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Effects of dopamine depletion on rotational behavior to dopamine agonists
358
Brain Research. 261 (t983)358 360 Elsevier Biomedical Press
Effects of dopamine depletion on rotational behavior to dopamine agonists OSCAR G E R S H A N I K * , R I C H A R D E. HEIKKILA** and ROGER C. DUVOISIN
University of Medicine and Dentistry of New Jersev-Rutgers Medical School The Mollie and Jerome Levine Neuroscw~u'e Research Laboratories, Department of Neurology, Piscatawav, NJ 08854 ( U. S.,4. ) (Accepted October 25th, 1982) Key words: dopamine depletion - dopamine receptors -- dopamine agonists -- contralateral rotation
The contralateral rotation to various dopamine agonists was determined in rats with unilateral lesions of the left nigrostriatal pathway both with and without dopamine depletion caused by dopamine synthesis inhibition. The rotation to drugs possessing D-2 dopamine agonist activity alone was greatly diminished by dopamine depletion. In contrast, the rotation induced by drugs possessing D-I dopamine agonist activity (either D-1 alone or D-I plus D-2) was affected to a much lesser extent by dopamine depletion.
Dopamine agonists are believed to act directly on the dopamine receptor regardless of the presence of the physiological neurotransmitter DA. Several ergolines with dopamine agonist properties including bromocriptine have been successfully tried in parkinsonian patients 3. Others are in various stages of clinical trial. Some patients that had become unresponsive to L-DOPA after long-term treatment showed moderate improvement when treated with direct acting DA agonists. However, a significant number of these chronic parkinsonians showed no beneficial effect after being administered these DA agonists. One of the explanations put forward to justify this puzzling phenomenon is the possibility of a degenerative process occurring at the postsynaptic level, resulting in a loss of receptors on which the agonists are supposed to exert their effect. Also puzzling is the finding in rats with a unilateral lesion of the nigr0striatal pathway that many of the ergolines originally used as antiparkinsonian agents show a marked decrease in their capacity to induce contralateral rotation after DA synthesis inhibition 4-~3. This suggests that these drugs might either act indirectly or perhaps might need the presence of DA to be effective.
Kebabian and Calne have proposed the existence of two classes of DA receptors based on their capacity to stimulate adenylate cyclase ~''. D-1 receptor activation brings about an enhancement in the production of cyclic AMP through the stimulation of an adenylate cyclase, whereas stimulation of the D-2 receptor does not cause increases in the levels of cyclic AMP "'.~'. In contrast, stimulation of the D-2 receptor brings about an inhibition of prolactin secretion, while stimulation of the D-1 receptor has no such effect. Dopamine receptor agonists can readily be classified according to their selective effects on these two receptor subtypes. Bromocriptine has been shown to be a D-1 receptor antagonist and a D-2 receptor agonist. The same holds true for lergotrile ~-~.7.t~.Pergolide, in contrast, has agonist properties on both the D- 1 and D-2 receptors ~as does a compound recently made available by Sandoz (CQ 32084) 6,~z. There are also drugs with relatively specific effects on either D-I or D-2 receptors; for example the selective D-1 agonist SKF 38393 H and the selective D-2 agonists LY 14186Y 7 and RU 242135 . In the present study we have determined the effect of dopamine depletion on the contralateral rotation induced by these various DA agonists. It should be em-
