In this thesis, an attempt has been made to characterize the storage and release of somatodendritic dopamine in the substantia nigra, and to elucidate its role within the basal ganglia circuitry. The role of somatodendritic dopamine release in the pathophysiology of disabling motor syndromes, like Parkinson's disease and neuroleptic induced tardive dyskinesias, was investigated by using animal models. These studies will increase our understanding of basal ganglia pathology and might lead to more effective (pharmaco)therapeutic strategies in the future. ...

Zie: Summary

Heeringa, Marten,

Heeringa, Marten

University of Groningen

   University of GroningenSomatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterizationand effects of dopaminergic agentsHeeringa, MartenIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1999Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Heeringa, M. (1999). Somatodendritic dopamine in the substnatia nigra of the rat. Biochemicalcharachterization and effects of dopaminergic agents. Groningen: s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Dopaminergic neurons of the substantia nigra do not only release dopamine from nerveterminals in the striatum, but also from soma and dendrites in substantia nigra. Although theconcept of release of somatodendritic dopamine in the substantia nigra arose nearly twenty five)raÍs ago, many questions regarding its biochemistry and its role within normal andpathological basal ganglia remain (Geffen et a1,., !976; Korf et dl., 1976). This relative lack ofknowledge is, at least partly, related to technical difficulties; the extracellular level of dopaminein somatodendritic areas is about 6 times lower as compared to the striatum, a nerve terminalarea. In this thesis, an attempt has been made to characterize the storage and release ofsomatodendritic dopamine in the substantia nigra, and to elucidate its role within the basalganglia circuitry. The role of somatodendritic dopamine release in the pathophysiology ofdisabling motor ryndromes, like Parkinson's disease and neuroleptic induced tardivedyskinesias, was investigated by using animil models. These studies will increase ourunderstanding of basal ganglia pathologz and might lead to more effective(pharmaco)therapeutic strategies in the future.Chapter 2 of this thesis describes an extensive study on the nature of storage and release ofsomatodendritic dopamine. At the dopaminergic nerve terminal in the striatum, thephysiological release of dopamine generally is accepted as occuning via depolarization-inducedexog,tosis ffesterink and DeVries, 1988). Based exclusively on indirect indices, the storageand release of somatodendritic dopamine has been suggested to be non-vesicular in nature(Eiverfors and Nissbrand, 199I). We directly examined, by using in vivo microdialysis, whetherthe storage and/or release of somatodendritic dopamine is dependent upon a vesicular pool oftransmitter. The storage of dopamine appeared to be vesicular in nature in all brain areasexamined, since reserpine, a compound that disrupts vesicular sequestration of monoamines,significandy decreased the tissue levels of dopamine in substantia nigra reticulata, substantianigra compacta and striatum. Administration of reserpine also resulted in a rapid decrease ofextracellular dopamine in substantia nigra as well as in the striatum, both to non-detectablelevels. In order to further chatactenze and compare the intracellular compartmentalization ofsomatodendritic dopamine versus nerve terminal dopamine, we also employed microdialysis todetermine the effects of reserpine pretreatment on amphetamine-stimulated dopamine insubstantia nigra and striatum. In contrast to the effects of a low dose of amphetamine,dopamine efflu-r in response to a high dose of amphetamine was significantly attenuated byreserpine pretreatment both in substantia nigra and in the striatum. Previous studies haveshown that a low dose of amphetamine only induces release of the cytoplasmic store, while ahigh dose also releases from vesicular stores. Thus, our data support the idea of vesicularstorage of somatodendritic dopamine, similar to nerve terminal dopamine.In chdopatechrare ltexPe(the e.extrademcof sccondhowesimilithat ïcoulcthe eadmirBesidneur(rhar 1PaftelsomaAdmdopahavegenernecesexplaheterthe plre uraffertspikirchargsomaBecarpath<Chapinflut1 1 6nerveqh thpD__ " ' -ty fiveLl andack of,aminerminalase of: basal'tsr .