Effects of the D3 preferring dopamine agonist pramipexole on sleep and waking, locomotor activity and striatal dopamine release in rats

European Neuropsychopharmacology 8 (1998) 113–120

Effects of the D 3 preferring dopamine agonist pramipexole on sleep and waking, locomotor activity and striatal dopamine release in rats a a b, b a ´ Patricia Lagos , Cecilia Scorza , Jaime M. Monti *, Hector Jantos , Miguel Reyes-Parada , a b Rodolfo Silveira , Ana Ponzoni a

b

Division of Cellular Biology, Institute of Biological Sciences ‘ Clemente Estable’, Montevideo 11600, Uruguay Department of Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, Montevideo 11600, Uruguay Received 17 December 1996; accepted 3 June 1997

Abstract Quantitation of 2 h sessions after administration of the D 3 preferring dopamine (DA) agonist pramipexole (10–500 mg / kg) showed dose-related effects on wakefulness (W), slow wave sleep (SWS) and REM sleep in rats. The 30 mg / kg dose of the DA agonist increased SWS and REM sleep and reduced W during the first recording hour, while the 500 mg / kg dose augmented W. On the other hand, W was increased while SWS and REMS were decreased after the 500 mg / kg dose during the second recording hour. The mixed D 2 - and D 3 receptor antagonist YM-09151-2 (30–500 mg / kg), which per se affected sleep variables prevented the increase of REMS induced by pramipexole. Furthermore, the highest doses (500–1000 mg / kg) of the DA antagonist effectively antagonized the increase of W and reduction of SWS induced by the 500 mg / kg dose of the DA agonist. Pramipexole (30–100 mg / kg) induced a decrease of locomotor activity during the 2 h recording period. In addition, the 500 mg / kg dose gave rise to an initial reduction of motor behavior which was reverted 2 h later. Pramipexole (30 and 500 mg / kg) did not significantly affect striatal DA release during the first two hours following drug administration, as measured by microdialysis. It is tentatively suggested that D 3 receptor could be involved in the pramipexoleinduced increase of sleep and reduction of locomotor activity. On the other hand, the increase of W and of motor behavior after relatively high doses could be related to activation of postsynaptic D 2 receptor.  1998 Elsevier Science B.V. / ECNP Keywords: Pramipexole; YM-09151-2; Sleep-wakefulness; Locomotor activity; Dopamine

1. Introduction Until recently, the actions of dopamine (DA) on sleep and waking and on locomotor activity were proposed to be mediated by D 1 - and D 2 receptors. Thus, activation of postsynaptic DA D 1 - or D 2 receptor or blockade of presynaptic D 2 receptor reduces sleep and increases waking. Opposite effects are observed following blockade of the postsynaptic receptors or activation of the autoreceptor (Wauquier et al., 1980; Ongini et al., 1986, Ongini and Caporali, 1987; Monti et al., 1988, 1989, 1990). Moreover, drugs that interfere with postsynaptic D 1 - or D 2 receptor activity are known to suppress motor behavior. *Corresponding author. Tel.: 1598 2 470782; fax: 1598 2 473787; e-mail: [email protected]

Stimulation of postsynaptic D 2 receptor increases forward locomotion and stereotypes, while activation of D 1 receptor produces a syndrome characterized mainly by increased grooming and sniffing (Murray and Waddington, 1988; Jackson and Westlind-Danielsson, 1994). The application of molecular cloning techniques during the last few years led to the identification of novel DA receptors. They include the D 5 receptor which displays structural and pharmacological similarities to the D 1 receptor and is part of the D 1 -like subfamily, and the D 3 and D 4 receptors which show molecular and pharmacological homology with the D 2 receptor, and are included in the D 2 -like subfamily (Schwartz et al., 1992; Sibley and Monsma, 1992). The D 3 receptor is much less abundant and more narrowly distributed in the rat brain as compared to D 1 and