* Permanent address: Centro Neurologico, Hospital Frances, Buenos Aires, Argentina. ** To whom reprint requests should be addressed. 0006-8993/83/0000-0000/$03.00 ~: 1983 Elsevier Biomedical Press
359 phasized that these drugs which are classified as specific agonists of one receptor or another, can in general, at very high concentrations lose their relative specificity. Rotational experiments were carried out with female Sprague-Dawley rats weighing approximately 200 g. At least 3 months prior to the experiment these animals had received a unilateral lesion of the left nigrostriatal pathway by the stereotaxic injection of 8/~g of 6-hydroxydopamine hydrobromide (6-OHDA) in 4 ~1 of 0.02% ascorbic acid solution into the left median forebrain bundle. A David Kopfmode1900 stereotaxic apparatus was used. Lesion coordinates from the K 6 n i ~ K l i p p e l atlas ~1 were: A + 4.9, L + 1.6, and DV-2.4. Rats were pretreated with 25 m g / k g of desmethylimipramine, 3(~45 min before stereotaxic lesioning to protect norepinephrine terminals. The rotational response was then determined as described previously 2.8,9 in rats that had reached a stable rate of rotation to 10 m g / k g L-DOPA/cai'bidopa. All injections were i.p. Drugs used, their sources, and the vehicle in which they were injected are as follows. Alpha-methyl-para-tyrosine (AMPT, Aldrich Chemicals, Milwaukee, WI) was injected in an aqueous solution at a dose of 75 m g / k g 3 h before and repeated 1 h before the experiment with the test drug ~3. RU 24213 (Roussel UCLAF, Romainville, France), LY 141865 (Eli Lilly, Indianapolis, IN), SKF 38393 (Smith Kline and French, Philadelpha, Penn.), Lergotrile mesylate (Eli Lilly, Indianapolis, IN), and Pergolide mesylate (Eli Lilly,
Indianapolis, IN) were dissolved in distilled water and injected in an aqueous solution. Bromocriptine methane sulphonate (Sandoz, East Hanover, N J) and CQ 32084 (Sandoz, East Hanover, N J) were injected in an acidified solution (HC10.05 N). Rotational behavior to the various DA agonists was then measured in our colony of unilaterally lesioned 6-OHDA rats before and after DA synthesis inhibition with AMPT. Results are summarized in Table 1. Lergotrile, LY 141865, RU 24213, and Bromocriptine showed a marked reduction in their capacity to induce rotation in rats that had received A M P T compared to their effects in untreated animals. After A M P T pretreatment, the contralateral rotation caused by pergolide and CQ 32084 was moderately reduced to about 60% of their previous capacity to induce rotation. The contralateral rotation caused by SKF 38393, on the other hand, was not reduced after A M P T pretreatment. It appears that only those drugs possessing D-1 agonist properties either alone or combined with D-2 agonist effects (e.g. SKF 38393, CQ 32084 and Pergolide) are capable of inducing extensive rotational behavior in the absence of striatal DA. It has previously been shown that rotation to apomorphine, a D-1/D-2 agonist was not influenced by A M P T treatment ~3. In contrast all drugs without D-1 agonist actions (e.g. Lergotrile, LY 141865, RU 24213 and Bromocriptine lost their capacity to induce rotation by over 50% after A M P T pretreatment. This demonstration of a behavioral correlation with the
TABLE I
Effect of alpha-methyl-para-tyrosine (,4 M PT) on drug-induced rotations in 6-O H DA -lesioned rats Data are expressed as m e a n contralateral turns for 6 h (except S K F 38393, 3 h) ___ the S . E M . All drugs were injected intraperitoneally. The total A M P T dose was 150 m g / k g (75 m g / k g 3 h and 75 m g / k g I h before the test drug).