í' ó J  - 'ardivee our[ective:ase of.  th"rducedtoragenaturehetherrool of. areasmines,stantiaase of:ctableion ofysis toine inrmine,;ed byr haveÀile a;icularIn chapter 3 and 4, we examined both reguiation and effects of the release of somatodendriticdopamine within the intact basal ganglia circuitry. Chapter 3 utilizes the microdialysistechnique in order to examine whether somatodendritic autoreceptors in the substantia nigraare involved in the regulation of the release of somatodendritic dopamine. Contrary to theexpectations, local blockade of nigral dopamine D2 receptors by haloperidol failed to increasethe extracellular levels of nigral dopamine. This haloperidol treatment abolished the decrease inextracellular levels of dopamine induced by local perfusion of the D2 agonist quinpirole, thusdemonstrating effective blockade of D2 receptors. These observations suggest that the releaseof somatodendritic dopamine is not under tonic inhibitory control, at least under basalconditions. The results were verified by systemic administration of haloperidol. This treatment,however, resulted in a dose dependent increase of extracellular dopamine in substantia nigra. Asimilar increase was observed after microinjection of haloperidol in the striatum, suggestingthat blockade of striatal dopamine D2 receptors, rather thanD2 receptors in substantia nigra,could underlie the effect caused by qystemic administration of the drug. Our observation thatthe effect of intrastriatal microinjection of haloperidol was not altered by simultaneousadministration of haloperidol via the systemic route, is in agreement with this hlpothesis.Besides these direct conclusions, the studies could also shed light on the relationship betweenneurona-l firing and release of somatodendritic dopamine. Gonon and coworkers have shownthat the release o{ nmx terminal dopamine depends, among others, on changes in the firingpattern of dopaminergic neurons. 'Whether a similar mechanism also underlies the release ofsomatodendritic dopamine is questionable, at least under the curent experimental conditions.Administration of 0.05 mglkg haloperidol did not alter the release of somatodendriticdopamine in substantia nigra. Flowever, other studies using similar experimental conditionshave shown that this dose causes a maximal increase in striatal dopamine release, an effectgenerally accepted to reflect autoreceptor blockade. A ten times higher dose, 0.5 mg,/kg, wasnecessary to cause an increase in somatodendritic dopamine release. This effect is likely to beexplained by blockade of heteroreceptors; Skirboll and collegues demonstrated thatheteroreceptors might be ten times less sensitive as compared to autoreceptors. Thus, underthe present experimental conditions, the basal release of somatodendritic dopamine may notl,e under influence of substantia nigra neuronal firing, but instead under influence of nigralafferent projections. Evidence for functional compartmentilization of dendritic and axonalspiking regions on dopaminergic neurons, which may differentially utilize Na* and Ca** ascharge carriers, may support such a differential release mechanism for the release ofsomatodendritic dopamine (Llinás et d,., 1,984; Nedergaard et al., 1988; Grace, 1990).Because a "dopamine-acety'lcholine imbalance" is likely to play a role in basal gangliapatholory, the dopaminergic regulation of striatal acerylcholine has been studied extensively.Chapter 4 addresses the question whether striatal or nigral D1 receptors, the latter being underinfluence of somatodendritic dopamine, are involved in the inhibitorv effect of direadopamine agonists on striatal acerylcholine release. Therefore, the dose-related effect of thedirect dopamine D2 agonist quinpirole on the extracellular concentration of dopamine insubstantia nigra and striatum and oÍ acetylcholine in the striatum were measured using inaiwmicrodialysis. If the inhibitory effect of systemic administration of quinpirole would be due toa diminished stimulation of D1 receptors, a low, autoreceptor sensitive dose of quinpirolewould be expected to cause an inhibition of the release of dopamine and of acetylcholine. Incontrast, we observed an increase of the ertracellular