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Treatment with GM1 ganglioside reverses dopamine D-2 receptor supersensitivity induced by the neurotoxin MPTP
261
European Journal of Pharmacology, 168 (1989) 261-264 Elsevier
WP 20464
Short communication
Treatment with GM1 ganglioside reverses dopamine D-2 receptor supersensitivity induced by the neurotoxin MPTP Maria
Hadjiconstantinou
1*2, Frederic
Weihmuller
3 and Norton
H. Neff
’
’ Department of Pharmacology and -’ Department of Pqxhiatry, College of Medicrne, and’ Department of PsycholoW, College of Social and Behavioral Studies, The Ohio State University, Columbus. OH 43210. lJ.S.A
Received 19 July 1989. accepted 25 July 1989
Treatment of mice with the neurotoxin MPTP to destroy nigrostriatal dopaminergic neurons results in up-regulation of D-2 receptors in the striatum when studied after 30 days. Administration of GM1 ganglioside after inducing the lesion prevents D-2 receptor up-regulation. The ganglioside has no apparent effect when administered to normal animals.
MPTP; Nigrostriatal dopaminergic neurons; GM1 ganglioside; Dopamine receptors
2. Materials and methods
1. Introduction We recently reported that chronic administration of GM1 ganglioside partially restores striatal dopamine (DA) content (Hadjiconstantinou and Neff, 1988) as well as neuroleptic-induced behavioral deficits (Weihmuller et al., 1988b) in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mouse model of parkinsonism. The reversal of neuroleptic-behavioral deficits paralleled the return of striatal DA content. In this paper we show that the B,,, for [3H]spiperone, a ligand selective for D-2 receptors, is increased in mouse striatum following MPTP treatment and that GM1 ganglioside administration prevents the development of receptor supersensitivity in this animal model.
Correspondence to: N.H. Neff, Department of Pharmacology, The Ohio State University College of Medicine, 5198 Graves Hall, Columbus, OH 43210, U.S.A. 0014-2999/89/$03.50
0 1989 Elsevier Science Publishers
Male Swiss-Webster (Zivic-Miller, Zelienople, PA) mice (25-30 g) were housed in groups of eight and given constant access to food and water. They were assigned to one of four treatment groups. (1) Saline, mice were given daily injections of saline for 30 days and then killed. (2) GMI, mice were given daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and then killed. (3) MPTP + GMl, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and then killed. (4) MPTP-30, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of saline for 23 days and then killed. For receptor binding studies, mice were decapitated 24 h after the last treatment day and striatal tissue dissected and homogenized withTris-HCl buffer 50 mM, pH 7.5, in a Brinkmann polytron and centrifuged at 20000 X g for 10 min. The particulate fraction was washed twice with
B.V. (Biomedical
Division)
262
buffer and then suspended in the Tris-HCl buffer containing (mM) M&l, 1, NaCl 120, KC1 5 and CaCl z 2. The ligands studied were [ 3H]SCH 23390 (80 Ci/mmol) and [‘Hlspiperone (30 Ci/mmol) for D-l and D-2 receptor sites, respectively. Incubations were carried out for 15 min at 37” C. The reaction was stopped by rapid filtration through Whatman GF/B filters followed by four 4 ml rinses with buffer solution using a Brandel cell harvester. Radioactivity on the filters was determined using a liquid scintillation spectrometer. Specific binding was defined as the difference between total binding and that found in the presence of 1 PM ketanserin and sulpiride for [3H]spiperone, and in the presence of 1 PM SCH 23390 for [‘H]SCH 23390. Plotting and curve fitting were performed using the microcomputer program GraphPAD (I.S.I. Philadelphia, PA). B,,, and K, values were calculated from Scatchard curve analysis. Multiple group comparisons were performed using a Newman-Keuls post hoc test after analysis of variance.
3. Results Thirty days after treating mice with MPTP there was about a 50% depletion of striatal DA and a concomitant enhanced behavioral sensitivity to haloperidol (Hadjiconstantinou and Neff, 1988; Weihmuller et al., 1988a). Treatment with GM1 ganglioside after MPTP restores striatal DA to about 90% of control values and reverses the supersensitivity to haloperidol (Weihmuller et al., 1988b). MPTP treatment induces about a 30% depletion of tyrosine hydroxylase immunoreactive cell in the substantia nigra. GM1 treatment does not, however restore the number immunoreactive cells in the substantia nigra of the MPTP-treated group (Hadjiconstantinou et al., 1989). Thirty days after initiating MPTP treatment we found a significant increase of the B,,, for [ 3Hlspiperone (table 1). GM1 ganglioside administered alone had no apparent effect on B,,, for either ligand. In contrast, GM1 treatment prevented the rise of the B,,, for [3H]spiperone in the MPTP-treated mice. The K, values were not significantly effected by the treatments.