Drug (n)
S K F 38393 (8) CQ 32084 (5) Pergolide(8) Lergotrile (8) LY 141865 (4) RU24213(5) Bromocriptine (8)
Dose (mglkg)
1.0 1.0 0.25 0.5 0.25 1.0 1.0
Turns
Ratio
no A M P T
plus A M P T
plus A M P T / n o A M P T
1158 2270 1960 1179 882 1341 1582
958 1476 1261 417 293 380 263
0.83 0.65 0.64 0.35 0.33 0.28 0.17
-4- 120 + 473 _ 344 + 259 __. 161 ___ 379 ± 361
_ 201 + 409 _+ 237 _ 72 ___ 29 +-- 190 ± 60
360 classification s c h e m e o f d o p a m i n e receptors into two types as p r o p o s e d by K e b a b i a n a n d C a l n e lends f u r t h e r validity to that s c h e m e . It m i g h t be r e a s o n e d that all the d r u g s w h i c h exhibited a significantly d i m i n i s h e d r e s p o n s e after A M P T p r e t r e a t m e n t act indirectly t h r o u g h d o p a m i n e . This is unlikely, h o w e v e r , b e c a u s e other drugs including amphetamine, cocaine a n d m a z i n d o l , that act indirectly, cause an ipsilateral r o t a t i o n ~.~ in c o n t r a s t to the c o n t r a l a t e r a l r o t a t i o n o b s e r v e d with all o f the D A agonists used in the p r e s e n t study. T h e d a t a do seem to suggest that a c t i v a t i o n o f the D-1 r e c e p t o r is crucial in this a n i m a l m o d e l for circling to occur. A c c o r d i n g to this premise, the available d o p a -
I Bach. N. J., Kornfeld, E. C., Jones, N. D., Chaney, M. O., Dorman, D. E., Paschal. J. W.. Clemens, J. A. and Smalstig. E. B., Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl) pyrroles and 3-and 4-(2-aminoethyl) pyrazoles as dopamine agonists, J. med. Chem.. 23 (1980)481 491. 2 Duvoisin. R. C.. Heikkila, R. E. and Manzino, L., Circling induced by dopamine uptake inhibitors, J. Pharm. Pharmacol.. 30 (1978) 714 716. 3 Duvoisin. R. C., Mendoza, M. M. and Yahr, M. D., A comparative study of bromocriptine and levodopa in Parkinson's disease. In M. Goldstein, D. B. Calne, A. Lieberman and M. O. Thorner (Eds.), Ergot Compounds and Brain Function: Neuroendocrine and Neuropsvchiatric A,spects. 1/oL 23, Raven, NewYork, 1980, pp. 271 275.
4 Duvoisin, R. C., Heikkila, R. E. and Manzino, L., Pergolide induced circling in rats with 6-hydroxydopamine lesions in the nigrostriatal pathway, Neurology, in press. 5 Euvrard, C., Ferland, k., Di Paolo. T.. Beaulieu. M., Labrie, F.. Oberlander. C., Raynaud, J. P. and Boissier, J. R., Activity of two new potent dopaminergic agonists at the striatafand anterior pituitary levels, Neuropharmacologr, 19(1980)379 386. 6 Fuxe. K.. Agnati. L. F.. Kohler, C.. Kuonen, D.. Ogren, S.-O., Andersson. K. and Hokfelt, T., Characterization of normal and supersensitive dopamine receptors: effects of ergot drugs and neuropeptides, J. neural Trans.. 51( 1981) 3 37. 7 Goldstein. M., kieberman, A., Lew. J. Y., Asano, T., Rosenfeld, M. R. and Makman, M. H., Interaction of pergolide with central dopaminergic receptors, Proc. nat. A cad. Sci. U.S.A., 77 (1980) 3725- 3728. 8 Heikkila. R. E.. Cabbat, F. S.. Manzino, L. and Duvoisin, R. C.. Rotational behavior induced by cocaine analogs in rats with unilateral 6-hydroxydopamine lesions of the
m i n e in the s t r i a t u m on the lesioned side b e f o r e A M P T t r e a t m e n t ( w h i c h is a p p r o x i m a t e l y 10% o f c o n t r o l levels) w o u l d p r o v i d e e n o u g h D-1 rec e p t o r s t i m u l a t i o n to m a i n t a i n responsivity o f the D - 2 r e c e p t o r a n d cause rotation. But the further d e p l e t i o n i n d u c e d by A M P T t r e a t m e n t results in loss o f activity. E v e n if this s p e c u l a t i o n proves to be e r r o n e o u s , the a p p a r e n t p a t t e r n o f r e s p o n s e to D A synthesis inhibition in relation to the r e c e p t o r a c t i v a t i o n profile o f the different D A agonists r e m a i n s a p u z z l i n g p h e n o m e n o n the e x p l a n a t i o n o f w h i c h is w o r t h p u r s u i n g . T h e a u t h o r s wish to t h a n k L a w r e n c e M a n z i n o for his assistance.