levels of acetylcholine in the strianrm by alow dose of quinpirole. These data argue strongly in favor of a directly mediated inhibition ofstriatal acerylcholine by dopamine D2 receptor agonists. The data also elucidate some issuesconcerning the autoregulation of somatodendritic dopamine in comparison with nerveterminal dopamine. Perhaps one of the most remarkable differences is the ma-ximum decreaseof dopamine release in substantia nigra and striatum after administration of systemicquinpirole; dopamine levels in substantia nigra decrease to 5Oo/o f basal levels, whereas striataldopamine decreases to 20o/o of basal levels. Thus, autoregulation of somatodendritic dopaminerelease might be less imponant when compared to release of dopamine from nerve terminals.The lack of endogenous tone at D2 receptors in the substantia nigra, as suggested by thefailure to increase locai dopamine levels by intranigral administration of D2 antagonists inchapter 3, suppons this hlpothesis.The concept of a dopaminergic involvement in motor behavior arose from two importantclinical observations nearly three decades ago. First, Birkmayer and Hornykiewicz observed adopamine deficienry in the striatum of parkinsonian brains. This finding led to treatment withthe dopamine precursor levodopa, which appeared to diminish the ryrnptoms of this motordisease. Secondly, the discovery that (qpical) antipsychotics, which treatment is accompaniedby ertraplramidal motor s).rnptoms, are in fact dopaminergic antagonists also suggested thatan intact dopaminergic neurotransmission is essential for normal motor behavior (Burt et al.,1977). Snce these key observations, many studies have been performed in an attempt toelucidate the role of dopaminergic neurotransmission in normal motor behavior and inparticular in motor disease. In chapter 5 and 6, the dopaminergic system is examined n ani,rwlnrdels of Parkinson's disease and antipsychotics-induced tardive dyskinesias, respectively.Levodopa-induced contralateral rurning in 6-OHDA-lesioned rats, the animal model used inchapter 5, has been widely used as a behavioral testing paradigm for the potency of anti-parkinsonian agents (I-lngerstedt and Arbuthnon, 1,97A). In order to know whether enry-tneinhibition may potentiate levodopa-induced contralateral turning, and thus possibly increasethe therapeutic benefit of levodopa in humans, er,.zyme inhibitors involved in the metabolicinactivation of levodopa or dopamine were co-administered. Inhibition of MAO-A with Ro41.-1049 potentiated levodopa-induced contralateral turning, in contrast to MAO-B-inhibitionwhich only increased the duration of turning but not the total number of turns. Indeed, MAGA appears to be, at least in the rat, the predominant subq?e for oxidative deamination of1 1 8:ffect of thelopamine inusing inainLId be due to,f quinpiroleylcholine. In;triatum by arrlibition ofsome issueswith nerveum decreaseof qystemicereas triatalic dopaminere terminals.:sted by theLtagonists inc importantobserved aatment withthis motor:companied;gested that(Burt et al.,attempt toior and in:dn anirulespectively.Cel used incy of anti-ler en4./rnely increasemetabolic{ with Ro-inhibitioned, MAOination ofendogenous dopamine and ievodopa derived dopamine (Kato et aJ., 1,986; Butcher et aI., I99a;CoIà et aI., l99a; Mannisto and Toumainen, 1991; \lachtel and Abercrombte, 1994). COMT-inhibition with Ro 4A-7592 resulted in the largest potentiation of levodopa-induced turningwhen compared to inhibition of MAO, which suggests a potential role for COMT-inhibitors asadjuvants to the levodopa therapy in the treatment of Parkinson's disease. The site of action ofthe COMT-inhibitor is not yet known. Earlier studies have shown that Ro 40-7592 might notonly inhibit the metaboiic inactivation of levodopa in the periphery, but also of dopamine inthe striatum (Acquas et d,., 1992). Flowever, the observation that turning behavior can beelicited by an increase in the amount of dopamine in the substantia nigra, together with a majorrole of COMT in the catabolism of nigral dopamine, suggests a contributary role ofsomatodendritic dopamine to be likely (\Testerink and Korf, 1976; Robertson et aJ., 1991.;Robertson and Robertson, 1988, 1989; Kelly eÍ aJ,., 1,999).Ro 40-7592, known as tolcapone,was registered in 1997 for the treatment of