0924-977X / 98 / $19.00  1998 Elsevier Science B.V. / ECNP. All rights reserved. PII S0924-977X( 97 )00054-0

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D 2 receptors. It is expressed as postsynaptic receptor primarily in the olfactory tubercle, the islands of Calleja, the nucleus accumbens and the bed nucleus of the stria terminalis. The D 3 receptor is also expressed in the substantia nigra (pars compacta) and the ventral tegmental area, which indicates that it may serve a presynaptic function (Sibley and Monsma, 1992; Schwartz et al., 1992; Meador-Woodruff, 1995). Pramipexole (2-amino-4, 5, 6, 7-tetrahydro-6-propylamino-benzethiazole-dihydrochloride) is a novel DA D 2 like subfamily receptor agonist. It shows a much higher affinity for the D 3 receptor vs the D 2 receptor, Ki (D 2 ) / Ki (D 3 ) ratio amounting to 138.9 (Kreiss et al., 1995). The present study was designed to quantify the effect of the preferring D 3 receptor agonist pramipexole on sleep and waking, locomotor activity and striatal DA release in the rat. Since selective D 3 antagonists were not available at the time we performed our study, an attempt was made to ascertain whether pretreatment with the predominantly D 2 antagonist YM-09151-2 [cis-N-(1-benzyl-2-methylpyrrolidin-3yl)-5-chloro - 2 - methoxy-4-methylaminobenzamide], which shows also affinity for the D 3 receptor (Koshiya et al., 1991), would prevent the effect of pramipexole on sleep variables.

2. Methods

2.1. Sleep-waking recordings Male Wistar rats (School of Medicine Breeding Laboratories, Montevideo, Uruguay) weighing 350–380 g were implanted under general anesthesia (sodium pentobarbital 40.0 mg / kg) with Nichrome electrodes (200 mm diameter) for chronic sleep recording from the frontal and occipital cortex and from dorsal neck musculature. The animals were housed individually in a temperature controlled room (22618C) under 12 h light:12 h dark cycle (lights went on at 7.00 a.m. and went off at 7.00 p.m.), and with food and water ad libitum. Ten days after surgery the animals were habituated for three days to a chamber fitted with slip-rings and cable connectors, and the injection procedure. Thereafter they were given either a control solution or the drug(s) to be tested. The electrographic activity of 25 s epochs was analyzed and assigned to the following categories based on the waveform: waking (W), characterized by low-voltage fast waves in frontal cortex, and mixed theta rhythm (4–7 Hz) in occipital cortex and relatively high EMG activity; light sleep (LS), distinguished by high-voltage slow cortical waves interrupted by low-voltage fast EEG activity; slow wave sleep (SWS), individualized by continuous high-amplitude slow frontal and occipital waves combined with a reduced EMG, and REM sleep, characterized by low-voltage fast frontal waves, a regular theta rhythm in the occipital cortex, and a silent EMG except for occasional twitchings (Monti et al.,

1988). In addition, SWS and REM sleep latencies and the number of REM periods were determined. We studied the effects of pramipexole (Boehringer Ingelheim, Germany) 10–500 mg / kg and YM-09151-2 30–1000 mg / kg (Yamanouchi Pharmaceutical, Japan) given s.c. In the second set of experiments 30–500 mg / kg pramipexole was injected into animals pretreated with YM-09151-2 (30–1000 mg / kg). The drugs were given 15 min apart in the interaction experiments. YM-09151-2 was dissolved in a small volume of glacial acetic acid and was diluted with distilled water; the pH was adjusted to 6.0– 6.5. The rats were given the corresponding volume of control solution in the control sessions. Ten minutes after the last injection a 2 h sleep recording was started at approximately 8.00 a.m. One way analysis of variance with multiple measures was used for statistical comparison of three or more samples. The results showing overall changes were subjected to a Newman–Keuls test to identify the changes that differed significantly (P,0.05) from the baseline values.