substantia nigra: dependence upon dopamine uptake inhibition, J. PharmacoZ exp. Ther., 211 (1979) 189-194. 9 Heikkila. R. E., Cabbat, F. S., Manzino, L., Babington, R. G. and Houlihan, W. J., Unexpected differences between mazindol and its homologs on biochemical and behavioral responses, J. Pharmacol. exp. Ther, 217 (1981) 745-749. 10 Kebabian, J. W. and Calne, D. B., Multiple receptors for dopamine, Nature (Lond.), 277 (1979) 93-96. 11 K6nig, J. F. and Klippel, R. A., The Rat Brain. A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem, Williams and Wilkins, Baltimore, 1963.
12 Markstein, R., Neurochemical effects of some ergot derivatives: a basis for their anti-Parkinson actions, J. neural Transm., 51 ( 1981) 39- 59. 13 McDevitt, J. T. and Setler, P., Dopaminergic effects of lergotrile: possible involvement ofa metabolite, Neuropharmacologv, 19 (1980) 537 542. 14 Setler, P. E., Sarau, H. M., Zirkle, C. L. and Saunder, H. L., The central effects of a novel dopamine agonist, Europ. J. Pharmacol., 50 (1978) 419-430. 15 Spano, P. F., Frattola, l., Govoni, S., Tonon, G. C. and Trabucchi, M., Dopaminergic ergot derivatives: selective agonists of a new class of dopamine receptors? In K. Fuxe and D. B. Calne (Eds.), Dopaminergic Ergot Deriv. atives and Motor Function, Pergamon, Oxford, 1979, pp. 159 171. 16 Stoof, J. F. and Kebabian, J. W., Opposing roles for D-I and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum, Nature (Lond.), 294 (1981) 366368. 17 Tsuruta, K., Frey, E. A., Grewe, C. W., Cote, T. E., Eskay, R. L. and Kebabian, J. W., Evidence that LY141865 specifically stimulates the D-2 dopamine receptor. Nature (Lond.), 292 (1981) 463--465.
Brain Research. 261 (t983)358 360 Elsevier Biomedical Press
Effects of dopamine depletion on rotational behavior to dopamine agonists OSCAR G E R S H A N I K * , R I C H A R D E. HEIKKILA** and ROGER C. DUVOISIN
University of Medicine and Dentistry of New Jersev-Rutgers Medical School The Mollie and Jerome Levine Neuroscw~u'e Research Laboratories, Department of Neurology, Piscatawav, NJ 08854 ( U. S.,4. ) (Accepted October 25th, 1982) Key words: dopamine depletion - dopamine receptors -- dopamine agonists -- contralateral rotation
The contralateral rotation to various dopamine agonists was determined in rats with unilateral lesions of the left nigrostriatal pathway both with and without dopamine depletion caused by dopamine synthesis inhibition. The rotation to drugs possessing D-2 dopamine agonist activity alone was greatly diminished by dopamine depletion. In contrast, the rotation induced by drugs possessing D-I dopamine agonist activity (either D-1 alone or D-I plus D-2) was affected to a much lesser extent by dopamine depletion.
Dopamine agonists are believed to act directly on the dopamine receptor regardless of the presence of the physiological neurotransmitter DA. Several ergolines with dopamine agonist properties including bromocriptine have been successfully tried in parkinsonian patients 3. Others are in various stages of clinical trial. Some patients that had become unresponsive to L-DOPA after long-term treatment showed moderate improvement when treated with direct acting DA agonists. However, a significant number of these chronic parkinsonians showed no beneficial effect after being administered these DA agonists. One of the explanations put forward to justify this puzzling phenomenon is the possibility of a degenerative process occurring at the postsynaptic level, resulting in a loss of receptors on which the agonists are supposed to exert their effect. Also puzzling is the finding in rats with a unilateral lesion of the nigr0striatal pathway that many of the ergolines originally used as antiparkinsonian agents show a marked decrease in their capacity to induce contralateral rotation after DA synthesis inhibition 4-~3. This suggests that these drugs might either act indirectly or perhaps might need the presence of DA to be effective.