Parkinson's disease.The potentiai role of somatodendritic dopamine in the mediation of antipsychotics-inducedtardive dyskinesias is examined in chapter 6, using the vacuous chewing movement trCN4)animal model. Long term treatment with antipsychotics results in tardive dyskinesia in some,but not all individuals. Such an individual suscepdbiliryis also observed in rats, a characteristicexploited in the VCM-model. After long-term treatment with the antipsychotic haloperidol,some rats exhibit vacuous chewing movements (VCM-positive), while others fail to show thesedyskinesias (VCM-negative). Since previous neuroanatomical studies have shown that theoccurrence of dyskinesias correlates with specific decreases in dopamine D1 receptors in thesubstantia nigra, we hlpothesized a potentiation of the release of somatodendritic dopamine inthe VCM-positive group. Flowever, our results showed that both basal release and the releaseinduced by an acute haloperidol challenge or tail-pinch stress were unaltered in the VOvI-positive group. In contrast, the effect of these challenges on the release of striatal acetylcholineappeared to be significantlypotentiated in the VCM-positive group. The basal levels of striatalacetylcholine showed a tendenry to increase in VCM-positive rats, which did not reachsignificance. The exact way in which these changes in cholinergic transmission are broughtabout is not exactly known. Several lines of evidence suggest that an enhanced glutamatergicdrive by cortical efferents might play a role (Yamamoto and Cooperman, 1994, Roberts et al.,1995). Since previous studies have shown neurochemical correlates of the occurrence of VCMsin both substantia nigra and thalamus, these brain areas are also likely to be involved(Shirakawa and Tamminga, 1994). Recently, it was shown that striatal acerylcholine is underexcitatory control of somatodendritic dopamine, a proces depending on striatal glutamarergicafferents. In this way, alterations in the nigrothalamocortical circuitry might underlie theenhanced release of striatal acetylcholine rather than a potentiated release of somatodendriticdopamine in the substantia nigra (Abercrombie and DeBoer, 1992).Taken together, the present thesis characterizes the release of somatodendritic dopamine in thesubstantia nigra, and elucidates the mechanisms underlying the effects of dopaminergic agentsin both normal basal ganglia circuitry and animal models of basal ganglia diseases. The mainconclusion that can be drawn from the results of this thesis, is that the pharmacologicalprofiles of antiparkinsonian and antipsychotic agents are not only determined by dopaminergicreceptors in nerve terminal areas like the striatum, but also by dopamine receptors in thesubstantia nigra: the targets of somatodendritic dopamine.REFERENCESAbercrombie, E.D., DeBoer, P. (1997). Substantia nigra D1 Íeceptors and stimulation of striatal cholinergicinterneurons by dopamine: a proposed circuit mechanism. J Neurosci. 17:8498-8505.Acquas, E., E. Carboni, R.H.A. de Ree, M. Da Prada and G. Di Cfuara (1992) Extracellular concentr*ions ofdopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methy'ltransferaseinhibitor Ro 40 -7 59 2. I. Neurochem. 59 (1) : 3 26 -3 3 A.Birkmayer,'Sí. and Hornykiecz, O (eds). 1976. Advances in Parkinsonism: Biochemnistry, Physiolory, Treatment.Fifth International Syrnposium on Parkinson's Disease. Vienna, Basel: Roche.Bun, D.R., Creese, I., Snyder, S.H. (1972). Antischizophrenic drugs: chronic treatment elevates dopaminereceptor binding in brain. Science 196:326-328.Butcher, S.P., I.S. Fairbrother, J.S. Kelly and G.V. Arbuthnon (1990) EÍfect of selective monoamine oxidaseinhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J. Neurochem. 55: 981-988.Crlzi, A., F. dAgostini, R. Kettler, E. Borroni and M. DaPrada (199A) Effect of selective and reversible MAOinhibitors on dopamine outflow in rat striatum: a microdialysis study. J. Neural Transmission 32 (suppl): 79-84.Elverfors, A. and Nissbrandt, H. (1991) Reserpine-insensitive dopamine release in the substantia nigra? Brain Res.\ 5 7  \ - 1 )Geffen, L. B.,Jessel, T. M., Cuello, A. C., and Iversen, L.L. (1976) Release of dopanime from dendrites in ratsubstantia nigra. Nature 260, 258-260.Gonon, F.G., Buda, MJ. (1985). Regulation of dopamine release by impulse flow and by autoreceptors as studiesby in vivo voltammatry in the rat striatum. Neuroscience 14,765-774.Grace, A. A. 0990) Evidence for the functional companment,lization of spike generating regions of rat midbraindoparnine neurons recorded in vitro. Brain Res.524,31-41..Kato, T., B. Dong, K. Ishii and H Kinemuchi (1986) Brain dialpis: in vivo metabolism of dopamine andserotonine by monoamine oxidase A but not by B in the striatum of unrestrained rats. J. Neurochem. 46: 1,277-1282.Necmo(BraiKor258Llinsub,MádoPmetRoLhalcRohnigRobNer-Roto n lShirhal(Skirev(Undol'sí;stflinl'Sírdia120

Somatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterization and effects of dopaminergic agents

University of Groningen Research Database

  
 University of Groningen
Somatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterization
and effects of dopaminergic agents
Heeringa, Marten
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
1999
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Heeringa, M. (1999). Somatodendritic dopamine in the substnatia nigra of the rat. Biochemical
charachterization and effects of dopaminergic agents Groningen: s.n.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 11-02-2018
Dopaminergic neurons of the substantia nigra do not only release dopamine from nerve
terminals in the striatum, but also from soma and dendrites in substantia nigra. Although the
concept of release of somatodendritic dopamine in the substantia nigra arose nearly twenty five
)raÍs ago, many questions regarding its biochemistry and its role within normal and
pathological basal ganglia remain (Geffen et a1,., !976; Korf et dl., 1976). This relative lack of
knowledge is, at least partly, related to technical difficulties; the extracellular level of dopamine
in somatodendritic areas is about 6 times lower as compared to the striatum, a nerve terminal
area. In this thesis, an attempt has been made to characterize the storage and release of
somatodendritic dopamine in the substantia nigra, and to elucidate its role within the basal
ganglia circuitry. The role of somatodendritic dopamine release in the pathophysiology of
disabling motor ryndromes, like Parkinson's disease and neuroleptic induced tardive
dyskinesias, was investigated by using animil models. These studies will increase our
understanding of basal ganglia pathologz and might lead to more effective
(pharmaco)therapeutic strategies in the future.
Chapter 2 of this thesis describes an extensive study on the nature of storage and release of
somatodendritic dopamine. At the dopaminergic nerve terminal in the striatum, the
physiological release of dopamine generally is accepted as occuning via depolarization-induced
exog,tosis ffesterink and DeVries, 1988). Based exclusively on indirect indices, the storage
and release of somatodendritic dopamine has been suggested to be non-vesicular in nature
(Eiverfors and Nissbrand, 199I). We directly examined, by using in vivo microdialysis, whether
the storage and/or release of somatodendritic dopamine is dependent upon a vesicular pool of
transmitter. The storage of dopamine appeared to be vesicular in nature in all brain areas
examined, since reserpine, a compound that disrupts vesicular sequestration of monoamines,
significandy decreased the tissue levels of dopamine in substantia nigra reticulata, substantia
nigra compacta and striatum. Administration of reserpine also resulted in a rapid decrease of
extracellular dopamine in substantia nigra as well as in the striatum, both to non-detectable
levels. In order to further chatactenze and compare the intracellular compartmentalization of
somatodendritic dopamine versus nerve terminal dopamine, we also employed microdialysis to
determine the effects of reserpine pretreatment on amphetamine-stimulated dopamine in
substantia nigra and striatum. In contrast to the effects of a low dose of amphetamine,
dopamine efflu-r in response to a high dose of amphetamine was significantly attenuated by
reserpine pretreatment both in substantia nigra and in the striatum. Previous studies have
shown that a low dose of amphetamine only induces release of the cytoplasmic store, while a
high dose also releases from vesicular stores. Thus, our data support the idea of vesicular
storage of somatodendritic dopamine, similar to nerve terminal dopamine.