2.2. Motor activity observations Male rats weighing 200–240 g were housed in groups of 6–8 under controlled conditions of temperature and light– dark cycle as described above, and were allowed free access to food and water. Rats were injected with pramipexole (2–500 mg / kg, s.c.) or saline, and placed immediately (group I) or two hours later (group II) onto the floor of an individual plastic cage (60360330 cm) equipped with photocells sensitive to infrared light, placed 40 mm above the floor. The photocells were spaced 40 mm apart. Locomotor activity, defined as the number of photocell beams interruptions was recorded during the light phase for a period of 30 min, starting 5 min after placing the animals into the cage (Scorza et al., 1996). The significance of drug effects was determined by one-way analysis of variance with multiple measures. Post-hoc analyses were made with the t-test. Significance level was set at P,0.05.

2.3. In vivo brain microdialysis Brain microdialysis experiments were performed in male rats weighing 200–240 g, anesthetized with urethane (3.0 g / kg, i.p.) and mounted in a Kopf stereotaxic frame. The skull was exposed and a hole was drilled in the area overlying the striatum. The coordinates to which the tip of the microdialysis probe (dialyzing length, 4.0 mm; diameter, 0.5 mm; CMA / Microdialysis AB, Stockholm, Sweden) was lowered with respect to bregma were A51 0.5; L513.0 and V517.0, according to the atlas of Paxinos and Watson, 1986. Body temperature was maintained at 378C using an electric heating pad. The microdialysis probes were perfused (2 ml / min) with artificial cerebrospinal fluid (aCSF; mM: NaCl, 140; KCl, 2.75;

P. Lagos et al. / European Neuropsychopharmacology 8 (1998) 113 – 120

CaCl 2 , 1.2; MgCl 2 , 0.85; pH56.7–6.8) by means of a microinjection pump (CMA / 100) and a syringe switch (CMA / 110). Samples (80 ml) were collected every 40 min into 5 ml of 0.1 M perchloric acid using a microfraction collector (CMA / 140). The animals were treated with pramipexole (30 or 500 mg / kg, s.c.) at 160 min. The extracellular concentration of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were then measured off-line by HPLC (PM-80, BAS, USA) with C-18 column (5 mm particles, 220 mm34.6 mm; BAS, USA), and an electrochemical detector (LC-4C, BAS, USA). Under our experimental conditions, the detection limit of the assay was 0.7 nM of DA (signal:noise ratio of 2:1). The mobile phase was composed of citric acid (0.15 M), sodium octyl sulfate (0.6 mM), 4% of acetonitrile and 1.6% of tetrahydrofuran at pH 3.0, with a flow-rate of 1.0 ml / min. Following each experiment, the animals were sacrificed and their brains removed to verify the probe location. The placement of the probes was examined microscopically. The significance of drug effects was determined by one-way analysis of variance. Post-hoc analyses were made with the t-test.

3. Results Quantitation of 2 h sessions after pramipexole (10–500 mg / kg) administration showed dose-related effects on W, SWS and REM sleep. The 30 mg / kg dose of the DA agonist decreased W and increased SWS, REM sleep and the number of REM periods during the first recording hour, while the largest dose (500 mg / kg) augmented W. On the other hand, W and REM sleep latency were increased while SWS, REM sleep and the number of REM periods were reduced after the 500 mg / kg dose during the second recording hour (Tables 1 and 2). As can be seen from Tables 3 and 4 the benzamide derivative YM-09151-2 (30–1000 mg / kg) significantly reduced REM sleep and the number of REM periods during the second recording hour. Light sleep and W showed significant increments after the 30–50 mg / kg and 1000 mg / kg doses, respectively. YM-09151-2 (30–500 mg / kg) prevented the increase of REM sleep and of the number of REM periods produced by pramipexole (30 mg / kg) during the first recording hour. In contrast, W showed a further reduction while SWS was increased (Tables 5 and 6). Moreover, YM-09151-2 (500– 1000 mg / kg) effectively antagonized the increase of W and reduction of SWS induced by the 500 mg / kg dose of pramipexole. Slow wave sleep latency was no longer significantly different as compared to control. Nevertheless, pramipexole-related increase of REM sleep latency, and reduction of REM sleep and of the number of REM periods during the second recording hour was not prevented by pretreatment with YM-09151-2 (Tables 7 and 8).