Kebabian and Calne have proposed the existence of two classes of DA receptors based on their capacity to stimulate adenylate cyclase ~''. D-1 receptor activation brings about an enhancement in the production of cyclic AMP through the stimulation of an adenylate cyclase, whereas stimulation of the D-2 receptor does not cause increases in the levels of cyclic AMP "'.~'. In contrast, stimulation of the D-2 receptor brings about an inhibition of prolactin secretion, while stimulation of the D-1 receptor has no such effect. Dopamine receptor agonists can readily be classified according to their selective effects on these two receptor subtypes. Bromocriptine has been shown to be a D-1 receptor antagonist and a D-2 receptor agonist. The same holds true for lergotrile ~-~.7.t~.Pergolide, in contrast, has agonist properties on both the D- 1 and D-2 receptors ~as does a compound recently made available by Sandoz (CQ 32084) 6,~z. There are also drugs with relatively specific effects on either D-I or D-2 receptors; for example the selective D-1 agonist SKF 38393 H and the selective D-2 agonists LY 14186Y 7 and RU 242135 . In the present study we have determined the effect of dopamine depletion on the contralateral rotation induced by these various DA agonists. It should be em-
* Permanent address: Centro Neurologico, Hospital Frances, Buenos Aires, Argentina. ** To whom reprint requests should be addressed. 0006-8993/83/0000-0000/$03.00 ~: 1983 Elsevier Biomedical Press
359 phasized that these drugs which are classified as specific agonists of one receptor or another, can in general, at very high concentrations lose their relative specificity. Rotational experiments were carried out with female Sprague-Dawley rats weighing approximately 200 g. At least 3 months prior to the experiment these animals had received a unilateral lesion of the left nigrostriatal pathway by the stereotaxic injection of 8/~g of 6-hydroxydopamine hydrobromide (6-OHDA) in 4 ~1 of 0.02% ascorbic acid solution into the left median forebrain bundle. A David Kopfmode1900 stereotaxic apparatus was used. Lesion coordinates from the K 6 n i ~ K l i p p e l atlas ~1 were: A + 4.9, L + 1.6, and DV-2.4. Rats were pretreated with 25 m g / k g of desmethylimipramine, 3(~45 min before stereotaxic lesioning to protect norepinephrine terminals. The rotational response was then determined as described previously 2.8,9 in rats that had reached a stable rate of rotation to 10 m g / k g L-DOPA/cai'bidopa. All injections were i.p. Drugs used, their sources, and the vehicle in which they were injected are as follows. Alpha-methyl-para-tyrosine (AMPT, Aldrich Chemicals, Milwaukee, WI) was injected in an aqueous solution at a dose of 75 m g / k g 3 h before and repeated 1 h before the experiment with the test drug ~3. RU 24213 (Roussel UCLAF, Romainville, France), LY 141865 (Eli Lilly, Indianapolis, IN), SKF 38393 (Smith Kline and French, Philadelpha, Penn.), Lergotrile mesylate (Eli Lilly, Indianapolis, IN), and Pergolide mesylate (Eli Lilly,
Indianapolis, IN) were dissolved in distilled water and injected in an aqueous solution. Bromocriptine methane sulphonate (Sandoz, East Hanover, N J) and CQ 32084 (Sandoz, East Hanover, N J) were injected in an acidified solution (HC10.05 N). Rotational behavior to the various DA agonists was then measured in our colony of unilaterally lesioned 6-OHDA rats before and after DA synthesis inhibition with AMPT. Results are summarized in Table 1. Lergotrile, LY 141865, RU 24213, and Bromocriptine showed a marked reduction in their capacity to induce rotation in rats that had received A M P T compared to their effects in untreated animals. After A M P T pretreatment, the contralateral rotation caused by pergolide and CQ 32084 was moderately reduced to about 60% of their previous capacity to induce rotation. The contralateral rotation caused by SKF 38393, on the other hand, was not reduced after A M P T pretreatment. It appears that only those drugs possessing D-1 agonist properties either alone or combined with D-2 agonist effects (e.g. SKF 38393, CQ 32084 and Pergolide) are capable of inducing extensive rotational behavior in the absence of striatal DA. It has previously been shown that rotation to apomorphine, a D-1/D-2 agonist was not influenced by A M P T treatment ~3. In contrast all drugs without D-1 agonist actions (e.g. Lergotrile, LY 141865, RU 24213 and Bromocriptine lost their capacity to induce rotation by over 50% after A M P T pretreatment. This demonstration of a behavioral correlation with the
TABLE I
Effect of alpha-methyl-para-tyrosine (,4 M PT) on drug-induced rotations in 6-O H DA -lesioned rats Data are expressed as m e a n contralateral turns for 6 h (except S K F 38393, 3 h) ___ the S . E M . All drugs were injected intraperitoneally. The total A M P T dose was 150 m g / k g (75 m g / k g 3 h and 75 m g / k g I h before the test drug).
