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The dopamine D2 agonist LY 141865, but not the D1 agonist SKF 38393, reverses parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset
Neuroscience Letters, 57 (1985) 37-41
37
Elsevier Scientific Publishers Ireland Ltd.
NSL 03324
THE DOPAMINE D 2 AGONIST LY 141865, BUT NOT THE Dt AGONIST SKF 38393, REVERSES PARKINSONISM INDUCED BY 1 - M E T H ~ P H E N Y L 1,2,3,6-TETRAHYDROPYRIDINE (MPTP) IN THE COMMON MARMOSET
M. NOMOTO, P. JENNER and C.D. MARSDEN*
MRC Movement Disorder Research Group, University Department of Neurology and Parkinson's Disease Society Research Centre, Institute of Psychiatry & King's College Hospital Medical School, Denmark Hill, London SE5 ( U.K. ) (Received October 2nd, 1984; Revised version received March 5th, 1985; Accepted March 16th, 1985)
Key words: l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine- MPTP - parkinsonian akinesia - marmoset -
LY 141865 - SKF 38393
Marmosets treated with l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) (1-4 mg/kg i.p. daily for up to 8 days) develop profound parkinsonian akinesia. Administration of the Dt agonist SKF 38393 (1-20 mg/kg i.p.) 4-6 weeks later had no effect on the motor activity of animals pretreated with MPTP. In contrast, the administration of the D2 agonist LY 141865 (0.1 or 0.5 mg/kg i.p.) caused a marked increase in motor activity lasting for up to 2 h. We conclude that stimulation of D2 dopamine receptors is essential for motor activation of parkinsonian marmosets and that D~ stimulation alone is not sufficient to overcome the akinesia induced by MPTP treatment.
Dopamine (DA) receptors in brain can be divided into at least two classes, namely D~ receptors linked to adenylate cyclase and D2 receptors which are not directly linked to this enzyme [5]; each may exist in different afinity states [3]. All functional effects of DA receptor activation, such as the inhibition of apomorphine-induced motor behaviours [8], drug potency in the control of schizophrenia [11] and the control of Parkinson's disease [10], hitherto have been attributed to the action of drugs on the D2 receptor population. The function of Dl receptors in brain has been uncertain. SKF 38393, which selectively activates Di receptors, but is only weakly effective on D2 sites [13], has been found to cause contralateral rotation in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigro-striatal pathway but not to cause stereotypy or rotation in rats with a unilateral electrolesion of the striatum or to cause emesis or prolactin release [2, 12]. To determine whether stimulation of Dt receptors is important in the control of parkinsonian symptoms, we have compared the ability of SKF 38393 with that of the D2 agonist LY 141865 [14] to reverse akinesia induced by the prior treatment of marmosets with the selective DA neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [1, 4, 7]. *Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
38 Thirteen c o m m o n marmosets of either sex (weight range 280 to 430 g) were treated with M P T P in doses of 1~4 mg/kg i.p. daily for up to 8 days. Since the individual response of animals differed markedly, variable dosage regimes were used so as to render them parkinsonian. Following treatment, animals were allowed to recover from the acute effects of M P T P treatment for up to 6 weeks. M P T P was dissolved in a minimum quantity of 70~o alcohol and diluted to volume with 0.9!