TABLE
1
GM1 treatment prevents D-2 receptor up-regulation in the striatum of MPTP-treated mice. Treatment groups: saline, mice were given daily injections of saline for 30 days and then killed. MPTP-30, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of saline for 23 days and then killed 24 h after the last injection. GMl, mice were given daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and then killed 24 h after the last injection. MPTP+ GMl, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and killed 24 h after the last injection. Bmar is expressed in fmol/mg protein+ S.E.M. and K, in nM + S.E.M. N = 5 experiments. Treatment
Saline MPTP-30 GM1 MPTP+GMl
[ ‘H]SCH
[ 3Hlspiperone
23390
Bmax
Kll
BInax
995f51 902+79 916,79 1044?36
1.10+0.09 1.7OkO.40 l.lO+O.lE l.lOkO.22
247k8 367+13 250+3 254f4b
a P < 0.05 when compared compared with MPTP-30.
with saline group;
K, 0.26 & 0.002 a 0.27+0.002 0.26 f 0.015 0.28~0.007 h P i 0.05 when
From the binding isotherms for [3H]spiperone, it is evident that MPTP up-regulated [ 3H]spiperone binding when studied on day 30 (fig. 1). Up-regu-
0’ 0.5
1.0 Ligand
1.5
2.0
h-M)
Fig. 1. Specific binding of [3H]spiperone to membranes prepared from the striatum of mice treated with MPTP and/or GM1 ganglioside versus the concentration of ligand. See table 1 for drug treatments. Data are presented as the means f S.E.M. for five experiments: squares, MPTP-30; circles, MPTP+ GMI. Values for saline- and GMl-treated mice are not shown, as they fell together with values for MPTP+GMl.
263
lation is prevented by treatment with GM1 ganglioside. The isotherm for saline- and GMl-treated animals (data not shown) fell together with the values for the MPTP-GMl-treated group. GM1 when added in vitro to membranes at concentrations up to 0.5 PM had no effect on [ 3H]spiperone binding.
4. Discussion The neurotoxin MPTP destroys nigrostriatal dopaminergic neurons and induces clinical symptoms in humans that are indistinguishable from Parkinson’s disease. The mouse MPTP model of parkinsonism shows many of the same biochemical and pathological deficits associated with the human disorder. In our strain of mouse, when 30 mg/kg i.p. of MPTP is administered daily for 7 days, there is about a 50-60s loss of DA from the striatum and of tyrosine hydroxylase immunoreactive cells from the substantia nigra when evaluated 7 or 30 days after initiating the treatment (Hadjiconstantinou et al., 1989). At the same time there is about a 50% fall of DA uptake while the rate of DA formation is below normal (Hadjicontantinou and Neff, 1988). At this stage the animals appear normal behaviorally. These observations are consistent with the observation that about 80-90s loss of dopaminergic neurons are needed before clinical symptoms become evident. Even though our MPTP-treated animals appear normal, their nigrostriatal dopaminergic deficit could be unmasked by administering a low dose of haloperidol, a dose that has no apparent effect on normal untreated mice. Challenged with halothe MPTP-treated animals become peridol, bradykinetic and show somatosensory deficits (Weihmuller et al., 1988a). Treatment with GM1 ganglioside reverses the supersensitivity of MPTP mice to haloperidol (Weihmuller et al., 1988b) and increases the formation of DA to about normal (Hadjiconstantinou and Neff, 1988). Three weeks after MPTP treatment D-l receptor density appeared normal, whereas the density of D-2 receptors was elevated, suggesting receptor up-regulation. Our findings agree with reports of an increase of D-2 B,,,,, after MPTP administra-
