Lasting effects of dopamine receptor agonists upon striatal dopamine release in free-moving rats: an in vivo voltammetric study

BRAIN RESEARCH ELSEVIER

Brain Research 642 (1994) 199-205

Lasting effects of dopamine receptor agonists upon striatal dopamine release in free-moving rats: an in vivo voltammetric study Jacques H. Abraini *, Taoufiq Fechtali, Jean-Claude Rostain Laboratoire de Physiopathologie Int~gr~e et Cellulaire, CNRS URA 1630, Facult~ de M~decine Nord, 13916 Marseille C~dex 20, France (Accepted 16 December 1993)

Abstract

It is now well known that dopamine (DA) receptors agonists can reduce striatal DA release. These compounds are generally thought to produce short-term effects. However, in a recent in vivo study we have reported that the D1/D 2 receptor agonist apomorphine might induce decrements in striatal DA release that lasted several hours. In order to establish whether the effect of apomorphine was idiosyncratic or extended to other DA receptor agonists, we have investigated the effects of the selective D 1 receptor agonist SKF 38393 and of the selective D 2 receptor agonist LY 171555 upon striatal DA release using differential pulse voltammetry and multi-fibre carbon electrodes selective for DA. Results support that these DA receptor agonists can reduce DA release for several hours. The effects of SKF 38393 and of LY 171555 would be DA receptor-mediated since they can be blocked by the selective D 1 receptor antagonist SCH 23390 and the selective D 2 receptor antagonist sulpiride respectively. These findings are discussed at the light of current literature including methodological and biological data.

Key words: Dopamine; Dopamine receptor agonist; Dopamine receptor antagonist; Voltammetry

1. Introduction

Since evidence for D 1 and D z dopamine (DA) receptor subtypes has been demonstrated [16], considerable attention has been directed toward understanding the contributions of these receptor subtypes to the mediation of biochemical, physiological, and behavioral p h e n o m e n a induced by D A and its agonists. Since the pionner works, various groups have confirmed that D A receptor agonists can reduce D A release [26,28]. These effects are considered to be receptor-mediated since they can be blocked by well-known D A receptor antagonists. Opposingly, D A receptor antagonists can increase D A release [13,14,22]. D o p a m i n e receptor agonists are generally thought to produce upon striatal D A release short-term effects up to 3 h. However, recent data have reported, in rats implanted with microdialysis probe, dramatical changes in striatal D A release with no signs of return to D A basal value even 4 - 5 h following systemic injection of

D A receptor agonists [22]. Furthermore, in a recent report that followed an earlier in vivo voltammetric study on the effects of apomorphine [7], we have also reported, in free-moving rats implanted with DA-sensirive voltammetric electrodes, that intracerebroventricular (i.c.v.) administration of apomorphine might induce a decrease in striatal D A release that lasted several hours [3]. Thus, in order to establish whether the effect of apomorphine was idiosyncratic or extended to other D A receptor agonists, we have investigated the effects of the D1 receptor agonist SKF 38393 and of the D e receptor agonist LY 171555. Striatal D A release was monitored using differential pulse voltammetry and multi-fibre carbon electrodes selective for DA, that present the advantage of being suitable for use in chronically implanted animals for very long periods of time [9,10,11].

2. Materials and methods Animals and surgery * Corresponding author. Fax: (33) (91) 69-8927. 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved

SSDI 0 0 0 6 - 8 9 9 3 ( 9 3 ) E 1 6 5 8 - P

Male Sprague-Dawley rats weighing 300-350 g at the time of surgery were used. Rats were housed at 21+0.5°C in individual