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Table 1 Effects of pramipexole on waking (W), light sleep (LS), slow wave sleep (SWS) and REM sleep (REMS) during 2 h sessions

0 –1 h Control Pramipexole 10 30 100 500 1 –2 h Control Pramipexole 10 30 100 500

W

LS

SWS

REMS

26.962.9

7.561.7

24.864.1

0.860.3

18.162.9 13.262.7 a 22.665.4 37.163.7 a

5.760.8 5.960.7 4.660.8 5.560.4

35.162.9 35.663.0 a 31.064.8 17.363.9

1.160.7 5.361.2 b 1.860.6 0

10.261.6

4.560.4

39.061.9

6.361.1

13.265.0 8.662.5 17.462.7 32.466.1 b

4.561.3 3.560.7 4.460.6 4.060.5

35.363.6 38.362.9 34.663.0 22.865.6 b

7.061.7 9.660.4 3.660.9 0.860.5 b

All values are the means 6 S.E.M. (min). Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.05; b P.0.01 (Neuman–Keuls test).

As illustrated in Fig. 1, pramipexole (10–500 mg / kg) caused a dose-dependent decrease of locomotor activity during the first 30 min after its administration. Locomotor activity was still reduced 2 h after the injection of the 30–100 mg / kg doses. On the other hand, rats given the 500 mg / kg dose showed a significant increase of motor behavior (Fig. 2). In the microdialysis experiments, following an 80–120 min baseline period, basal absolute levels (mean 6 S.E.M., nM) of DA, DOPAC and HVA in striatum dialysates were 6.562.6, 2008.06627.2 and 1440.36267.0, respectively. Figs. 3 and 4 show the effect of pramipexole 30 or 500 mg / kg on DA, DOPAC and HVA release. Either dose of pramipexole induced a slight-to-moderate decrease of dialysate DA and of its two principal metabolites during the first 2 h following drug administration (three collected fractions). However, changes did not attain significance as compared to control.

4. Discussion The D 3 preferring DA agonist pramipexole (30–500 mg / kg) caused a dose-dependent decrease of locomotor activity shortly after its administration. This effect was still evident 2 h later in the 30–100 mg / kg treated animals. In contrast, rats given 500 mg / kg pramipexole were significantly more active as compared to control. Pramipexole induced dose-related effects on sleep and waking. A low dose (30 mg / kg) increased SWS and REM sleep and reduced W, and a large dose (500 mg / kg) induced opposite changes. Truly selective DA D 3 antagonists were not available at the time we performed our study, which precluded estab-

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Table 2 Effects of pramipexole on sleep latencies and number of REM periods Slow wave sleep latency (min)

Control Pramipexole 10 30 100 500

REM sleep latency (min)

No. of REM periods 0–1 h

1–2 h

11.164.2

47.768.1

0.860.3

2.660.4

5.561.3 6.061.2 5.861.0 2.661.0

58.568.5 29.664.6 60.3612.8 143.8620.4 b

0.560.3 2.560.5 a 0.860.3 0

3.060.4 3.660.4 1.860.7 0.560.3 a

All values are the means 6 S.E.M. Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.01; b P,0.001 (Newman–Keuls test).