~ saline. For comparison 4 normal marmosets were also employed. Behavioural testing was carried out by removing each animal from its home cage and placing it in a novel cage environment in isolation from other animals in the colony, after which a video sequence of its behaviour was filmed. The animal was allowed 30 min to acclimatize to this novel environment. Animals then received either S K F 38393 (1-20 mg/kg i.p., 5 animals) or LY 141865 (0.1 mg/kg i.p., 4 animals; or 0.5 mg/kg i.p., 8 animals), or (+)-sulpiride (20 mg/kg i.p.) which was administered 1 h prior to LY 141865 (0.5 mg/kg i.p.) in 4 animals, or 0.9<,~ saline (4 animals). Untreated control marmosets (4 animals) received either LY 141865 (0.1 or 0.5 mg/kg i.p.) or 0.9','~o saline. The behaviour of the animals was observed over the following I20 min by video recording. The number of movements of the animal across either the 4 base segments of the cage or in a vertical direction between the floor and perches of the cages was recorded every 5 min. The intensity of checking behaviour was assessed every 5 rain as follows: 0, nil; 1, occasional; 2, frequent; 3, discontinuous; 4, continuous. When an animal was reexamined there was an interval of at least l0 days before the next experiment. When observed 30 rain following introduction into the novel cage environment,
A
B F "°° lOO-
.'\
c \
"
h
J
"
-
z 6o-
~
_
~ 2o-
o-
10
20
30
40
50 TIME
60
70
80
90
100 110 120
rnin
Fig. 1. A: the effect of administration of L Y 141865 (0.5 mg/kg i.p., m ) or SKF 38393 0 - 2 0 mg/kg !.P,; Q) on the number of movements made by animals previously treated with MPTP (1-4 mg/kg i.p. daily)~
The results are expressed as the mean value for 5 or 8 animals in each treatment group. B: the total number of movements made by MPTP-treated animals receiving either LY 141865 (0.5 mg/kg i.p., I ) or SKF 38393 (I .0-20 mg/kg i.p.; 0) over a 5-min period starting 30 min followingdrug administration.
39 TABLE I M O V E M E N T C O U N T S A N D T H E I N T E N S I T Y O F C H E C K I N G B E H A V I O U R IN T H E P E R I O D 30-35 min F O L L O W I N G D R U G O R S A L I N E T R E A T M E N T O F N O R M A L A N D M P T P TREATED MARMOSETS The results are expressed as the mean value for 4-8 animals in each treatment group. Details of the experiment are described in the text and in the legend to the figure. Treatment group
N u m b e r of animals
Drug treatment (mg/kg)
Total movements/5 min
Intensity of checking behaviour
Control Control Control MPTP MPTP MPTP MPTP
4 4 4 4 4 8 4
4 13 84 0 19 102 0
1.0 1.7 3.0 0 2.3 3.8 0
MPTP
5
Saline LY 141865 (0.1) LY 141865 (0.5) Saline LY 141865 (0.1) LY 141865 (0.5) LY 141865 (0.5) + ( _)-sulpiride (20) S K F 38393 (1-20)
0
0
MPTP-treated animals were usually immobile, either on the perch or floor of the cage, and showed little or no spontaneous checking or blinking movements. Any movement made was slow and deliberate. Control animals also showed relatively few movements following the acclimatization period. However, the quality of motor behaviour differed markedly in that their movements occupied a greater cage area and were faster and better coordinated than those observed in the MPTP-treated group. In addition, control animals exhibited frequent blinking. The administration of SKF 38393 (1-20 mg/kg i.p.) did not alter the behaviour of any MPTP-treated animal over the next 30-120 min (Fig. 1, Table I). The animals remained immobile in a fixed position with little or no checking or blinking movements. In contrast, the administration of LY 141865 (0.1 or 0.5 mg/kg i.p.) caused profound dose-dependent behavioural activation of MPTP-treated animals (Fig. 1, Table I). Within a few minutes of drug administration most of the animals either retched or vomited for up to 10 min. After approximately 10 min all of the animals began to become alert, with an increase in the number of checking movement and a gradual increase in general movement from place to place within the test cage. Movements were well coordinated and included normal running on the floor of the cage, jumping up to high perches or down to the floor, grasping of perches and cage walls, feeding and grooming, and continuous checking behaviour. Most of this repertoire of movement appeared normal, but occasionally there were brief periods of explosive motor action, and sometimes inappropriate chewing occurred. In addition, these animals also exhibited frequent checking and blinking movements. The duration o f effect of LY 141865 (0.5 mg/kg i.p.) varied between animals from approximately 30 min to 2 h. The behaviourai activation caused by LY 141865 in
