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Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice
European Journal of Pharmacology, 236 (1993) 487-489 © 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
487
EJP 21247
Short communication
Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice M a r c M a r i e n , M i k e Briley and F r a n c i s C o l p a e r t Division Neurobiologie I, Centre de Recherche Pierre Fabre, 17Avenue Jean Moulin, 81106 Castres Cddex, France Received 21 January 1993, revised MS received 31 March 1993, accepted 6 April 1993
Injection of C57B1/6 mice with 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP; 4 x 10 mg/kg i.p. over 8 h) resulted in a partial (40%) striatal dopamine depletion at 7 days post-drug. Pretreatment with the selective noradrenergic neurotoxin N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine(DSP-4; 40 mg/kg i.p.), while having no effect per se on striatal dopamine levels, exacerbated the MPTP-induced dopamine deficit to 60%. Results support the hypothesis that damage to the locus coeruleusnoradrenergic system, by removing a facilitatory influence on the nigrostriatal dopamine system, interferes with the ability of the nigrostriatal pathway to compensate for or recover from injury. Parkinson's disease; Locus coeruleus; MPTP (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine); Striatal dopamine; DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine);C57B1/6 mouse
1. Introduction
Along with cell body loss in the substantia nigra compacta and profound deficits in basal ganglia levels of dopamine, a degeneration of noradrenergic neurons in the locus coeruleus and reductions in the regional levels of noradrenaline are characteristic postmortem findings in the brain of parkinsonian patients (Hornykiewicz and Kish, 1986). Although the role of the locus coeruleus-noradrenergic system in the etiology of Parkinson's disease is unknown, it has been proposed that a defective locus coeruleus system might underlie the progression of the disease (Colpaert, 1987). In support of this hypothesis, we have shown in a primate model of Parkinson's disease, the MPTP (1-methyl4-phenyl- 1,2,3,6-tetrahydropyridine)-treated monkey, that 6-hydroxydopamine lesioning of the locus coeruleus impairs the recovery that otherwise occurs in behavioral symptoms, striatal dopamine depletion, and cell loss in the substantia nigra (Mavridis et al., 1991). Since the availability of a more accessible animal model of Parkinson's disease would provide a means of studying this phenomenon in greater detail, we were interested to determine if similar effects could be demonstrated in the MPTP-treated C57B1/6 mouse (Heikkila
Correspondence to: M. Marien, Division Neurobiologie I, Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106 Castres C6dex, France. Tel. 33-63-71-42-71, fax 33-63-35-66-29.
et al., 1984). In the present study, we have examined the effect of a selective noradrenaline depletion on the loss of striatal dopamine induced by MPTP. The selective noradrenergic neurotoxin DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) was utilized as a noradrenaline depleting agent since it preferentially affects those noradrenergic projections which derive from the locus coeruleus, and produces robust (8085%), reproducible and rapid depletions ( < 24 h) in noradrenaline levels while sparing dopamine and serotonin neurons (Jonsson et ai., 1981; Hallman and Jonsson, 1984).
2. Materials and methods
M P T P (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) and DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) were both obtained from Sigma Chemical Co. as the hydrochloride salts. Citalopram hydrobromide was obtained from Lundbeck Chemicals (Copenhagen). Drugs were dissolved in 0.9% NaC1 containing 2% Tween 80, and injected in a volume of 10 m l / k g . Doses refer to the free base equivalent of drug. Male C57BI/6N CrlDR mice (22 g body weight at the beginning of the experiment; Charles River, E1beuf, France) were injected with the serotonin uptake blocker citalopram (10 m g / k g i.p.) 1 h prior to DSP-4 (40 m g / k g i.p.), to prevent concurrent damage to sero-
488
tonergic neurons (Delini-Stula et al., 1984). The control group of animals received citalopram alone. MPTP was injected 24 h later in four doses of 10 mg/kg i.p. at 2 h intervals. The control animals received vehicle injections. Seven days later, the animals were killed by cervical dislocation and the brains rapidly removed and dissected on an ice-cold glass plate. The frontoparietal cortex and striatum were isolated, weighed, frozen on dry ice and stored at -80°C. Tissues were homogenized by brief sonication in ice-cold 0.2 M perchloric acid containing 6.72 mM disodium EDTA, 13.2 mM sodium metabisulfite and 0.47/zM isoproterenol (internal standard), centrifuged at 20,000 x g for 20 min, and the supernatants analyzed for monoamines and metabolites by high performance liquid chromatography with electrochemical detection (Lategan et al., 1990). Levels of monoamines were expressed as /zg/g tissue.