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In chapter 3 and 4, we examined both reguiation and effects of the release of somatodendritic
dopamine within the intact basal ganglia circuitry. Chapter 3 utilizes the microdialysis
technique in order to examine whether somatodendritic autoreceptors in the substantia nigra
are involved in the regulation of the release of somatodendritic dopamine. Contrary to the
expectations, local blockade of nigral dopamine D2 receptors by haloperidol failed to increase
the extracellular levels of nigral dopamine. This haloperidol treatment abolished the decrease in
extracellular levels of dopamine induced by local perfusion of the D2 agonist quinpirole, thus
demonstrating effective blockade of D2 receptors. These observations suggest that the release
of somatodendritic dopamine is not under tonic inhibitory control, at least under basal
conditions. The results were verified by systemic administration of haloperidol. This treatment,
however, resulted in a dose dependent increase of extracellular dopamine in substantia nigra. A
similar increase was observed after microinjection of haloperidol in the striatum, suggesting
that blockade of striatal dopamine D2 receptors, rather thanD2 receptors in substantia nigra,
could underlie the effect caused by qystemic administration of the drug. Our observation that
the effect of intrastriatal microinjection of haloperidol was not altered by simultaneous
administration of haloperidol via the systemic route, is in agreement with this hlpothesis.
Besides these direct conclusions, the studies could also shed light on the relationship between
neurona-l firing and release of somatodendritic dopamine. Gonon and coworkers have shown
that the release o{ nmx terminal dopamine depends, among others, on changes in the firing
pattern of dopaminergic neurons. 'Whether a similar mechanism also underlies the release of
somatodendritic dopamine is questionable, at least under the curent experimental conditions.
Administration of 0.05 mglkg haloperidol did not alter the release of somatodendritic
dopamine in substantia nigra. Flowever, other studies using similar experimental conditions
have shown that this dose causes a maximal increase in striatal dopamine release, an effect
generally accepted to reflect autoreceptor blockade. A ten times higher dose, 0.5 mg,/kg, was
necessary to cause an increase in somatodendritic dopamine release. This effect is likely to be
explained by blockade of heteroreceptors; Skirboll and collegues demonstrated that
heteroreceptors might be ten times less sensitive as compared to autoreceptors. Thus, under
the present experimental conditions, the basal release of somatodendritic dopamine may not
l,e under influence of substantia nigra neuronal firing, but instead under influence of nigral
afferent projections. Evidence for functional compartmentilization of dendritic and axonal
spiking regions on dopaminergic neurons, which may differentially utilize Na* and Ca** as
charge carriers, may support such a differential release mechanism for the release of
somatodendritic dopamine (Llinás et d,., 1,984; Nedergaard et al., 1988; Grace, 1990).
Because a "dopamine-acety'lcholine imbalance" is likely to play a role in basal ganglia
patholory, the dopaminergic regulation of striatal acerylcholine has been studied extensively.
Chapter 4 addresses the question whether striatal or nigral D1 receptors, the latter being under
influence of somatodendritic dopamine, are involved in the inhibitorv effect of direa
dopamine agonists on striatal acerylcholine release. Therefore, the dose-related effect of the
direct dopamine D2 agonist quinpirole on the extracellular concentration of dopamine in
substantia nigra and striatum and oÍ acetylcholine in the striatum were measured using inaiw
microdialysis. If the inhibitory effect of systemic administration of quinpirole would be due to
a diminished stimulation of D1 receptors, a low, autoreceptor sensitive dose of quinpirole
would be expected to cause an inhibition of the release of dopamine and of acetylcholine. In
contrast, we observed an increase of the ertracellular levels of acetylcholine in the strianrm by a
low dose of quinpirole. These data argue strongly in favor of a directly mediated inhibition of
striatal acerylcholine by dopamine D2 receptor agonists. The data also elucidate some issues
concerning the autoregulation of somatodendritic dopamine in comparison with nerve
terminal dopamine. Perhaps one of the most remarkable differences is the ma-ximum decrease
of dopamine release in substantia nigra and striatum after administration of systemic
quinpirole; dopamine levels in substantia nigra decrease to 5Oo/o f basal levels, whereas striatal
dopamine decreases to 20o/o of basal levels. Thus, autoregulation of somatodendritic dopamine
release might be less imponant when compared to release of dopamine from nerve terminals.