40
MPTP-treated animals was prevented by the prior administration of (+_)-sulpiride (20 mg/kg, 1 h previously). In control animals, the administration of LY 141865 (0.1 or 0.5 mg/kg i.p.) also produced dose-dependent behavioural activity (Table I). The results suggest that stimulation of D2 receptors but not D~ receptors causes activation of motor behaviour in parkinsonian marmosets pretreated with the nigrostriatal DA neurotoxin MPTP. The lack of effect of SKF 38393 was surprising in view of reports that this compound can induce contralateral rotation in rats with a prior unilateral 6-OHDA lesion of the nigro-striatal pathway [2, 12]. This suggested that SKF 38393 might alleviate parkinsonian symptoms, even though it does not produce classical DA agonist behaviours in normal animals. DA agonist drugs used to control Parkinson's disease vary in their Dr/D2 characteristics. L-dihydroxyphenylalanine itself presumably gives rise to activation of both D1 and D2 receptors, whereas a drug such as bromocriptine activates D2 receptors but does not stimulate Di receptors and may even inhibit the stimulant effects of DA on adenylate cyclase activity [9]. Pergolide on the other hand, which is another effective anti-parkinsonian DA agonist, can activate both D 1 and D2 receptors [6, 15]. From this study it would appear that it is the effects of these drugs on D2 receptors that are important in reversing parkinsonian symptoms. However, these studies do not reveal whether or not the addition of Dl receptor activation (or indeed inhibition) to D2 agonist properties may provide added advantage or disadvantage to the benefit received by parkinsonian patients when treated with such drugs. If the conclusions drawn from these experiments in marmosets are borne out by the effects of Di agonists in man, then it may be that the MPTP-treated marmosets will provide a more useful means of screening novel anti-parkinsonian compounds than the currently used rodent models. This study was supported by the Medical Research Council, the Parkinson's Disease Society and the Research Funds of Bethlem Royal and Maudsley Hospitals and King's College Hospital. M.N. is a British Council Scholar. We wish to thank Mr. Alan Brady and Mr. Michael Jackson for their excellent technical assistance in the undertaking of these experiments. We also thank Dr. Alan Marriott, Dr. S. Pay and Mr. S.P. Close, Glaxo Laboratories, for their help in initiating these experiments.
1 Burns, R.S., Chiueh, C.C., Markey, S.P., Ebert, M.H., Jacobowitz, D.M. and Kopin, 1.J., A primate model for Parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l,2,5,6-tetrahydropyridine, Proc. Natl. Acad. Sci. USA, 80 (1983) 454&4550. 2 Costall, B., Kelly, M.E. and Naylor, R.J., Unilateral striatal dopamine destruction: reduced motor inhibiting effects of dopamine antagonists reveal~l in models of asymmetry and circling behaviour, Naunyn-Schmiedeberg's Arch. Pharmacol., 326 (1984) 29-35. 3 Grigoriadis, D. and Seman, P., The dopamine/neuroleptic receptors, Canad. J. Neurol. Sci., I I (1984) 108-113. 4 Jenner, P., Rupniak, N.M.J., Rose, S., Kelly, E., Kilpatrick, G., Lees, A. and Marsden, C.D., 1Methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset, Neurosci. Lett., 50 (1984) 85-90.