Table 3 Effects of YM-09151-2 on waking (W), light sleep (LS), slow wave sleep (SWS) and REM sleep (REMS) during 2 h sessions W

0 –1 h Control YM-09151-2 30 50 500 1000 1 –2 h Control YM-09151-2 30 50 500 1000

LS

SWS

REMS

26.962.9

7.561.7

24.864.1

0.860.3

16.963.4 23.662.6 29.963.8 31.164.1

10.461.2 11.161.5 8.462.3 7.861.7

32.164.2 25.363.2 21.462.5 21.165.0

0.660.4 0 0.360.3 0

10.261.6

4.560.4

39.061.9

6.361.1

4.761.3 7.461.6 14.960.7 19.262.1 b

9.961.7 a 10.161.8 a 5.861.0 5.560.8

42.362.0 40.561.6 38.360.9 35.362.9

3.161.0 b 2.061.2 b 1.060.5 b 0c

All values are the means 6 S.E.M. (min). Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.02; b P,0.01; c P,0.001 (Newman–Keuls test).

lishing conclusively the functional role of D 2 - or D 3 receptor in the effect of pramipexole on sleep and wakefulness. The predominantly D 2 antagonist YM-09151-2 which shows also affinity for the D 3 receptor (Koshiya et al., 1991), did not antagonize the increase of SWS and reduction of W induced by 30 mg / kg pramipexole. Al-

though REM sleep regained control values, it should be taken into consideration that YM-09151-2 suppressed REM sleep per se. On the other hand, the DA blocker prevented the increase of W and reduction of SWS caused by 500 mg / kg pramipexole. Thus, it could be tentatively suggested that opposite effects observed on sleep variables and on locomotor activity after low or high doses of pramipexole, are related to different mechanisms of action. Our experimental conditions do not discriminate between the involvement of D 2 - or D 3 receptor in the pramipexole-induced changes of locomotor behavior and sleep variables. However, the reduction of locomotor activity and increase of sleep cannot be attributed to presynaptic mechanisms involving changes in DA release (e.g., presynaptic D 2 receptors), because pramipexole did not significantly affect striatal DA release during the first 2 h following drug administration. Pertinent to our discussion are the studies with 3 Hpramipexole showing its preference for D 3 -binding sites, both at presynaptic (ventral tegmental area and substantia nigra) and postsynaptic (islands of Calleja, nucleus accumbens, olfactory tubercle, amygdala, caudate) regions (Camacho-Ochoa et al., 1995). In addition, pramipexole’s in vivo potency to reduce spontaneous locomotor activity in mice shows a significant correlation with its in vitro D 3 binding affinity as compared to other DA agonists (Sautel et al., 1995). Thus, it could be speculated that the reduction of locomotor activity and increase of sleep after a low dose pramipexole (30 mg / kg) depends upon the

Table 4 Effects of YM-09151-2 on sleep latencies and number of REM periods Slow wave sleep latency (min)

Control YM-09151-2 30 50 500 1000

REM sleep latency (min)

No. of REM periods 0–1 h

1–2 h

11.164.2

47.068.1

0.860.3

2.660.4

4.661.4 15.562.9 19.065.1 12.661.8

76.6616.6 100.0624.8 82.0615.6 131.0610.6 c

0.360.2 1.661.6 1.661.6 0

1.360.4 a 1.060.6 b 0.660.3 c 0d

All values are the means 6 S.E.M. Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.05; b P,0.02; c P,0.01; d P,0.001 (Newman–Keuls test)

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Table 5 Effect of YM-09151-2 (30–50 mg / kg) pretreatment on the pramipexole (30 mg / kg)-induced changes of sleep and wakefulness W

LS

SWS

REMS

0 –1 h Control Pramipexole 30 YM-09151-2 30 1 Pramipexole 30 YM-09151-2 50 1 Pramipexole 30

28.662.3 14.962.2 d 9.262.2 d 7.662.1 d

8.061.6 5.760.8 10.862.8 10.762.2

22.863.6 34.662.4 b 39.564.7 d 41.163.5 d

0.660.2 4.861.4 c 0.560.3 0.660.4

1 –2 h Control Pramipexole 30 YM-09151-2 30 1 Pramipexole 30 YM-09151-2 50 1 Pramipexole 30

9.961.5 7.462.3 8.163.4 6.461.5

39.161.9 41.363.1 42.364.1 43.363.0

6.661.0 8.161.7 1.160.6 c 1.660.9 c

4.460.4 3.260.6 8.561.6 b 8.761.5 a

All values are the means 6 S.E.M. min. Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.05; b P,0.02; c P,0.01; d P,0.001 (Newman–Keuls test).