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home cage under a 12-12 h light-dark cycle (lights on from 07.00 to 19.00 h) with free access to food and water. Multi-fibre working carbon electrodes (see below) and stainless steel cannulae (for i.c.v, administration of drugs) were stereotaxically implanted, according to the atlas of Konig and Klippel [19], in the dorsal caudate-putamen (A 8.62, L 2, H 1.4) and the right lateral ventricle (A 5.91, L 1.4, H 2), respectively, under general anaesthesia (pentobarbital sodium 30 mg/kg i.p. and ketamine 100 mg/kg i.m.). The reference and auxiliary electrodes (stainless steel screws) were fixed to the bone. The electrodes were attached to a miniconnector, and the whole assembly of electrodes, connector and cannulae was held in place with dental cement (reference resin cement, Ivoclar, Switzerland). After surgery, the animals were allowed to recover one week before being submitted to the pharmacological investigations. At the end of the experiments, histological control were performed. The brain was removed and sliced and the location of the working carbon electrode in the dorsal caudate-putamen was histologically checked, referring to the atlas of Konig and Klippel [19]. Electrodes and electrochemical measurements Multi-fibre working carbon electrodes were made, as described previously [10], from a rigid rod of 10,000 carbon fibres (ref. AGT 4F 10,000, Carbone Lorraine, France) sharpened at one extremity to reduce the external diameter of the electrode from 1 mm to 50 t~m at the tip. The entire electrode was encased in an insulating resin and the tip was exposed using an abrasive disc to shape the active surface of the electrode. Before use, the working carbon electrodes were electrochemically pretreated by applying a triangular wave potential of 0-3 V, 70 Hz, 20 s; 0-2 V, 70 Hz, 20 s; 0-1 V, 70 Hz, 15 s, to increase their sensitivity to DA, as previously described by Forni and Nieoullon [11]. In vivo electrochemical measurements were made as first developed by Kissinger et al. [18] in the rat brain, using differential pulse voltammetry according to the method developed by Forni and Nieoullon [11]. Voltammetric measurements were performed on unrestrained awake animals using a PRG5 polarograph (Tacussel,

10

France), and a classical 3-electrode potentiostatic system with reference, auxiliary, and working electrodes. During voltammetric in vivo recordings, the animals were connected to the polarograph through a flexible cable and a swivel connector. The polarograph was set to the following parameters: scan rate 10 m V / s or 20 mV/s, voltage range 0-1000 mV, pulse modulation amplitude 50 mV, pulse modulation duration 48 ms, pulse period 0.2 s. Electrochemical signals were amplified ( x 10) and recorded every 3 rain; and DA release was quantified automatically by measuring the height of the oxidation peak, using a computerized device. Electrode calibration Before being implanted, as it has been demonstrated that compounds such as ascorbic acid (AA), 3,4-dihydroxyphenylacetic acid (DOPAC), uric acid (UA), and homovanilic acid (HVA) slightly change the amplitude of the electrochemical response of the pretreated multi-fibre carbon electrodes for DA [9,11], the electrodes were calibrated in vitro in various solutions of these compounds of 10 -8 M to 10 -3 M to control their responsivity and their selectivity for DA as compared to these compounds. As previously described [9,11], the oxidation peaks of DA and DOPAC both occurred at 160 mV, while those of AA, UA, and HVA occurred at 90, 300 and 450 mV, respectively. The height of the voltammograms recorded in DA solutions of 10 -8 M to 10 -4 M consisted of electrochemical signals ranging from 3 nA to 40 nA (Fig. 1A). During in vivo recordings in awake~animals, voltammograms were amplified ( x 10). Electrochemical responses, with similar oxidation peaks than those recorded in DA solutions (peak-range 150-180 mV), were obtained ranging from 1.5 nA to 4 nA; the corresponding extracellular striatal DA concentration ranged from 5 x 10 -9 M to 5 x 10 -8 M (Fig. 1B). In some animals, preliminary pharmacological experiments were performed to further assess the in vivo selectivity of the pretreated multi-fibre carbon electrode for DA as compared to DOPAC. During these experiments, the following compounds were delivered i.c.v, at the doses stated: 10 -7 tool., i.e. 50 /zg/kg,

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Fig. 1. In vitro and in vivo calibration of the multi-fibre carbon working electrode. A: typical electrochemical response during in vitro calibration in various solutions of DA, DOPAC, ascorbic acid, HVA, and uric acid, ranging from 10 -8 M to 10 -3 M. B: in vivo amplified ( x l 0 ) electrochemical responses in awake animals, and calibration according to in vitro data. AA, ascorbic acid; DA, dopamine, DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanilic acid; UA, uric acid.