3. Results
At 7 days following treatment of C57B1/6 mice with 40 mg/kg MPTP, striatal levels of dopamine were 10
A. STRIATAL DA *
--lr-
==
i
i
T
* * T
,< ,.r',t
DSP4
vehicle
MPTP
I
DSP4+MPTP
B. FRONTOCORTICAL NA .3 -)(-% /
/
"
1
/
-r-
.2
1
1
+ ,< Z
i •
l i
l i
+
* *
"/// .
¢///
vehicle
I
I DSP4
I MPTP
I
DSP4+MPTP
Fig. 1. Brain regional levels of dopamine (DA) and noradrenaline (NA) in C57B1/6 mice 7 days following t r e a t m e n t with DSP-4, MPTP or the combination (refer to text for details). (A) Striatal dopamine levels. (B) Frontocortical noradrenaline levels. Values are means + S.E.M., n = 5 - 7 animals per group. * P < 0.05, * * P < 0.01 compared to vehicle (or as indicated otherwise); ÷ P < 0.01 compared to MPTP alone. Differences were analyzed by A N O V A + Neuman-Keuls test.
reduced by 39.5% (fig. 1). Although DSP-4 pretreatm e n t by itself did not affect striatal dopamine levels, the combination of DSP-4 pretreatment followed by MPTP produced a 59.9% depletion of dopamine which was significantly greater that the depletion caused by MPTP alone (fig. 1A). DSP-4 and MPTP by themselves reduced cortical noradrenaline levels by 84.1 and 20.4%, respectively. In animals with the combined neurotoxin treatment, cortical noradrenaline was depleted to the same extent (-86.0%) as with DSP-4 alone (fig. 1B). Cortical and striatal levels of serotonin were not significantly altered in any of the treatment groups (data not shown).
4. Discussion
Similar to previous reports (e.g. Janson et al., 1992), a 40 mg/kg dose of MPTP in the C57B1/6 mouse strain produced a partial (39.5%) but significant loss of striatal dopamine after 7 days. The key finding of the present study was that prior damage to the locus coeruleus-noradrenergic system with DSP-4, which by itself had no significant effect on striatal dopamine levels, clearly exacerbated the MPTP-induced depletion of dopamine. The mechanisms underlying this effect are unknown at present. Conceivably, damage to noradrenergic terminals may reduce the number of potential sites for active uptake of the toxic metabolite of MPTP, 1-methyl-4-phenylpyridine (MPP ÷), thus increasing its effective extracellular concentration and availability to dopaminergic neurons in the brain. However, the rate of MPP+ uptake by noradrenergic neurons is an order of magnitude lower than in dopaminergic neurons (Javitch and Snyder, 1985). In addition, relative to the density of dopamine terminal fibres in the rodent striatum, the noradrenergic innervation is sparse if at all existent (Jones and Moore, 1977) and thus unlikely to contribute significantly to the removal of MPP+. Alternatively, injury to the locus coeruleus might aggravate the energy crisis that is thought to be a final step of MPTP neurotoxicity (Kinemuchi et al., 1987), by impairing restorative mechanisms mediated in part by glial cells (see review by Stone and Ariano, 1989). The dopamine deficits found in these mouse experiments reflect the pattern of changes observed in our previous monkey study, in which animals receiving a bilateral 6-hydroxydopamine lesion of the locus coeruleus immediately prior to systemic administration of MPTP showed significantly greater depletions of basal ganglia dopamine after 9 weeks, in comparison to those animals which were administered with MPTP alone. Interestingly, the present data are complemented by the recent findings of Bing et al. (1992) who have shown that prior lesioning of the locus coeruleus
489
with 6-hydroxydopamine enhanced the disappearance of tyrosine hydroxylase immunoreactive fibres in the striatum and cell bodies in the substantia nigra of C57B1/6 mice, at 7 days following the same dose regimen of MPTP used in the present study. Together, these results provide further evidence to support the hypothesis that destruction of the locus coeruleusnoradrenergic system removes a facilitatory or trophic influence on the nigrostriatal dopaminergic pathway (Lategan et al., 1990, 1992), and that such a deficit may somehow interfere with the ability of the dopamine system to compensate for or recover from injury (Mavridis et al., 1991). These present findings suggest that the MPTP mouse may be a useful and particularly accessible model to study the influence of the locus coeruleus-noradrenergic system in dopamine neuronal degeneration, recovery and survival in vivo.