Table 6 Effects of pramipexole (30 mg / kg) and YM-09151-2 (30–50 mg / kg) pretreatment on sleep latencies and number of REM periods Slow wave sleep latency (min)

Control Pramipexole 30 YM-09151-2 30 1 Pramipexole 30 YM-09151-2 50 1 Pramipexole 30

12.064.1 6.161.1 2.161.0 4.061.8

REM sleep latency (min)

No. of REM periods

47.368.1 48.6621.2 107.0628.4 a 79.6616.5

0–1 hr

1–2 hr

0.660.2 2.160.7 c 0.360.2 0.360.2

2.860.4 3.160.7 0.860.4 a 1.060.4 b

All values are the means 6 S.E.M. Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.05; b P,0.02; c P,0.01 (Newman–Keuls test).

Table 7 Effect of YM-09151-2 (500–1000 mg / kg) pretreatment on the pramipexole (500 mg / kg)-induced changes of sleep and wakefulness W

LS

SWS

REMS

0 –1 h Control Pramipexole 500 YM-09151-2 500 1 Pramipexole 500 YM-09151-2 1000 1 Pramipexole 500

26.962.9 37.263.7 a 13.963.9 a 23.663.7

7.561.7 5.560.4 13.061.7 b 8.061.7

24.864.1 17.363.9 33.163.9 28.164.8

0.860.3 0 0 0.360.3

1 –2 h Control Pramipexole 500 YM-09151-2 500 1 Pramipexole 500 YM-09151-2 1000 1 Pramipexole 500

10.261.6 32.466.1 d 7.762.5 13.961.2

4.560.4 4.060.5 9.462.1 a 7.561.9

39.061.9 22.865.6 c 42.862.4 37.162.3

6.361.1 0.860.5 d 0.160.1 d 1.560.7 d

All values are the means 6 S.E.M. min. Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.05; b P,0.02; c P,0.01; d P,0.001 (Newman–Keuls test).

Table 8 Effects of pramipexole (500 mg / kg) and YM-09151-2 (500–1000 mg / kg) pretreatment on sleep latencies and number of REM periods Slow wave sleep latency (min)

Control Pramipexole 500 YM-09151-2 500 1 Pramipexole 500 YM-09151-2 10001 Pramipexole 500

11.164.2 2.661.0 a 3.361.2 a 11.062.3

REM sleep latency (min)

47.068.1 143.8620.4 b 145.1612.8 a 131.1631.9 c

All values are the means 6 S.E.M. Six animals were in each experimental group. The doses are in mg / kg. Compared with control values: a P,0.05; b P,0.02; c P,0.01; d P,0.001 (Newman–Keuls test).

No. of REM periods 0–1 h

1–2 h

0.860.3 0 0 0.160.1

2.660.4 0.560.3 d 0.160.1 d 0.660.3 d

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Fig. 1. Effect of pramipexole on locomotor activity in the photobeam actometer. Rats were injected s.c. with either drug (2–500 mg / kg) or saline and recorded during the next 30 min. Each bar represents the mean6S.D. of beam crosses of 8–9 rats per condition. Compared with control values: * p,0.05; ** p,0.001 (t-test).