J.H. Abraini et al. /Brain Research 642 (1994) 199-205 a-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis; and 2 × 10 -7 mol, i.e. 75/.tg/kg, pargyline, a monoamine oxydase inhibitor which block DOPAC formation. These drugs were administered using a microsyringe in 10/*l phosphate-buffered saline (PBS) (pH 7.4) at a rate of injection of 2/zl/min.

Drug treatments Drugs were purchased from Research Biochemicals Inc., Natick, MA, USA, and delivered i.c.v, in 10/zl PBS using microsyringe (rate of injection 2 /zl/min). The following drugs were used at the doses stated: 5×10 -8 mol (16 /xg/kg) SCH 23390; 10 -8 mol (7/xg/kg) sulpiride; 2× 10 -8 mol (12/xg/kg) SKF 38393; 10 -8 mol (5/zg/kg) LY 171555; and 2 x 10 -8 mol (12 ~ g / k g ) S K F 38393 + 10 -8 tool (5 #g/kg) LY 171555. Control animals received vehicle alone. Data presentation and statistical analysis Drug-induced changes in DA release were expressed as a percentage change (positive or negative) relative to the mean of the electrochemical signals recorded before drug administration during a 2-h period of control taken as the 100% value, using median value and the 25th-75th percentiles. Statistical comparisons of drug- and vehicle-treated animals were made by a Kruskal-Wallis analysis of variance by ranks; following a significant H value, post hoc comparisons were made using the Mann-Whitney U-test.

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3. Results

Preliminary pharmacological experiments In some animals, preliminary pharmacological experiments were performed to further assess the in vivo selectivity of the pretreated multi-fibre carbon electrode for D A as compared to DOPAC. Results showed that AMPT, an inhibitor of DA synthesis, decreased the electrochemical response by 20-25%, whereas pargyline, a monoamine oxydase inhibitor that block D O P A C formation, increased it by 2 5 - 3 0 % (Fig. 2).

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t PARGYLINE

Vehicle controls on a 24-h period of time Basal values in striatal D A release were recorded during more than a 24-h period of time in non-injected animals, and in others injected with PBS. No significant difference was found between the data obtained in non-injected animals and those injected with PBS (Kruskall-Wallis, H 1 = 3.7, n.s.). D A release was found to be higher during the dark period than during the light period. This should be related to the fact that the dark period is the animal's active period, and therefore that D A release should increase in the striatum as a function of motor control. However, in both cases, the maximal fluctuations from the mean value of the 24-h of recording were less than + 8% during the dark period, and less than + 4% during the light period (Fig. 3).

Effects of dopamine receptor agonists Statistical analysis revealed a significant treatment effect of DA receptor agonists SKF 38393, LY 171555, and mixed SKF 38393 + LY 171555 ( H 3 = 61.5, P <

0.001).

so a

9

1'0 1'1 1'2 13 1'4 1'5 1'6 1'7 18 h

Fig. 2. Preliminary pharmacological experiments to further assess the in vivo selectivity of the pretreated multi-fibre carbon electrode for DA as compared to DOPAC. A: effect of i.c.v, administration of a-methyl-p-tyrosine (AMPT) at dose of 10 7 mol. (50/zg/kg) in four rats. B: effect of i.c.v, administration of pargyline, a monoamine oxydase inhibitor, which blocks DOPAC formation at dose of 2 × 10- 7 mol (75 ~tg/kg) in four other animals.