Acknowledgements The authors gratefully acknowledge the technical assistance of Nathalie Morfin and Veronique Nguyen.
References Bing, G., Y. Zhang and E.A. Stone, 1992, Protective action of locus coeruleus noradrenergic system on substantia nigra of mice treated with MPTP, Soc. Neurosci. Abstr. 18, 1375. Colpaert, F.C., 1987, Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in the rat, Neuropharmacology 26, 1431. Delini-Stula, A., E. Mogilnicka, C. Hunn and D.J. Dooley, 1984, Novelty-oriented behavior in the rat after selective damage of locus coeruleus projections by DSP-4, a new noradrenergic neurotoxin, Pharmacol. Biochem. Behav. 20, 613.
Hallman, H. and G. Jonsson, 1984, Pharmacological modifications of the neurotoxic action of the noradrenaline neurotoxin DSP-4 on central noradrenaline neurons, Eur. J. Pharmacol. 103, 269. Heikkila, R.E., A. Hess and R.C. Duvoisin, 1984, Dopaminergic neurotoxicity of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine in mice, Science 224, 1451. Hornykiewicz, O. and S.J. Kish, 1986, Biochemical pathophysiology of Parkinson's disease, Adv. Neurol. 45, 19. Janson, A.M., K. Fuxe and M. Goldstein, 1992, Differential effects of acute and chronic nicotine treatment on MPTP (1-methyl-4phenyl-l,2,3,6-tetrahydropyridine) induced degeneration' of nigrostriatal dopamine neurons in the black mouse, Clin. Invest. 70, 232. Javitch, J.A. and S.H. Snyder, 1985, Uptake of MPP( + ) by dopamine neurons explains selectivity of parkinsonism-inducing neurotoxin, MPTP, Eur. J. Pharmacol. 106, 455. Jones, B.E. and R.Y. Moore, 1977, Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study, Brain Res. 127, 23. Jonsson, G., H. Hallman, F. Ponzio and S. Ross, 1981, DSP-4 (N-(2-chloroethyl]-N-ethyl-2-bromobenzylamine)- a useful denervation tool for central and peripheral noradrenaline neurons, Eur. J. Pharmacol. 72, 173. Kinemuchi, H., C.J. Fowler and K.F. Tipton, 1987, The neurotoxicity of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) and its relevance to Parkinson's disease, Neurochem. Int. 11,359. Lategan, A.J., M.R. Marien and F.C. Colpaert, 1990, Effects of locus coeruleus lesions on the release of endogenous dopamine in rat nucleus accumbens and caudate nucleus as determined by intracerebral microdialysis, Brain Res. 523, 134. Lategan, A.J., M.R. Marien and F.C. Colpaert, 1992, Suppression of nigrostriatal and mesolimbic dopamine release in vivo following noradrenaline depletion by DSP-4: a microdialysis study, Life Sci. 14, 995. Mavridis, M., A.-D. Degryse, A.J. Lategan, M.R. Marien and F.C. Colpaert, 1991, Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after lmethyl-4-phenyl-l,2,3,6-tetrahydropyridinein monkeys: a possible role for the locus coeruleus in the progression of Parkinson's disease, Neuroscience 41,507. Stone, E.A. and M.A. Ariano, 1989, Are glial cells targets of the central noradrenergic system? A review of the evidence, Brain Res. Rev. 14, 297.