activation of D 3 receptor, while a preferential stimulation of postsynaptic D 2 receptor could tentatively explain the increase of wakefulness and of motor behavior following the 500 mg / kg dose (Maj et al., 1996; Piercey et al., 1995). However, further studies with selective D 3 antagonists are needed to resolve this issue. How do our findings with pramipexole relate to previous work where the effects of selective or relatively selective D 2 agonists were assessed on sleep variables? Studies where the predominantly D 2 agonists apomorphine, bromocriptine and quinpirole were given to rats over a wide range of doses showed biphasic effects such that low doses decreased wakefulness and increased slow wave sleep and REM sleep, while large doses induced opposite Fig. 3. Effect of pramipexole 30 mg / kg, administered s.c. at 160 min, on the extracellular concentration of DA, DOPAC and HVA in the striatum of urethane-anesthetized rats, as measured by microdialysis associated with HPLC–ED. Results are the means6S.E.M. of nine different experiments and are expressed as the percentage of baseline levels. Analysis of variance showed no statistically significant differences as compared to baseline.

Fig. 2. Effect of pramipexole on locomotor activity in the photobeam actometer. Rats were recorded during a 30 min period, 2 hours after s.c. injection of either drug (30–500 mg / kg) or saline. Each bar represents the mean 6 S.D. of beam crosses of 8–9 rats per condition. Compared with control values: * p,0.01; ** p,0.001 (t-test).

effects. Pretreatment with haloperidol in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine or bromocriptine (Wauquier, 1985, 1995; Monti et al., 1988, 1989). The increase of sleep after doses of D 2 agonists which reduce striatal DOPA and HVA levels (Baudry et al., 1977; Summers et al., 1981) could be related to activation of presynaptic D 2 receptors located on DA axons of mesolimbic and mesocortical systems. Interpretation of the postsynaptic effects of D 2 agonists is hampered by the lack of information about the neuroanatomy and neurophysiology involved in translating the effects of stimulation of D 2

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References

Fig. 4. Effect of pramipexole 500 mg / kg, administered at 160 min on the extracellular concentrations of DA, DOPAC and HVA in the striatum of urethane-anesthetized rats as measured by microdialysis associated with HPLC–ED. Results are the means6S.E.M. expressed as in Figure 3. Analysis of variance showed no statistically significant differences as compared to baseline.

receptors into a reduction of sleep and increase of wakefulness. Concerning extrapolation of our findings to clinical applications, the property of a low dose pramipexole to reduce locomotor activity could make it a practical drug for administration in patients who have Parkinson’s disease with short duration L-dopa responses.

Acknowledgments This work was supported by grants from BIDCONICYT (038 / 94) and PEDECIBA.