Fig. 4 shows the effect of SKF 38393 upon striatal DA release over a 24-h period. After administration of SKF 38393, a sustained decline in D A release was observed during the following 5 h, reaching a decrease of 20-30% that lasted the course of the experiment [H~ = 38.3, P < 0.001; U-test, P < 0.02]. This effect was blocked by the administration of the D 1 receptor antagonist SCH 23390, as injection of SKF 38393, 1 h after pretreatment with SCH 23390, had no effect ( H t = 0.48, n.s.) on D A increase induced by the administration of SCH 23390 that reached 20-25% from

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Fig. 3. Basal value in DA release recorded from the dorsal caudateputamen of free-moving rats during a 24-h period of control from 08.00 to 12.00 h next day in non-injected animals (line with open squares) and in animals i.c.v, injected with PBS saline solution (line with full squares). DA release is expressed as a percentage from the 24-h DA mean value; in each case, median values and the 25th-75th percentiles were obtained from n = 6. No significant difference was found between DA basal values recorded in non-injected animals and those injected with PBS. In both cases, an increase in striatal DA release can be seen during the dark period. This should be related to the fact that the dark period is the animal's active period, and therefore that DA release should increase in the striatum as a function of motor control.

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Fig. 5. Effect of 2×10 8 mol (12 tzg/kg) SKF 38393 i.c.v, after pretreatment with 5 × 10 -8 mol (16 /xg/kg) SCH 23390 i.c.v. (line with full squares) compared to the effect of 5×10 -8 (16 ~g/kg) SCH 23390 i.c.v, administered alone (line with open squares). In both cases, data were expressed as a percentage from a 2-h period of control before drug administration; raw basal values were not statistically different, ranging from 2 to 4 nA. Median values and the 25th-75th percentiles were obtained from n = 4 rats. Error bars on line with open squares (SCH 23390) were deleted for clarity of presentation.

20-30%

f r o m c o n t r o l value at t h e e n d o f t h e experi-

m e n t ( H t = 37.7, P < 0.001; U - t e s t , P < 0.02) ( F i g . 6). c o n t r o l d a t a ( H 1 = 9.50, P < 0.02) ( F i g . 5). A d m i n i s t r a t i o n o f t h e D 2 a g o n i s t L Y 171555 r e s u l t e d in a p r o g r e s -

This effect was b l o c k e d by t h e D 2 r e c e p t o r a n t a g o n i s t s u l p i r i d e . I n d e e d , i n j e c t i o n o f L Y 171555, 1 h 30 m i n

sive d e c l i n e in D A r e l e a s e t h a t r e a c h e d a d e c r e a s e o f

% DA baseline

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Fig. 4. Effect of 2× 10 -8 mol (12/xg/kg) SKF 38393 i.c.v, upon DA release in the dorsal caudate-putamen, recorded during a 24 h period and expressed as a percentage from a 2-h period of control before drug administration; raw basal values of drug- and vehicletreated animals were not statistically different, ranging for each group from 2 to 4 nA. Median values and the 25th-75th percentiles were obtained from n = 4 rats. ** P < 0.02, * P < 0.05 vs. vehicle controls (line with no squares).

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Fig. 6. Effect of 10 8 mo] (5 p,g/kg) LY 171555 i.c.v, upon DA release in the dorsal caudate-putamen recorded during a 24-h period and expressed as a percentage from a 2-h period of control before drug administration; raw basal values of drug- and vehicle-treated animals were not statistically different, ranging for each group from 2 to 4 hA. Median values and the 25th-75th percentiles were obtained from n = 4 rats. ** P < 0.02, * P < 0.05 vs. vehicle controls (line with no squares).

J.H. Abraini et al. /Brain Research 642 (1994) 199-205

140

203

ture of SKF 38393 + L Y 171555 resulted in a progressive decrease in striatal D A release significantly detectable only 2 h after injection ( H 1 = 35.9, P < 0.001; U-test, P < 0.05). This decrease in D A release was of lower amplitude than that of SKF 38393 administered alone, reaching only 1 5 - 2 0 % (Fig. 8).