Drug (n)
S K F 38393 (8) CQ 32084 (5) Pergolide(8) Lergotrile (8) LY 141865 (4) RU24213(5) Bromocriptine (8)
Dose (mglkg)
1.0 1.0 0.25 0.5 0.25 1.0 1.0
Turns
Ratio
no A M P T
plus A M P T
plus A M P T / n o A M P T
1158 2270 1960 1179 882 1341 1582
958 1476 1261 417 293 380 263
0.83 0.65 0.64 0.35 0.33 0.28 0.17
-4- 120 + 473 _ 344 + 259 __. 161 ___ 379 ± 361
_ 201 + 409 _+ 237 _ 72 ___ 29 +-- 190 ± 60
360 classification s c h e m e o f d o p a m i n e receptors into two types as p r o p o s e d by K e b a b i a n a n d C a l n e lends f u r t h e r validity to that s c h e m e . It m i g h t be r e a s o n e d that all the d r u g s w h i c h exhibited a significantly d i m i n i s h e d r e s p o n s e after A M P T p r e t r e a t m e n t act indirectly t h r o u g h d o p a m i n e . This is unlikely, h o w e v e r , b e c a u s e other drugs including amphetamine, cocaine a n d m a z i n d o l , that act indirectly, cause an ipsilateral r o t a t i o n ~.~ in c o n t r a s t to the c o n t r a l a t e r a l r o t a t i o n o b s e r v e d with all o f the D A agonists used in the p r e s e n t study. T h e d a t a do seem to suggest that a c t i v a t i o n o f the D-1 r e c e p t o r is crucial in this a n i m a l m o d e l for circling to occur. A c c o r d i n g to this premise, the available d o p a -
I Bach. N. J., Kornfeld, E. C., Jones, N. D., Chaney, M. O., Dorman, D. E., Paschal. J. W.. Clemens, J. A. and Smalstig. E. B., Bicyclic and tricyclic ergoline partial structures. Rigid 3-(2-aminoethyl) pyrroles and 3-and 4-(2-aminoethyl) pyrazoles as dopamine agonists, J. med. Chem.. 23 (1980)481 491. 2 Duvoisin. R. C.. Heikkila, R. E. and Manzino, L., Circling induced by dopamine uptake inhibitors, J. Pharm. Pharmacol.. 30 (1978) 714 716. 3 Duvoisin. R. C., Mendoza, M. M. and Yahr, M. D., A comparative study of bromocriptine and levodopa in Parkinson's disease. In M. Goldstein, D. B. Calne, A. Lieberman and M. O. Thorner (Eds.), Ergot Compounds and Brain Function: Neuroendocrine and Neuropsvchiatric A,spects. 1/oL 23, Raven, NewYork, 1980, pp. 271 275.