Baudry, M., Costentin, J., Marcais, H., Martres, M.P., Protais, P., Schwartz, J.C., 1977. Decreased responsiveness to low doses of apomorphine after dopamine agonists and the possible involvement of hyposensitivity of dopamine ‘autoreceptors’. Neurosci. Lett. 4, 203– 207. Camacho-Ochoa, M., Walker, E.L., Evans, D.L., Piercey, M.F., 1995. Rat brain binding sites of pramipexole, a clinically useful D 3 -preferring dopamine agonist. Neurosci. Lett. 196, 97–100. Jackson, D.M., Westlind-Danielsson, A., 1994. Dopamine receptors: molecular biology, biochemistry and behavioral aspects. Pharmacol. Ther. 64, 291–369. Koshiya, K., Hidaka, K., Usuda, S., 1991. YM-09151-2 reverses quinpirole-induced immobility in mice: Possible interaction with D 3 receptor. Biol. Psychiatry 29, 610. ´ Kreiss, D.S., Bergstrom, D.A., Gonzalez, A.M., Huang, K.-X., Sibley, D.R., Walters, J.R., 1995. Dopamine receptor agonist potencies for inhibition of cell firing correlate with dopamine D 3 receptor binding affinities. Eur. J. Pharmacol. 277, 209–214. ´ Z., Skuza, G., 1996. Pramipexole, a selective dopamine Maj, J., Rogoz, receptor agonist with potential antidepressant activity. Eur. Neuropsychopharmacol. Abstr. 3, 11. Meador-Woodruff, J.H., 1995. Neuroanatomy of dopamine receptor gene expression: potential substrates for neuropsychiatric illness. Clin. Neuropharmacol. 18, 14–24. ´ Monti, J.M., Hawkins, M., Jantos, H., D’Angelo, L., Fernandez, M., 1988. Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat. Psychopharmacology 95, 395–400. ´ Monti, J.M., Jantos, H., Fernandez, M., 1989. Effects of the selective dopamine D-2 receptor agonist, quinpirole on sleep and wakefulness in the rat. Eur. J. Pharmacol. 169, 61–66. ´ Monti, J.M., Fernandez, M., Jantos, H., 1990. Sleep during acute dopamine D 1 agonist SKF 38393 or D 1 antagonist SCH 23390 administration in rats. Neuropsychopharmacology 3, 153–162. Murray, A.M., Waddington, J.L., 1988. The behavioral role of the D-1 dopamine receptor probed with the new putative agonist CY 208-243. Psychopharmacology 96, 40. Ongini, E., Caporali, M.G., Massotti, M., 1986. Selective stimulation of dopamine D-1 and D-2 receptors leads to EEG activation and behavioral arousal. In: Biggio, G., Spano, P.F., Toffano, G., Gessa, G.L. (Eds.), Modulation of Central and Peripheral Transmitter Function. Fidia Research Series. Symposia in Neuroscience, vol. 3, Liviana Press, Padova, pp. 37–46. Ongini, E., Caporali, M.G., 1987. Differential effects of dopamine D-1 and D-2 receptor agonists on EEG activity and behavior in the rabbit. Neuropharmacology 26, 355–360. Paxinos, G., Watson, C., 1986. The Rat Brain, 2nd. ed., Academic Press, Sydney. Piercey, M.F., Camacho-Ochoa, M., Smith, M.W., 1995. Functional roles for dopamine-receptor subtypes. Clin. Neuropharmacol. 18, 34–42. ´ Sautel, F., Griffon, N., Levesque, D., Pilon, C., Schwartz, J.-C., Sokoloff, P., 1995. A functional test identifies dopamine agonists selective for D 3 versus D 2 receptors. Neuroreport 6, 329–332. Schwartz, J.C., Giros, B., Martres, M.P., Sokoloff, P., 1992. The dopamine receptor family: molecular biology and pharmacology. Semin. Neurosci. 4, 99–108. Scorza, M.C., Reyes-Parada, M., Silveira, R., Viola, H., Medina, J.H., Viana, M.B., Zangrossi, H., Graeff, F.G., 1996. Behavioral effects of the putative anxiolytic (6)-1-(2,5-dimethoxy-4-ethylthiophenyl)-2aminopropane (ALEPH-2) in rats and mice. Pharmacol. Biochem. Behav. 54, 355–361. Sibley, D.R., Monsma, F.J., 1992. Molecular biology of dopamine receptors. Trends Pharmacol. Sci. 13, 61–69. Sumners, C., De Vries, J.B., Horn, A.S., 1981. Behavioral and neurochemical studies on apomorphine-induced hypomotility in mice. Neuropharmacology 20, 1203–1208.

120

P. Lagos et al. / European Neuropsychopharmacology 8 (1998) 113 – 120

Wauquier, A., Van den Broeck, W.A.E., Janssen, P.A.J., 1980. Biphasic effects of pimozide on sleep-wakefulness in dogs. Life Sci. 27, 1469–1475. Wauquier, A., 1985. Active and permissive roles of dopamine in sleepwakefulness regulation. In: Wauquier, A., Gaillard, J.M., Monti, J.M.,

Radulovacki, M. (Eds.), Sleep: Neurotransmitters and Neuromodulators. Raven, New York, pp. 107–120. Wauquier, A., 1995. Pharmacology of the catecholaminergic system. In: Kales, A. (Ed.), The Pharmacology of Sleep. ch. 4, Springer, Berlin, pp. 65–90.