487
EJP 21247
Short communication
Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice M a r c M a r i e n , M i k e Briley and F r a n c i s C o l p a e r t Division Neurobiologie I, Centre de Recherche Pierre Fabre, 17Avenue Jean Moulin, 81106 Castres Cddex, France Received 21 January 1993, revised MS received 31 March 1993, accepted 6 April 1993
Injection of C57B1/6 mice with 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP; 4 x 10 mg/kg i.p. over 8 h) resulted in a partial (40%) striatal dopamine depletion at 7 days post-drug. Pretreatment with the selective noradrenergic neurotoxin N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine(DSP-4; 40 mg/kg i.p.), while having no effect per se on striatal dopamine levels, exacerbated the MPTP-induced dopamine deficit to 60%. Results support the hypothesis that damage to the locus coeruleusnoradrenergic system, by removing a facilitatory influence on the nigrostriatal dopamine system, interferes with the ability of the nigrostriatal pathway to compensate for or recover from injury. Parkinson's disease; Locus coeruleus; MPTP (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine); Striatal dopamine; DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine);C57B1/6 mouse
1. Introduction
Along with cell body loss in the substantia nigra compacta and profound deficits in basal ganglia levels of dopamine, a degeneration of noradrenergic neurons in the locus coeruleus and reductions in the regional levels of noradrenaline are characteristic postmortem findings in the brain of parkinsonian patients (Hornykiewicz and Kish, 1986). Although the role of the locus coeruleus-noradrenergic system in the etiology of Parkinson's disease is unknown, it has been proposed that a defective locus coeruleus system might underlie the progression of the disease (Colpaert, 1987). In support of this hypothesis, we have shown in a primate model of Parkinson's disease, the MPTP (1-methyl4-phenyl- 1,2,3,6-tetrahydropyridine)-treated monkey, that 6-hydroxydopamine lesioning of the locus coeruleus impairs the recovery that otherwise occurs in behavioral symptoms, striatal dopamine depletion, and cell loss in the substantia nigra (Mavridis et al., 1991). Since the availability of a more accessible animal model of Parkinson's disease would provide a means of studying this phenomenon in greater detail, we were interested to determine if similar effects could be demonstrated in the MPTP-treated C57B1/6 mouse (Heikkila
Correspondence to: M. Marien, Division Neurobiologie I, Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, 81106 Castres C6dex, France. Tel. 33-63-71-42-71, fax 33-63-35-66-29.
et al., 1984). In the present study, we have examined the effect of a selective noradrenaline depletion on the loss of striatal dopamine induced by MPTP. The selective noradrenergic neurotoxin DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) was utilized as a noradrenaline depleting agent since it preferentially affects those noradrenergic projections which derive from the locus coeruleus, and produces robust (8085%), reproducible and rapid depletions ( < 24 h) in noradrenaline levels while sparing dopamine and serotonin neurons (Jonsson et ai., 1981; Hallman and Jonsson, 1984).
2. Materials and methods
M P T P (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) and DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine) were both obtained from Sigma Chemical Co. as the hydrochloride salts. Citalopram hydrobromide was obtained from Lundbeck Chemicals (Copenhagen). Drugs were dissolved in 0.9% NaC1 containing 2% Tween 80, and injected in a volume of 10 m l / k g . Doses refer to the free base equivalent of drug. Male C57BI/6N CrlDR mice (22 g body weight at the beginning of the experiment; Charles River, E1beuf, France) were injected with the serotonin uptake blocker citalopram (10 m g / k g i.p.) 1 h prior to DSP-4 (40 m g / k g i.p.), to prevent concurrent damage to sero-
488
tonergic neurons (Delini-Stula et al., 1984). The control group of animals received citalopram alone. MPTP was injected 24 h later in four doses of 10 mg/kg i.p. at 2 h intervals. The control animals received vehicle injections. Seven days later, the animals were killed by cervical dislocation and the brains rapidly removed and dissected on an ice-cold glass plate. The frontoparietal cortex and striatum were isolated, weighed, frozen on dry ice and stored at -80°C. Tissues were homogenized by brief sonication in ice-cold 0.2 M perchloric acid containing 6.72 mM disodium EDTA, 13.2 mM sodium metabisulfite and 0.47/zM isoproterenol (internal standard), centrifuged at 20,000 x g for 20 min, and the supernatants analyzed for monoamines and metabolites by high performance liquid chromatography with electrochemical detection (Lategan et al., 1990). Levels of monoamines were expressed as /zg/g tissue.