% DA baseline

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4. D i s c u s s i o n 100

Voltammetry, drugs and dosing

A

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Fig. 7. Effect of 10 -8 mol (5/xg/kg) LY 171555 i.c.v, after pretreatment with 10-8 mol (7 gg/kg) sulpiride i.c.v. (line with full squares) compared to the effect of 10 -8 mol (7/~g/kg) sulpiride i.c.v, administered alone (line with open squares). In both cases, data were expressed as a percentage from a 2-h period of control before drug administration; raw basal values were not statistically different, ranging from 2 to 4 nA. Median values and the 25th-75th percentiles were obtained from n = 4 rats. Error bars on line with open squares (SCH 23390) were deleted for clarity of presentation.

after p r e t r e a t m e n t with sulpiride, p r o d u c e d no significant change ( H 1 = 0.22, n.s.) on the sulpiride-induced D A increase that r e a c h e d 1 5 - 2 0 % from control data ( H 1 = 9.48, P < 0.02) (Fig. 7). Administration of a mix-

% DA baseline

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at

T h e present in vitro calibration data confirmed that the pretreated multi-fibre carbon electrode has a high sensitivity for D A as c o m p a r e d to o t h e r e n d o g e n o u s c o m p o u n d s such as A A , D O P A C , H V A , and U A , although these c o m p o u n d s have b e e n d e m o n s t r a t e d to slightly alter the amplitude of the D A electrochemical response [9,11]. However, the most significant data in favour of the selectivity of the pretreated multi-fibre c a r b o n electrode for D A were obtained from in vivo preliminary pharmacological experiments. These control data showed that A M P T , an inhibitor of D A synthesis, decreased the electrochemical response, while pargyline, a M A O I which blocks D O P A C formation, increased it. These results confirm therefore that the p r e t r e a t e d multi-fibre working carbon electrode enable to m o n i t o r changes in striatal D A release. T h e p u r p o s e of the present study was to establish w h e t h e r the lasting decrease in striatal D A release induced by i.c.v, administration of a p o m o r p h i n e that we r e p o r t e d previously [3] was idiosyncratic or ext e n d e d to o t h e r D A r e c e p t o r agonists. Thus, the selective D 1 agonist SKF 38393 [25] and the selective D 2 agonist L Y 171555 [27] were used. Moreover, to further assess that the electrochemical responses were receptor-mediated, the selective D 1 antagonist S C H 23390 [13,15] and the selective D 2 antagonist sulpiride [24] were used. To avoid effects not related to D A r e c e p t o r activation because o f supramaximal doses, the doses chosen for each drug were selected to be in the middle of the dose-range described in the literature for intracranial administration of these compounds.

at

Effects o f DA receptor agonists 60 ¸

A Mixed SKF 38393 + LY 171555

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Fig. 8. Effect of i.c.v, administration of a mixture of 2× 10 s mol (12 /~g/kg) SKF 38393+10 -8 mol (5 /zg/kg) LY 171555 upon DA release in the dorsal caudate-putamen recorded during a 24-h period and expressed as a percentage from a 2-h period of control before drug administration; raw basal values of drug- and vehicle-treated animals were not statistically different, ranging for each group from 2 to 4 nA. Median values and the 25th-75th percentiles were obtained from n = 4 rats. * P < 0.05 vs. vehicle controls (line with no squares).

T h e effects r e p o r t e d in the present experiments confirmed previous data in which we r e p o r t e d similar effects of a p o m o r p h i n e u p o n striatal D A release [3]. This do not fit with the classical p h a r m a c o l o g y of drugs acting at the D A receptor level, as D A receptor agonists are t h o u g h t to induce u p o n D A release short-term effects up to 3 h. However, although H V A may not be a very accurate indicator of D A release, support for such lasting effects can be obtained from previous data which also r e p o r t e d similar effects of a p o m o r p h i n e and haloperidol, lasting 8 and 48 h, respectively, u p o n striatal D A release as reflected by striatal H V A levels

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[20]. Thus, we cautiously propose, as we suggested in a previous study [3], in absence at the present time of other explanations that the effects recorded in the present experiments could be due to the fact that, using the i.c.v, route of injection, drugs are stored in the cerebrospinal fluid and thus would act longer. Whatever, the capacity of the central nervous system, and of the subcortical D A systems in particular, to homeostatically compensate for aberrations in neurotransmitters levels [17,29] is often overlooked, and such decreases in the DA steady-state level may rapidly induce compensatory changes in order to maintain the system in its original functional state [12], as classically observed in experimental and clinical psychopharmacology of drugs acting at the DA receptor level. However, the possibility that such lasting effects are methodological rather than biological, i.e. for instance the consequence of the type of electrode, must be examined. This could consist in the adsorption of material onto the electrode surface. If so, this should constitute a limiting factor for the use of the multi-fibre carbon electrode during in vivo experiments. Nevertheless, recent data still in development in our laboratory clearly show the reversible and dynamic responsivity of the multi-fibre carbon electrode to drug-induced changes in DA release in superfused striatal brain slices. Pharmacology