tion (Joyce et al., 1985; Lau and Fung, 1986; Falardeau et al., 1988). The lack of up-regulation of striatal D-l receptors 3 weeks post-MPTP is in agreement with observations that 6-hydroxydopamine lesions do not result in an increase of [3H]SCH 23390 sites 30 days post-lesion (Savasta et al., 1988; Langer et al., 1986). Chronic administration of GM1 ganglioside prevented the D-2 receptor changes in the striaturn of the MPTP-treated mice. A possible explanation for GM1 effect might be that the ganglioside, by increasing the rate of formation of DA in the striatum of the MPTP-treated mice (Hadjiconstantinou and Neff, 1988) provides sufficient amine to D-2 receptors to prevent up-regulation. However GM1 also prevents high dosage haloperidol-induced up-regulation of D-2 receptor (Agnati et al., 1983) suggesting a possible direct effect on the receptor. In conclusion, our studies have shown that treatment with GM1 ganglioside can facilitate the biochemical, histological and behavioral recovery of nigrostriatal dopaminergic neurons after moderate lesions induced by MPTP. We now provide evidence that GM1 ganglioside also prevents the up-regulation of D-2 receptors in the same model. Both biochemically and pathologically this model probably resembles the preclinical stages of parkinsonism. Screening of at-risk individuals for parkinsonism is a perquisite for early medical intervention and treatment for neurodegenerative diseases. Small doses of DA agonists or antagonists are known to induce abnormal motor behaviors, perhaps the equivalent of extrapyramidal sympin animals with nigrostriatal tomatology, dopaminergic lesions but not in normal animals. The administration of a short-acting DA agonists or antagonists would be expected to precipitate short-lasting extrapyramidal symptomatology in an individual at-risk for parkinsonism but not in a normal individual. For persons apparently at-risk, the administration of GM1 ganglioside may be beneficial for preserving neuronal function and prolonging the productive life of the individual. Successful therapy with GM1 ganglioside might be evaluated by re-administering the same low dose of the dopaminergic drug that was originally used to unmask the symptomatology.
264
Acknowledgements This work was supported, in part, by The American Parkinson Disease Association, FIDIA Research Laboratories and Grant NS23627 from the National Institutes of Health, GM1 ganglioside was a gift from FIDIA Research Laboratories. Expert technical assistance was provided by Trina Wemlinger and Lori Isaacs.
References Agnati, L.F., K. Fuxe. F. Benfenati, N. Battistini, I. Zini and G. Toffano, 1983a. Chronic ganglioside treatment counteracts the biochemical signs of dopamine receptor supersensitivity induced by chronic haloperidol treatment, Neurosci. Lett. 40, 293. Falardeau, P., P.J. Bedard and T. Di Paolo, 1988, Relation between brain dopamine loss and D2 dopamine receptor density in MPTP monkeys, Neurosci. Lett. 86, 225. Hadjiconstantinou, M., A.P. Mariani and N.H. Neff, 1989, GM1 ganglioside-induced recovery of nigrostriatal dopmaminergic neurons after MPTP: An immunohistochemical study, Brain Res. 484, 297. Hadjiconstantinou, M. and N.H. Neff, 1988, Treatment with GM1 ganglioside restores striatal dopamine in the I-
methyl-4-phenyl-l,2,3,6-tetrahydropyridine-treated mouse, J. Neurochem. 51. 1190. Joyce, J.N., J.F. Marshall, K.S. Bankiewicz, I.J. Kopin and D.M. Jacobowitz. 1985, Hemiparkinsonism in monkey after unilateral internal carotid artery infusion of l-methyl4-phenyl-1.2,3,6-tetrahydropyridine (MPTP) is associated with regional ipsilateral changes in striatal dopamine D-2 receptor density, Brain Res. 382, 360. Langer, S.Z., C. Pimoule, G.P. Reynolds and H.P. Schoemaker, 1986. Dopaminergic denervation does not affect 3H-SCH 23390 binding in the rat striatum, similarities to Parkinson’s disease, Br. J. Pharmacol. 87, 161. Lau. Y.-S. and Y.K. Fung, 1986. Pharmacological effects of I-methyl-4-phenyl-1,2,3,6_tetrahydropyridine (MPTP) on striatal dopamine receptors system, Brain Res. 369, 311. Savasta, M., A. Dubois, J. Benavides and B. Scatton, 1988. Different plasticity changes in Dl and D2 receptors in rat striatal subregions following impairment of dopaminergic transmission, Neurosci. Lett. 85, 119. Weihmuller, F.B., M. Hadjiconstantinou and J.P. Bruno, 1988a, Acute stress or neuroleptics elicit sensorimotor deficits in MPTP-treated mice, Neurosci. Lett. 85, 137. Weihmuller. F.B., M. Hadjiconstantinou, J.P. Bruno and N.H. Neff, 1988b, Administration of GM1 ganglioside eliminates neuroleptic-induced sensorimotor deficits in MPTP-treated mice, Neurosci. Lett. 92. 207.
