blocked the apomorphine-induced increase of SWS and REMS. The facilitation of sleep occurrence caused by small doses of apomorphine is in accord with results obtained by others. Thus, Mereu et al. (1979) found an increment of SWS and REMS in rats aftr SC doses of 0.025 and 0.050 mg/kg apomorphine. Cianchetti et al. (1981) found that apomorphine given to man in nonemetic doses by con- tinous IV infusion increased stage 2 sleep. However, in con- trast REMS was abolished. These findings suggest that there are species differences in the responses to apomor- phine of rat and man.  399 Bromocriptine and pergolide effects were also biphasic: low doses decreased W and increased SWS, and high doses induced opposite changes. The actions with bromocriptine on REMS were also biphasic. However, pergolide irrespec- tive of the dosage given significantly suppressed REMS, which tends to suggest that two different mechanisms could be involved in its effects on SWS and REMS. Haloperidol incompletely antagonized the bromocrip- fine-induced suppression of W, while REMS values were no longer significant as compared to control. Inhibition of pergolide effect on W and SWS was obtained after pre- treatment with haloperidol. In contrast, REMS remained suppressed. A likely explanation for this result could be that REMS suppression by pergolide is mediated through synaptic sites other than those influenced by haloperidol. The dose-related effects of pergolide on SWS and W have not been previously described. On the other hand, the arousing effect of relatively large doses of bromocriptine has been shown by Radulovacki et al. (1979, 1981) in con- trol and REMS-deprived animals, and this action was abol- ished by pretreatment with alpha-flupenthixol. In schizo- phrenic patients given bromocriptine in daily doses of up to 40 mg, no statistically significant changes were observed in sleep variables (Brambilla et al. 1983). These negative findings could be related to species differences in the re- sponse to bromocriptine. However, the discrepant results may also be related to the inclusion of patients with abnor- mal sleep patterns and to the administration of bromocrip- tine at various times before sleep onset. It has been suggested that sleep increase after low doses of apomorphine could be related to inhibition of dopamin- ergic mechanisms. This effect was also observed after low doses of bromocriptine and pergolide and could depend on the activation of presynaptic inhibitory D-2 receptors (Langer 1981). These receptors have been characterized in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic system and the rostral part of the cere- bral cortex of the rat (And+n et al. 1983). Selective stimula- tion of D-2 autoreceptors inhibits DA synthesis and release and DA neuronal firing at central sites (Langer et al. 1980; Yarbrough et al. 1984; Trulson 1985). In agreement with these findings, doses of apomorphine, bromocriptine or per- golide which provoke hypomotility and sleep induce a fall in striatal DOPA and HVA levels (Baudry et al. 1977; Di Chiara et al. 1976; Sumners et al. 1981; Fuller et al. 1982; Jiang et al. 1984). Moreover, pretreatment with a dose of haloperidol which preferentially acts at presynaptic DA sites reversed the increase of SWS and/or REMS, which further supports the contention that sleep induction after apomorphine, bromocripfine or pergolide is related to acti- vation of presynaptic D-2 receptors (Kendler et al. 1982). Dopaminergic receptors of the D-2 subtype have been also characterized in central norepinephrine (NE) and ace- tylcholine (ACh) neurons. In addition, it has been estab- lished that both apomorphine and pergolide inhibit the re- lease of NE in hypothalamus and cerebral cortex and of ACh in striatum, and these effects are selectively blocked by sulpiride or haloperidol (Galzin et al. 1982; Scatton 1982; Langer et al. 1983). Since a good deal of indirect evidence favors a role for NE and ACh neurons in waking EEG (Monti 1982; Gaillard 1985; Koella 1985), it could be tentatively suggested that inhibition of NE and ACh activity by the DA agonists could be partly responsible for sleep increase after small doses of either compound. In conclusion, the relatively selective DA D-2 receptor agonists apomorphine, bromocriptine and pergolide show biphasic effects on the sleep-wake cycle, with low doses increasing and high doses decreasing sleep. Sleep increase after low amounts of DA agonists is antagonized by halo- peridol in a dose which has been shown to preferentially act at presynaptic sites. References Altier H, Moldes M, Monti JM (1975) The actions of dihydroxy- phenylalanine and dihydroxyphenylserine on the sleep-wakeful- ness cycle of the rat after peripheral decarboxylase inhibition. 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Psychiatry Res 8 : 159-169 Carter CJ, Pycock CJ (1980) Behavioral and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat. Brain Res 192:163-172 Cianchetti C, Masala C, Magnoni A, Gessa GL (1980) Suppression of REM and delta sleep by apomorphine in man: a dopamine mimetic effect. Psychopharmacology 67 : 61-65 Di Chiara G, Porceddu ML, Vargiu L, Argiolas A, Gessa GL (1976) Evidence for dopamine receptors mediating sedation in the mouse brain. Nature 264: 564-566 Fuller RW, Clemens JA, Hynes MD (1982) Degree of selectivity of pergolide as an agonist at presynaptic versus postsynaptic dopamine receptors: implications for prevention of treatment of tardive dyskinesia. J Clin Psychopharmacol 2:371-375 Galzin AM, Dubocovich ML, Langer SZ (1982) Presynaptic inhibi- tion by dopamine receptor agonists of noradrenergic neu- rotransmission in the rabbit hypothalamus. 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