The present reported effect of the D 2 agonist LY 171555 upon striatal D A release is in excellent agreement with previous studies which have demonstrated that intracaudal [13] or systemic administration [22,26] of LY 171555 significantly decreased D A release via D 2 receptor-mediated mechanisms. The inhibitory effect of intracerebral administration of SKF 38393 upon striatal D A release has been also demonstrated previously by Imperato and DiChiara [13]. However, as SKF 38393 dramatically reversed the D A increase induced by DA receptor antagonists such as haloperidol or SCH 23390, these authors suggested that the effect of SKF 38393 on D A release would be not related to D 1 receptor activation, but rather the consequence of a direct inhibitory effect of the drug on D A synthesis [131. In the present experiments, administration of SKF 38393 after prior injection of SCH 23390 showed no significant effects upon striatal DA release. This differential effects could be due, as suggested by Stamford et al. [26], to the high dose used by Imperato and DiChiara [13], as SKF 38393 has been demonstrated to have D 1 receptor-mediated effects at lower doses [4]. Further support for this hypothesis can be obtained from previous experiments in which we have demonstrated in rats exposed to high pressure, using similar doses, that pressure exposure reversed the effect of SKF 38393

upon striatal D A release [2] while it failed to similarly act on the AMPT-induced decrease in striatal D A release [1]. Finally, although we cannot firmly exclude an inhibitory action of SKF 38393 on D A synthesis, our results and hypothesis rather suggest that the effect of SKF 38393 on D A release would be D 1 receptor-mediated. An alternative hypothesis for explaining the effect of SKF 38393 as described by Imperato and Di Chiara [13], could be based on older data which suggested that D l receptor would have a high affinity for D A receptor agonists while D z receptors would present a high affinity for DA receptor antagonists [8,23]. Such a hypothesis could explain the effectiveness of SKF 38393 to alter the effects of SCH 23390 upon striatal DA release respectively, while LY 171555 failed to change the sulpiride-induced increase in D A release. Administration of a mixture of SKF 38393 + LY 171555 (dose-ratio 2:1) that stimulated both D 1 and D 2 pre- and postsynaptic receptors was found to induce a lower effect than that of SKF 38393 or LY 171555 administered alone. This result do not corroborate with previous pharmaco-behavioral studies which reported that the administration of a mixture of SKF 38393 + LY 171555 (dose-ratio from 5:1 to 14:1) induced higher effects than SKF 38393 or LY 171555 injected separately [5,21]. Referring to previous data [6], the different drug dose-ratio used in all of these experiments could be the critical factor in explaining the discrepancies. Alternatively, this could also reflect neurochemical homeostatic processes to compensate for DA receptor activation. In conclusion, the present study, performed in awake and unrestrained rats treated with physiological doses of D A receptor agonists, supports that the effect of SKF 38393 upon striatal D A release would be D 1 receptor-mediated. The present data also suggest that D A receptor agonists may induce lasting effects upon striatal DA release. This remain however to be further confirmed by other experiments.

5. Acknowledgements This work was supported by D R E T 90/176.

6. References [1] Abraini, J.H. and Rostain, J.-C., Effects of the administration of a-methyl-p-tyrosine on the striatal dopamine increase and the behavioral motor disturbances in rats exposed to high pressure, PharmacoL Biochern. Behav., 40 (1991) 305-310. [2] Abraini, J.H., Fechtali, T. and Rostain, J.-C., Pressure reversed extracellular dopamine decrease produced by D 1 receptor agonist SKF 38393, and De receptor agonist LY 171555 but failed

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