European Journal of Pharmacology, 168 (1989) 261-264 Elsevier
WP 20464
Short communication
Treatment with GM1 ganglioside reverses dopamine D-2 receptor supersensitivity induced by the neurotoxin MPTP Maria
Hadjiconstantinou
1*2, Frederic
Weihmuller
3 and Norton
H. Neff
’
’ Department of Pharmacology and -’ Department of Pqxhiatry, College of Medicrne, and’ Department of PsycholoW, College of Social and Behavioral Studies, The Ohio State University, Columbus. OH 43210. lJ.S.A
Received 19 July 1989. accepted 25 July 1989
Treatment of mice with the neurotoxin MPTP to destroy nigrostriatal dopaminergic neurons results in up-regulation of D-2 receptors in the striatum when studied after 30 days. Administration of GM1 ganglioside after inducing the lesion prevents D-2 receptor up-regulation. The ganglioside has no apparent effect when administered to normal animals.
MPTP; Nigrostriatal dopaminergic neurons; GM1 ganglioside; Dopamine receptors
2. Materials and methods
1. Introduction We recently reported that chronic administration of GM1 ganglioside partially restores striatal dopamine (DA) content (Hadjiconstantinou and Neff, 1988) as well as neuroleptic-induced behavioral deficits (Weihmuller et al., 1988b) in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mouse model of parkinsonism. The reversal of neuroleptic-behavioral deficits paralleled the return of striatal DA content. In this paper we show that the B,,, for [3H]spiperone, a ligand selective for D-2 receptors, is increased in mouse striatum following MPTP treatment and that GM1 ganglioside administration prevents the development of receptor supersensitivity in this animal model.
Correspondence to: N.H. Neff, Department of Pharmacology, The Ohio State University College of Medicine, 5198 Graves Hall, Columbus, OH 43210, U.S.A. 0014-2999/89/$03.50
0 1989 Elsevier Science Publishers
Male Swiss-Webster (Zivic-Miller, Zelienople, PA) mice (25-30 g) were housed in groups of eight and given constant access to food and water. They were assigned to one of four treatment groups. (1) Saline, mice were given daily injections of saline for 30 days and then killed. (2) GMI, mice were given daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and then killed. (3) MPTP + GMl, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and then killed. (4) MPTP-30, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of saline for 23 days and then killed. For receptor binding studies, mice were decapitated 24 h after the last treatment day and striatal tissue dissected and homogenized withTris-HCl buffer 50 mM, pH 7.5, in a Brinkmann polytron and centrifuged at 20000 X g for 10 min. The particulate fraction was washed twice with
B.V. (Biomedical
Division)
262
buffer and then suspended in the Tris-HCl buffer containing (mM) M&l, 1, NaCl 120, KC1 5 and CaCl z 2. The ligands studied were [ 3H]SCH 23390 (80 Ci/mmol) and [‘Hlspiperone (30 Ci/mmol) for D-l and D-2 receptor sites, respectively. Incubations were carried out for 15 min at 37” C. The reaction was stopped by rapid filtration through Whatman GF/B filters followed by four 4 ml rinses with buffer solution using a Brandel cell harvester. Radioactivity on the filters was determined using a liquid scintillation spectrometer. Specific binding was defined as the difference between total binding and that found in the presence of 1 PM ketanserin and sulpiride for [3H]spiperone, and in the presence of 1 PM SCH 23390 for [‘H]SCH 23390. Plotting and curve fitting were performed using the microcomputer program GraphPAD (I.S.I. Philadelphia, PA). B,,, and K, values were calculated from Scatchard curve analysis. Multiple group comparisons were performed using a Newman-Keuls post hoc test after analysis of variance.
3. Results Thirty days after treating mice with MPTP there was about a 50% depletion of striatal DA and a concomitant enhanced behavioral sensitivity to haloperidol (Hadjiconstantinou and Neff, 1988; Weihmuller et al., 1988a). Treatment with GM1 ganglioside after MPTP restores striatal DA to about 90% of control values and reverses the supersensitivity to haloperidol (Weihmuller et al., 1988b). MPTP treatment induces about a 30% depletion of tyrosine hydroxylase immunoreactive cell in the substantia nigra. GM1 treatment does not, however restore the number immunoreactive cells in the substantia nigra of the MPTP-treated group (Hadjiconstantinou et al., 1989). Thirty days after initiating MPTP treatment we found a significant increase of the B,,, for [ 3Hlspiperone (table 1). GM1 ganglioside administered alone had no apparent effect on B,,, for either ligand. In contrast, GM1 treatment prevented the rise of the B,,, for [3H]spiperone in the MPTP-treated mice. The K, values were not significantly effected by the treatments.