3. Results
At 7 days following treatment of C57B1/6 mice with 40 mg/kg MPTP, striatal levels of dopamine were 10
A. STRIATAL DA *
--lr-
==
i
i
T
* * T
,< ,.r',t
DSP4
vehicle
MPTP
I
DSP4+MPTP
B. FRONTOCORTICAL NA .3 -)(-% /
/
"
1
/
-r-
.2
1
1
+ ,< Z
i •
l i
l i
+
* *
"/// .
¢///
vehicle
I
I DSP4
I MPTP
I
DSP4+MPTP
Fig. 1. Brain regional levels of dopamine (DA) and noradrenaline (NA) in C57B1/6 mice 7 days following t r e a t m e n t with DSP-4, MPTP or the combination (refer to text for details). (A) Striatal dopamine levels. (B) Frontocortical noradrenaline levels. Values are means + S.E.M., n = 5 - 7 animals per group. * P < 0.05, * * P < 0.01 compared to vehicle (or as indicated otherwise); ÷ P < 0.01 compared to MPTP alone. Differences were analyzed by A N O V A + Neuman-Keuls test.
reduced by 39.5% (fig. 1). Although DSP-4 pretreatm e n t by itself did not affect striatal dopamine levels, the combination of DSP-4 pretreatment followed by MPTP produced a 59.9% depletion of dopamine which was significantly greater that the depletion caused by MPTP alone (fig. 1A). DSP-4 and MPTP by themselves reduced cortical noradrenaline levels by 84.1 and 20.4%, respectively. In animals with the combined neurotoxin treatment, cortical noradrenaline was depleted to the same extent (-86.0%) as with DSP-4 alone (fig. 1B). Cortical and striatal levels of serotonin were not significantly altered in any of the treatment groups (data not shown).
4. Discussion
Similar to previous reports (e.g. Janson et al., 1992), a 40 mg/kg dose of MPTP in the C57B1/6 mouse strain produced a partial (39.5%) but significant loss of striatal dopamine after 7 days. The key finding of the present study was that prior damage to the locus coeruleus-noradrenergic system with DSP-4, which by itself had no significant effect on striatal dopamine levels, clearly exacerbated the MPTP-induced depletion of dopamine. The mechanisms underlying this effect are unknown at present. Conceivably, damage to noradrenergic terminals may reduce the number of potential sites for active uptake of the toxic metabolite of MPTP, 1-methyl-4-phenylpyridine (MPP ÷), thus increasing its effective extracellular concentration and availability to dopaminergic neurons in the brain. However, the rate of MPP+ uptake by noradrenergic neurons is an order of magnitude lower than in dopaminergic neurons (Javitch and Snyder, 1985). In addition, relative to the density of dopamine terminal fibres in the rodent striatum, the noradrenergic innervation is sparse if at all existent (Jones and Moore, 1977) and thus unlikely to contribute significantly to the removal of MPP+. Alternatively, injury to the locus coeruleus might aggravate the energy crisis that is thought to be a final step of MPTP neurotoxicity (Kinemuchi et al., 1987), by impairing restorative mechanisms mediated in part by glial cells (see review by Stone and Ariano, 1989). The dopamine deficits found in these mouse experiments reflect the pattern of changes observed in our previous monkey study, in which animals receiving a bilateral 6-hydroxydopamine lesion of the locus coeruleus immediately prior to systemic administration of MPTP showed significantly greater depletions of basal ganglia dopamine after 9 weeks, in comparison to those animals which were administered with MPTP alone. Interestingly, the present data are complemented by the recent findings of Bing et al. (1992) who have shown that prior lesioning of the locus coeruleus
489
with 6-hydroxydopamine enhanced the disappearance of tyrosine hydroxylase immunoreactive fibres in the striatum and cell bodies in the substantia nigra of C57B1/6 mice, at 7 days following the same dose regimen of MPTP used in the present study. Together, these results provide further evidence to support the hypothesis that destruction of the locus coeruleusnoradrenergic system removes a facilitatory or trophic influence on the nigrostriatal dopaminergic pathway (Lategan et al., 1990, 1992), and that such a deficit may somehow interfere with the ability of the dopamine system to compensate for or recover from injury (Mavridis et al., 1991). These present findings suggest that the MPTP mouse may be a useful and particularly accessible model to study the influence of the locus coeruleus-noradrenergic system in dopamine neuronal degeneration, recovery and survival in vivo.