41 5 Kebabian, J.W. and Calne, D.B., Multiple receptors for dopamine, Nature (Lond.), 277 (1979) 93-96. 6 Koller, W.C., Weiner, W.J., Diamond, B.I., Nausieda, P.A. and Klawans, H.L., The pharmacological evaluation of pergolide mesylate as a potential antiparkinsonian agent, Neuropharmacology, 19 (1980) 831-837. 7 Langston, J.W., Forno, L.S., Rebert, C.S. and Irwin, I., Selective nigral toxicity after synaptic administration of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine, Proc. Natl. Acad. Sci. USA, 80 (1983) 4546~550. 8 Leysen, J.E., Review on neuroleptic receptors: specificity and multiplicity of in vitro binding related to pharmacological activity. In E. Usdin, S.G. Dahl, L.F. Gram and O. Lingjaerde (Eds.), Clinical Pharmacology in Psychiatry: Neuroleptic and Antidepressant Research, Macmillan, London, 1981, pp. 35-62. 9 Markstein, R. and Herrling, P.L., The effect of bromocriptine on rat striatal adenylate cyclase and rat brain monoamine metabolism, J. Neurochem., 31 (1978) 1163-1172. 10 Schachter, M., Bedard, P., DeBono, A.G., Jenner, P., Marsden, C.D., Price, P., Parkes, J.D., Keenan, J., Smith, B., Rosenthaler, J., Horowski, R. and Dorrow, R., The role of D-I and D-2 receptors, Nature (Lond.), 286 (1980) 157-159. 11 Seeman, P., Brain dopamine receptors, Pharmacol. Rev., 32 (1980) 229-313. 12 Setler, P.E., Saray, H.M., Zirkle, C.L. and Saunders, H.L., The central effects of a novel dopamine agonist, Europ. J. Pharmacol., 50 (1978) 419-430. 13 Sibley, D.R., Leff, S.E. and Creese, I., Interactions of novel dopaminergic ligands with D-1 and D-2 dopamine receptors, Life Sci., 31 (1982) 637-645. 14 Tsuruta, K., Frey, E.A., Grewe, C.W., Cote, T.E., Eskay, R.L. and Kebabian, J.W., Evidence that LY 141865 specifically stimulates the D-2 dopamine receptor, Nature (Lond.), 292 (1981) 463-465. 15 Wong, D.T. and Reid, L.R., Activation of adenylate cyclase in rat striatum by an ergoline dopamine agonist pergolide, Commun. Psychopharmacol., 4 (1980) 269-275.
37
Elsevier Scientific Publishers Ireland Ltd.
NSL 03324
THE DOPAMINE D 2 AGONIST LY 141865, BUT NOT THE Dt AGONIST SKF 38393, REVERSES PARKINSONISM INDUCED BY 1 - M E T H ~ P H E N Y L 1,2,3,6-TETRAHYDROPYRIDINE (MPTP) IN THE COMMON MARMOSET
M. NOMOTO, P. JENNER and C.D. MARSDEN*
MRC Movement Disorder Research Group, University Department of Neurology and Parkinson's Disease Society Research Centre, Institute of Psychiatry & King's College Hospital Medical School, Denmark Hill, London SE5 ( U.K. ) (Received October 2nd, 1984; Revised version received March 5th, 1985; Accepted March 16th, 1985)
Key words: l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine- MPTP - parkinsonian akinesia - marmoset -
LY 141865 - SKF 38393
Marmosets treated with l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) (1-4 mg/kg i.p. daily for up to 8 days) develop profound parkinsonian akinesia. Administration of the Dt agonist SKF 38393 (1-20 mg/kg i.p.) 4-6 weeks later had no effect on the motor activity of animals pretreated with MPTP. In contrast, the administration of the D2 agonist LY 141865 (0.1 or 0.5 mg/kg i.p.) caused a marked increase in motor activity lasting for up to 2 h. We conclude that stimulation of D2 dopamine receptors is essential for motor activation of parkinsonian marmosets and that D~ stimulation alone is not sufficient to overcome the akinesia induced by MPTP treatment.