TABLE
1
GM1 treatment prevents D-2 receptor up-regulation in the striatum of MPTP-treated mice. Treatment groups: saline, mice were given daily injections of saline for 30 days and then killed. MPTP-30, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of saline for 23 days and then killed 24 h after the last injection. GMl, mice were given daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and then killed 24 h after the last injection. MPTP+ GMl, mice were given MPTP for 7 days (30 mg/kg i.p.) followed on day 8 by daily injections of GM1 ganglioside (30 mg/kg i.p.) for 23 days and killed 24 h after the last injection. Bmar is expressed in fmol/mg protein+ S.E.M. and K, in nM + S.E.M. N = 5 experiments. Treatment
Saline MPTP-30 GM1 MPTP+GMl
[ ‘H]SCH
[ 3Hlspiperone
23390
Bmax
Kll
BInax
995f51 902+79 916,79 1044?36
1.10+0.09 1.7OkO.40 l.lO+O.lE l.lOkO.22
247k8 367+13 250+3 254f4b
a P < 0.05 when compared compared with MPTP-30.
with saline group;
K, 0.26 & 0.002 a 0.27+0.002 0.26 f 0.015 0.28~0.007 h P i 0.05 when
From the binding isotherms for [3H]spiperone, it is evident that MPTP up-regulated [ 3H]spiperone binding when studied on day 30 (fig. 1). Up-regu-
0’ 0.5
1.0 Ligand
1.5
2.0
h-M)
Fig. 1. Specific binding of [3H]spiperone to membranes prepared from the striatum of mice treated with MPTP and/or GM1 ganglioside versus the concentration of ligand. See table 1 for drug treatments. Data are presented as the means f S.E.M. for five experiments: squares, MPTP-30; circles, MPTP+ GMI. Values for saline- and GMl-treated mice are not shown, as they fell together with values for MPTP+GMl.
263
lation is prevented by treatment with GM1 ganglioside. The isotherm for saline- and GMl-treated animals (data not shown) fell together with the values for the MPTP-GMl-treated group. GM1 when added in vitro to membranes at concentrations up to 0.5 PM had no effect on [ 3H]spiperone binding.
4. Discussion The neurotoxin MPTP destroys nigrostriatal dopaminergic neurons and induces clinical symptoms in humans that are indistinguishable from Parkinson’s disease. The mouse MPTP model of parkinsonism shows many of the same biochemical and pathological deficits associated with the human disorder. In our strain of mouse, when 30 mg/kg i.p. of MPTP is administered daily for 7 days, there is about a 50-60s loss of DA from the striatum and of tyrosine hydroxylase immunoreactive cells from the substantia nigra when evaluated 7 or 30 days after initiating the treatment (Hadjiconstantinou et al., 1989). At the same time there is about a 50% fall of DA uptake while the rate of DA formation is below normal (Hadjicontantinou and Neff, 1988). At this stage the animals appear normal behaviorally. These observations are consistent with the observation that about 80-90s loss of dopaminergic neurons are needed before clinical symptoms become evident. Even though our MPTP-treated animals appear normal, their nigrostriatal dopaminergic deficit could be unmasked by administering a low dose of haloperidol, a dose that has no apparent effect on normal untreated mice. Challenged with halothe MPTP-treated animals become peridol, bradykinetic and show somatosensory deficits (Weihmuller et al., 1988a). Treatment with GM1 ganglioside reverses the supersensitivity of MPTP mice to haloperidol (Weihmuller et al., 1988b) and increases the formation of DA to about normal (Hadjiconstantinou and Neff, 1988). Three weeks after MPTP treatment D-l receptor density appeared normal, whereas the density of D-2 receptors was elevated, suggesting receptor up-regulation. Our findings agree with reports of an increase of D-2 B,,,,, after MPTP administra-