Acknowledgements The authors gratefully acknowledge the technical assistance of Nathalie Morfin and Veronique Nguyen.
References Bing, G., Y. Zhang and E.A. Stone, 1992, Protective action of locus coeruleus noradrenergic system on substantia nigra of mice treated with MPTP, Soc. Neurosci. Abstr. 18, 1375. Colpaert, F.C., 1987, Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in the rat, Neuropharmacology 26, 1431. Delini-Stula, A., E. Mogilnicka, C. Hunn and D.J. Dooley, 1984, Novelty-oriented behavior in the rat after selective damage of locus coeruleus projections by DSP-4, a new noradrenergic neurotoxin, Pharmacol. Biochem. Behav. 20, 613.
Hallman, H. and G. Jonsson, 1984, Pharmacological modifications of the neurotoxic action of the noradrenaline neurotoxin DSP-4 on central noradrenaline neurons, Eur. J. Pharmacol. 103, 269. Heikkila, R.E., A. Hess and R.C. Duvoisin, 1984, Dopaminergic neurotoxicity of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine in mice, Science 224, 1451. Hornykiewicz, O. and S.J. Kish, 1986, Biochemical pathophysiology of Parkinson's disease, Adv. Neurol. 45, 19. Janson, A.M., K. Fuxe and M. Goldstein, 1992, Differential effects of acute and chronic nicotine treatment on MPTP (1-methyl-4phenyl-l,2,3,6-tetrahydropyridine) induced degeneration' of nigrostriatal dopamine neurons in the black mouse, Clin. Invest. 70, 232. Javitch, J.A. and S.H. Snyder, 1985, Uptake of MPP( + ) by dopamine neurons explains selectivity of parkinsonism-inducing neurotoxin, MPTP, Eur. J. Pharmacol. 106, 455. Jones, B.E. and R.Y. Moore, 1977, Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study, Brain Res. 127, 23. Jonsson, G., H. Hallman, F. Ponzio and S. Ross, 1981, DSP-4 (N-(2-chloroethyl]-N-ethyl-2-bromobenzylamine)- a useful denervation tool for central and peripheral noradrenaline neurons, Eur. J. Pharmacol. 72, 173. Kinemuchi, H., C.J. Fowler and K.F. Tipton, 1987, The neurotoxicity of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) and its relevance to Parkinson's disease, Neurochem. Int. 11,359. Lategan, A.J., M.R. Marien and F.C. Colpaert, 1990, Effects of locus coeruleus lesions on the release of endogenous dopamine in rat nucleus accumbens and caudate nucleus as determined by intracerebral microdialysis, Brain Res. 523, 134. Lategan, A.J., M.R. Marien and F.C. Colpaert, 1992, Suppression of nigrostriatal and mesolimbic dopamine release in vivo following noradrenaline depletion by DSP-4: a microdialysis study, Life Sci. 14, 995. Mavridis, M., A.-D. Degryse, A.J. Lategan, M.R. Marien and F.C. Colpaert, 1991, Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after lmethyl-4-phenyl-l,2,3,6-tetrahydropyridinein monkeys: a possible role for the locus coeruleus in the progression of Parkinson's disease, Neuroscience 41,507. Stone, E.A. and M.A. Ariano, 1989, Are glial cells targets of the central noradrenergic system? A review of the evidence, Brain Res. Rev. 14, 297.