Dopamine (DA) receptors in brain can be divided into at least two classes, namely D~ receptors linked to adenylate cyclase and D2 receptors which are not directly linked to this enzyme [5]; each may exist in different afinity states [3]. All functional effects of DA receptor activation, such as the inhibition of apomorphine-induced motor behaviours [8], drug potency in the control of schizophrenia [11] and the control of Parkinson's disease [10], hitherto have been attributed to the action of drugs on the D2 receptor population. The function of Dl receptors in brain has been uncertain. SKF 38393, which selectively activates Di receptors, but is only weakly effective on D2 sites [13], has been found to cause contralateral rotation in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigro-striatal pathway but not to cause stereotypy or rotation in rats with a unilateral electrolesion of the striatum or to cause emesis or prolactin release [2, 12]. To determine whether stimulation of Dt receptors is important in the control of parkinsonian symptoms, we have compared the ability of SKF 38393 with that of the D2 agonist LY 141865 [14] to reverse akinesia induced by the prior treatment of marmosets with the selective DA neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [1, 4, 7]. *Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
38 Thirteen c o m m o n marmosets of either sex (weight range 280 to 430 g) were treated with M P T P in doses of 1~4 mg/kg i.p. daily for up to 8 days. Since the individual response of animals differed markedly, variable dosage regimes were used so as to render them parkinsonian. Following treatment, animals were allowed to recover from the acute effects of M P T P treatment for up to 6 weeks. M P T P was dissolved in a minimum quantity of 70~o alcohol and diluted to volume with 0.9!~ saline. For comparison 4 normal marmosets were also employed. Behavioural testing was carried out by removing each animal from its home cage and placing it in a novel cage environment in isolation from other animals in the colony, after which a video sequence of its behaviour was filmed. The animal was allowed 30 min to acclimatize to this novel environment. Animals then received either S K F 38393 (1-20 mg/kg i.p., 5 animals) or LY 141865 (0.1 mg/kg i.p., 4 animals; or 0.5 mg/kg i.p., 8 animals), or (+)-sulpiride (20 mg/kg i.p.) which was administered 1 h prior to LY 141865 (0.5 mg/kg i.p.) in 4 animals, or 0.9<,~ saline (4 animals). Untreated control marmosets (4 animals) received either LY 141865 (0.1 or 0.5 mg/kg i.p.) or 0.9','~o saline. The behaviour of the animals was observed over the following I20 min by video recording. The number of movements of the animal across either the 4 base segments of the cage or in a vertical direction between the floor and perches of the cages was recorded every 5 min. The intensity of checking behaviour was assessed every 5 rain as follows: 0, nil; 1, occasional; 2, frequent; 3, discontinuous; 4, continuous. When an animal was reexamined there was an interval of at least l0 days before the next experiment. When observed 30 rain following introduction into the novel cage environment,
A
B F "°° lOO-
.'\
c \
"
h
J
"
-
z 6o-
~
_
~ 2o-
o-
10
20
30
40
50 TIME
60
70
80
90
100 110 120
rnin
Fig. 1. A: the effect of administration of L Y 141865 (0.5 mg/kg i.p., m ) or SKF 38393 0 - 2 0 mg/kg !.P,; Q) on the number of movements made by animals previously treated with MPTP (1-4 mg/kg i.p. daily)~
The results are expressed as the mean value for 5 or 8 animals in each treatment group. B: the total number of movements made by MPTP-treated animals receiving either LY 141865 (0.5 mg/kg i.p., I ) or SKF 38393 (I .0-20 mg/kg i.p.; 0) over a 5-min period starting 30 min followingdrug administration.