The lack of endogenous tone at D2 receptors in the substantia nigra, as suggested by the
failure to increase locai dopamine levels by intranigral administration of D2 antagonists in
chapter 3, suppons this hlpothesis.
The concept of a dopaminergic involvement in motor behavior arose from two important
clinical observations nearly three decades ago. First, Birkmayer and Hornykiewicz observed a
dopamine deficienry in the striatum of parkinsonian brains. This finding led to treatment with
the dopamine precursor levodopa, which appeared to diminish the ryrnptoms of this motor
disease. Secondly, the discovery that (qpical) antipsychotics, which treatment is accompanied
by ertraplramidal motor s).rnptoms, are in fact dopaminergic antagonists also suggested that
an intact dopaminergic neurotransmission is essential for normal motor behavior (Burt et al.,
1977). Snce these key observations, many studies have been performed in an attempt to
elucidate the role of dopaminergic neurotransmission in normal motor behavior and in
particular in motor disease. In chapter 5 and 6, the dopaminergic system is examined n ani,rwl
nrdels of Parkinson's disease and antipsychotics-induced tardive dyskinesias, respectively.
Levodopa-induced contralateral rurning in 6-OHDA-lesioned rats, the animal model used in
chapter 5, has been widely used as a behavioral testing paradigm for the potency of anti-
parkinsonian agents (I-lngerstedt and Arbuthnon, 1,97A). In order to know whether enry-tne
inhibition may potentiate levodopa-induced contralateral turning, and thus possibly increase
the therapeutic benefit of levodopa in humans, er,.zyme inhibitors involved in the metabolic
inactivation of levodopa or dopamine were co-administered. Inhibition of MAO-A with Ro
41.-1049 potentiated levodopa-induced contralateral turning, in contrast to MAO-B-inhibition
which only increased the duration of turning but not the total number of turns. Indeed, MAG
A appears to be, at least in the rat, the predominant subq?e for oxidative deamination of
1 1 8
:ffect of the
lopamine in
using inain
LId be due to
,f quinpirole
ylcholine. In
;triatum by a
rrlibition of
some issues
with nerve
um decrease
of qystemic
ereas triatal
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re terminals.
:sted by the
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c important
observed a
atment with
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:companied
;gested that
(Burt et al.,
attempt to
ior and in
:dn anirul
espectively.
Cel used in
cy of anti-
ler en4./rne
ly increase
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{ with Ro
-inhibition
ed, MAO
ination of
endogenous dopamine and ievodopa derived dopamine (Kato et aJ., 1,986; Butcher et aI., I99a;
CoIà et aI., l99a; Mannisto and Toumainen, 1991; \lachtel and Abercrombte, 1994). COMT-
inhibition with Ro 4A-7592 resulted in the largest potentiation of levodopa-induced turning
when compared to inhibition of MAO, which suggests a potential role for COMT-inhibitors as
adjuvants to the levodopa therapy in the treatment of Parkinson's disease. The site of action of
the COMT-inhibitor is not yet known. Earlier studies have shown that Ro 40-7592 might not
only inhibit the metaboiic inactivation of levodopa in the periphery, but also of dopamine in
the striatum (Acquas et d,., 1992). Flowever, the observation that turning behavior can be
elicited by an increase in the amount of dopamine in the substantia nigra, together with a major
role of COMT in the catabolism of nigral dopamine, suggests a contributary role of
somatodendritic dopamine to be likely (\Testerink and Korf, 1976; Robertson et aJ., 1991.;
Robertson and Robertson, 1988, 1989; Kelly eÍ aJ,., 1,999).Ro 40-7592, known as tolcapone,
was registered in 1997 for the treatment of Parkinson's disease.