4 Duvoisin, R. C., Heikkila, R. E. and Manzino, L., Pergolide induced circling in rats with 6-hydroxydopamine lesions in the nigrostriatal pathway, Neurology, in press. 5 Euvrard, C., Ferland, k., Di Paolo. T.. Beaulieu. M., Labrie, F.. Oberlander. C., Raynaud, J. P. and Boissier, J. R., Activity of two new potent dopaminergic agonists at the striatafand anterior pituitary levels, Neuropharmacologr, 19(1980)379 386. 6 Fuxe. K.. Agnati. L. F.. Kohler, C.. Kuonen, D.. Ogren, S.-O., Andersson. K. and Hokfelt, T., Characterization of normal and supersensitive dopamine receptors: effects of ergot drugs and neuropeptides, J. neural Trans.. 51( 1981) 3 37. 7 Goldstein. M., kieberman, A., Lew. J. Y., Asano, T., Rosenfeld, M. R. and Makman, M. H., Interaction of pergolide with central dopaminergic receptors, Proc. nat. A cad. Sci. U.S.A., 77 (1980) 3725- 3728. 8 Heikkila. R. E.. Cabbat, F. S.. Manzino, L. and Duvoisin, R. C.. Rotational behavior induced by cocaine analogs in rats with unilateral 6-hydroxydopamine lesions of the
m i n e in the s t r i a t u m on the lesioned side b e f o r e A M P T t r e a t m e n t ( w h i c h is a p p r o x i m a t e l y 10% o f c o n t r o l levels) w o u l d p r o v i d e e n o u g h D-1 rec e p t o r s t i m u l a t i o n to m a i n t a i n responsivity o f the D - 2 r e c e p t o r a n d cause rotation. But the further d e p l e t i o n i n d u c e d by A M P T t r e a t m e n t results in loss o f activity. E v e n if this s p e c u l a t i o n proves to be e r r o n e o u s , the a p p a r e n t p a t t e r n o f r e s p o n s e to D A synthesis inhibition in relation to the r e c e p t o r a c t i v a t i o n profile o f the different D A agonists r e m a i n s a p u z z l i n g p h e n o m e n o n the e x p l a n a t i o n o f w h i c h is w o r t h p u r s u i n g . T h e a u t h o r s wish to t h a n k L a w r e n c e M a n z i n o for his assistance.
substantia nigra: dependence upon dopamine uptake inhibition, J. PharmacoZ exp. Ther., 211 (1979) 189-194. 9 Heikkila. R. E., Cabbat, F. S., Manzino, L., Babington, R. G. and Houlihan, W. J., Unexpected differences between mazindol and its homologs on biochemical and behavioral responses, J. Pharmacol. exp. Ther, 217 (1981) 745-749. 10 Kebabian, J. W. and Calne, D. B., Multiple receptors for dopamine, Nature (Lond.), 277 (1979) 93-96. 11 K6nig, J. F. and Klippel, R. A., The Rat Brain. A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem, Williams and Wilkins, Baltimore, 1963.
12 Markstein, R., Neurochemical effects of some ergot derivatives: a basis for their anti-Parkinson actions, J. neural Transm., 51 ( 1981) 39- 59. 13 McDevitt, J. T. and Setler, P., Dopaminergic effects of lergotrile: possible involvement ofa metabolite, Neuropharmacologv, 19 (1980) 537 542. 14 Setler, P. E., Sarau, H. M., Zirkle, C. L. and Saunder, H. L., The central effects of a novel dopamine agonist, Europ. J. Pharmacol., 50 (1978) 419-430. 15 Spano, P. F., Frattola, l., Govoni, S., Tonon, G. C. and Trabucchi, M., Dopaminergic ergot derivatives: selective agonists of a new class of dopamine receptors? In K. Fuxe and D. B. Calne (Eds.), Dopaminergic Ergot Deriv. atives and Motor Function, Pergamon, Oxford, 1979, pp. 159 171. 16 Stoof, J. F. and Kebabian, J. W., Opposing roles for D-I and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum, Nature (Lond.), 294 (1981) 366368. 17 Tsuruta, K., Frey, E. A., Grewe, C. W., Cote, T. E., Eskay, R. L. and Kebabian, J. W., Evidence that LY141865 specifically stimulates the D-2 dopamine receptor. Nature (Lond.), 292 (1981) 463--465.