39 TABLE I M O V E M E N T C O U N T S A N D T H E I N T E N S I T Y O F C H E C K I N G B E H A V I O U R IN T H E P E R I O D 30-35 min F O L L O W I N G D R U G O R S A L I N E T R E A T M E N T O F N O R M A L A N D M P T P TREATED MARMOSETS The results are expressed as the mean value for 4-8 animals in each treatment group. Details of the experiment are described in the text and in the legend to the figure. Treatment group
N u m b e r of animals
Drug treatment (mg/kg)
Total movements/5 min
Intensity of checking behaviour
Control Control Control MPTP MPTP MPTP MPTP
4 4 4 4 4 8 4
4 13 84 0 19 102 0
1.0 1.7 3.0 0 2.3 3.8 0
MPTP
5
Saline LY 141865 (0.1) LY 141865 (0.5) Saline LY 141865 (0.1) LY 141865 (0.5) LY 141865 (0.5) + ( _)-sulpiride (20) S K F 38393 (1-20)
0
0
MPTP-treated animals were usually immobile, either on the perch or floor of the cage, and showed little or no spontaneous checking or blinking movements. Any movement made was slow and deliberate. Control animals also showed relatively few movements following the acclimatization period. However, the quality of motor behaviour differed markedly in that their movements occupied a greater cage area and were faster and better coordinated than those observed in the MPTP-treated group. In addition, control animals exhibited frequent blinking. The administration of SKF 38393 (1-20 mg/kg i.p.) did not alter the behaviour of any MPTP-treated animal over the next 30-120 min (Fig. 1, Table I). The animals remained immobile in a fixed position with little or no checking or blinking movements. In contrast, the administration of LY 141865 (0.1 or 0.5 mg/kg i.p.) caused profound dose-dependent behavioural activation of MPTP-treated animals (Fig. 1, Table I). Within a few minutes of drug administration most of the animals either retched or vomited for up to 10 min. After approximately 10 min all of the animals began to become alert, with an increase in the number of checking movement and a gradual increase in general movement from place to place within the test cage. Movements were well coordinated and included normal running on the floor of the cage, jumping up to high perches or down to the floor, grasping of perches and cage walls, feeding and grooming, and continuous checking behaviour. Most of this repertoire of movement appeared normal, but occasionally there were brief periods of explosive motor action, and sometimes inappropriate chewing occurred. In addition, these animals also exhibited frequent checking and blinking movements. The duration o f effect of LY 141865 (0.5 mg/kg i.p.) varied between animals from approximately 30 min to 2 h. The behaviourai activation caused by LY 141865 in
40
MPTP-treated animals was prevented by the prior administration of (+_)-sulpiride (20 mg/kg, 1 h previously). In control animals, the administration of LY 141865 (0.1 or 0.5 mg/kg i.p.) also produced dose-dependent behavioural activity (Table I). The results suggest that stimulation of D2 receptors but not D~ receptors causes activation of motor behaviour in parkinsonian marmosets pretreated with the nigrostriatal DA neurotoxin MPTP. The lack of effect of SKF 38393 was surprising in view of reports that this compound can induce contralateral rotation in rats with a prior unilateral 6-OHDA lesion of the nigro-striatal pathway [2, 12]. This suggested that SKF 38393 might alleviate parkinsonian symptoms, even though it does not produce classical DA agonist behaviours in normal animals. DA agonist drugs used to control Parkinson's disease vary in their Dr/D2 characteristics. L-dihydroxyphenylalanine itself presumably gives rise to activation of both D1 and D2 receptors, whereas a drug such as bromocriptine activates D2 receptors but does not stimulate Di receptors and may even inhibit the stimulant effects of DA on adenylate cyclase activity [9]. Pergolide on the other hand, which is another effective anti-parkinsonian DA agonist, can activate both D 1 and D2 receptors [6, 15]. From this study it would appear that it is the effects of these drugs on D2 receptors that are important in reversing parkinsonian symptoms. However, these studies do not reveal whether or not the addition of Dl receptor activation (or indeed inhibition) to D2 agonist properties may provide added advantage or disadvantage to the benefit received by parkinsonian patients when treated with such drugs. If the conclusions drawn from these experiments in marmosets are borne out by the effects of Di agonists in man, then it may be that the MPTP-treated marmosets will provide a more useful means of screening novel anti-parkinsonian compounds than the currently used rodent models. This study was supported by the Medical Research Council, the Parkinson's Disease Society and the Research Funds of Bethlem Royal and Maudsley Hospitals and King's College Hospital. M.N. is a British Council Scholar. We wish to thank Mr. Alan Brady and Mr. Michael Jackson for their excellent technical assistance in the undertaking of these experiments. We also thank Dr. Alan Marriott, Dr. S. Pay and Mr. S.P. Close, Glaxo Laboratories, for their help in initiating these experiments.