tion (Joyce et al., 1985; Lau and Fung, 1986; Falardeau et al., 1988). The lack of up-regulation of striatal D-l receptors 3 weeks post-MPTP is in agreement with observations that 6-hydroxydopamine lesions do not result in an increase of [3H]SCH 23390 sites 30 days post-lesion (Savasta et al., 1988; Langer et al., 1986). Chronic administration of GM1 ganglioside prevented the D-2 receptor changes in the striaturn of the MPTP-treated mice. A possible explanation for GM1 effect might be that the ganglioside, by increasing the rate of formation of DA in the striatum of the MPTP-treated mice (Hadjiconstantinou and Neff, 1988) provides sufficient amine to D-2 receptors to prevent up-regulation. However GM1 also prevents high dosage haloperidol-induced up-regulation of D-2 receptor (Agnati et al., 1983) suggesting a possible direct effect on the receptor. In conclusion, our studies have shown that treatment with GM1 ganglioside can facilitate the biochemical, histological and behavioral recovery of nigrostriatal dopaminergic neurons after moderate lesions induced by MPTP. We now provide evidence that GM1 ganglioside also prevents the up-regulation of D-2 receptors in the same model. Both biochemically and pathologically this model probably resembles the preclinical stages of parkinsonism. Screening of at-risk individuals for parkinsonism is a perquisite for early medical intervention and treatment for neurodegenerative diseases. Small doses of DA agonists or antagonists are known to induce abnormal motor behaviors, perhaps the equivalent of extrapyramidal sympin animals with nigrostriatal tomatology, dopaminergic lesions but not in normal animals. The administration of a short-acting DA agonists or antagonists would be expected to precipitate short-lasting extrapyramidal symptomatology in an individual at-risk for parkinsonism but not in a normal individual. For persons apparently at-risk, the administration of GM1 ganglioside may be beneficial for preserving neuronal function and prolonging the productive life of the individual. Successful therapy with GM1 ganglioside might be evaluated by re-administering the same low dose of the dopaminergic drug that was originally used to unmask the symptomatology.
264
Acknowledgements This work was supported, in part, by The American Parkinson Disease Association, FIDIA Research Laboratories and Grant NS23627 from the National Institutes of Health, GM1 ganglioside was a gift from FIDIA Research Laboratories. Expert technical assistance was provided by Trina Wemlinger and Lori Isaacs.
References Agnati, L.F., K. Fuxe. F. Benfenati, N. Battistini, I. Zini and G. Toffano, 1983a. Chronic ganglioside treatment counteracts the biochemical signs of dopamine receptor supersensitivity induced by chronic haloperidol treatment, Neurosci. Lett. 40, 293. Falardeau, P., P.J. Bedard and T. Di Paolo, 1988, Relation between brain dopamine loss and D2 dopamine receptor density in MPTP monkeys, Neurosci. Lett. 86, 225. Hadjiconstantinou, M., A.P. Mariani and N.H. Neff, 1989, GM1 ganglioside-induced recovery of nigrostriatal dopmaminergic neurons after MPTP: An immunohistochemical study, Brain Res. 484, 297. Hadjiconstantinou, M. and N.H. Neff, 1988, Treatment with GM1 ganglioside restores striatal dopamine in the I-
methyl-4-phenyl-l,2,3,6-tetrahydropyridine-treated mouse, J. Neurochem. 51. 1190. Joyce, J.N., J.F. Marshall, K.S. Bankiewicz, I.J. Kopin and D.M. Jacobowitz. 1985, Hemiparkinsonism in monkey after unilateral internal carotid artery infusion of l-methyl4-phenyl-1.2,3,6-tetrahydropyridine (MPTP) is associated with regional ipsilateral changes in striatal dopamine D-2 receptor density, Brain Res. 382, 360. Langer, S.Z., C. Pimoule, G.P. Reynolds and H.P. Schoemaker, 1986. Dopaminergic denervation does not affect 3H-SCH 23390 binding in the rat striatum, similarities to Parkinson’s disease, Br. J. Pharmacol. 87, 161. Lau. Y.-S. and Y.K. Fung, 1986. Pharmacological effects of I-methyl-4-phenyl-1,2,3,6_tetrahydropyridine (MPTP) on striatal dopamine receptors system, Brain Res. 369, 311. Savasta, M., A. Dubois, J. Benavides and B. Scatton, 1988. Different plasticity changes in Dl and D2 receptors in rat striatal subregions following impairment of dopaminergic transmission, Neurosci. Lett. 85, 119. Weihmuller, F.B., M. Hadjiconstantinou and J.P. Bruno, 1988a, Acute stress or neuroleptics elicit sensorimotor deficits in MPTP-treated mice, Neurosci. Lett. 85, 137. Weihmuller. F.B., M. Hadjiconstantinou, J.P. Bruno and N.H. Neff, 1988b, Administration of GM1 ganglioside eliminates neuroleptic-induced sensorimotor deficits in MPTP-treated mice, Neurosci. Lett. 92. 207.