1 Burns, R.S., Chiueh, C.C., Markey, S.P., Ebert, M.H., Jacobowitz, D.M. and Kopin, 1.J., A primate model for Parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l,2,5,6-tetrahydropyridine, Proc. Natl. Acad. Sci. USA, 80 (1983) 454&4550. 2 Costall, B., Kelly, M.E. and Naylor, R.J., Unilateral striatal dopamine destruction: reduced motor inhibiting effects of dopamine antagonists reveal~l in models of asymmetry and circling behaviour, Naunyn-Schmiedeberg's Arch. Pharmacol., 326 (1984) 29-35. 3 Grigoriadis, D. and Seman, P., The dopamine/neuroleptic receptors, Canad. J. Neurol. Sci., I I (1984) 108-113. 4 Jenner, P., Rupniak, N.M.J., Rose, S., Kelly, E., Kilpatrick, G., Lees, A. and Marsden, C.D., 1Methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset, Neurosci. Lett., 50 (1984) 85-90.
41 5 Kebabian, J.W. and Calne, D.B., Multiple receptors for dopamine, Nature (Lond.), 277 (1979) 93-96. 6 Koller, W.C., Weiner, W.J., Diamond, B.I., Nausieda, P.A. and Klawans, H.L., The pharmacological evaluation of pergolide mesylate as a potential antiparkinsonian agent, Neuropharmacology, 19 (1980) 831-837. 7 Langston, J.W., Forno, L.S., Rebert, C.S. and Irwin, I., Selective nigral toxicity after synaptic administration of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine, Proc. Natl. Acad. Sci. USA, 80 (1983) 4546~550. 8 Leysen, J.E., Review on neuroleptic receptors: specificity and multiplicity of in vitro binding related to pharmacological activity. In E. Usdin, S.G. Dahl, L.F. Gram and O. Lingjaerde (Eds.), Clinical Pharmacology in Psychiatry: Neuroleptic and Antidepressant Research, Macmillan, London, 1981, pp. 35-62. 9 Markstein, R. and Herrling, P.L., The effect of bromocriptine on rat striatal adenylate cyclase and rat brain monoamine metabolism, J. Neurochem., 31 (1978) 1163-1172. 10 Schachter, M., Bedard, P., DeBono, A.G., Jenner, P., Marsden, C.D., Price, P., Parkes, J.D., Keenan, J., Smith, B., Rosenthaler, J., Horowski, R. and Dorrow, R., The role of D-I and D-2 receptors, Nature (Lond.), 286 (1980) 157-159. 11 Seeman, P., Brain dopamine receptors, Pharmacol. Rev., 32 (1980) 229-313. 12 Setler, P.E., Saray, H.M., Zirkle, C.L. and Saunders, H.L., The central effects of a novel dopamine agonist, Europ. J. Pharmacol., 50 (1978) 419-430. 13 Sibley, D.R., Leff, S.E. and Creese, I., Interactions of novel dopaminergic ligands with D-1 and D-2 dopamine receptors, Life Sci., 31 (1982) 637-645. 14 Tsuruta, K., Frey, E.A., Grewe, C.W., Cote, T.E., Eskay, R.L. and Kebabian, J.W., Evidence that LY 141865 specifically stimulates the D-2 dopamine receptor, Nature (Lond.), 292 (1981) 463-465. 15 Wong, D.T. and Reid, L.R., Activation of adenylate cyclase in rat striatum by an ergoline dopamine agonist pergolide, Commun. Psychopharmacol., 4 (1980) 269-275.