The potentiai role of somatodendritic dopamine in the mediation of antipsychotics-induced
tardive dyskinesias is examined in chapter 6, using the vacuous chewing movement trCN4)
animal model. Long term treatment with antipsychotics results in tardive dyskinesia in some,
but not all individuals. Such an individual suscepdbiliryis also observed in rats, a characteristic
exploited in the VCM-model. After long-term treatment with the antipsychotic haloperidol,
some rats exhibit vacuous chewing movements (VCM-positive), while others fail to show these
dyskinesias (VCM-negative). Since previous neuroanatomical studies have shown that the
occurrence of dyskinesias correlates with specific decreases in dopamine D1 receptors in the
substantia nigra, we hlpothesized a potentiation of the release of somatodendritic dopamine in
the VCM-positive group. Flowever, our results showed that both basal release and the release
induced by an acute haloperidol challenge or tail-pinch stress were unaltered in the VOvI-
positive group. In contrast, the effect of these challenges on the release of striatal acetylcholine
appeared to be significantlypotentiated in the VCM-positive group. The basal levels of striatal
acetylcholine showed a tendenry to increase in VCM-positive rats, which did not reach
significance. The exact way in which these changes in cholinergic transmission are brought
about is not exactly known. Several lines of evidence suggest that an enhanced glutamatergic
drive by cortical efferents might play a role (Yamamoto and Cooperman, 1994, Roberts et al.,
1995). Since previous studies have shown neurochemical correlates of the occurrence of VCMs
in both substantia nigra and thalamus, these brain areas are also likely to be involved
(Shirakawa and Tamminga, 1994). Recently, it was shown that striatal acerylcholine is under
excitatory control of somatodendritic dopamine, a proces depending on striatal glutamarergic
afferents. In this way, alterations in the nigrothalamocortical circuitry might underlie the
enhanced release of striatal acetylcholine rather than a potentiated release of somatodendritic
dopamine in the substantia nigra (Abercrombie and DeBoer, 1992).
Taken together, the present thesis characterizes the release of somatodendritic dopamine in the
substantia nigra, and elucidates the mechanisms underlying the effects of dopaminergic agents
in both normal basal ganglia circuitry and animal models of basal ganglia diseases. The main
conclusion that can be drawn from the results of this thesis, is that the pharmacological
profiles of antiparkinsonian and antipsychotic agents are not only determined by dopaminergic
receptors in nerve terminal areas like the striatum, but also by dopamine receptors in the
substantia nigra: the targets of somatodendritic dopamine.
REFERENCES
Abercrombie, E.D., DeBoer, P. (1997). Substantia nigra D1 Íeceptors and stimulation of striatal cholinergic
interneurons by dopamine: a proposed circuit mechanism. J Neurosci. 17:8498-8505.
Acquas, E., E. Carboni, R.H.A. de Ree, M. Da Prada and G. Di Cfuara (1992) Extracellular concentr*ions of
dopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methy'ltransferase
inhibitor Ro 40 -7 59 2. I. Neurochem. 59 (1) : 3 26 -3 3 A.
Birkmayer,'Sí. and Hornykiecz, O (eds). 1976. Advances in Parkinsonism: Biochemnistry, Physiolory, Treatment.
Fifth International Syrnposium on Parkinson's Disease. Vienna, Basel: Roche.
Bun, D.R., Creese, I., Snyder, S.H. (1972). Antischizophrenic drugs: chronic treatment elevates dopamine
receptor binding in brain. Science 196:326-328.
Butcher, S.P., I.S. Fairbrother, J.S. Kelly and G.V. Arbuthnon (1990) EÍfect of selective monoamine oxidase
inhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J. Neurochem. 55: 981-988.
Crlzi, A., F. dAgostini, R. Kettler, E. Borroni and M. DaPrada (199A) Effect of selective and reversible MAO
inhibitors on dopamine outflow in rat striatum: a microdialysis study. J. Neural Transmission 32 (suppl): 79-84.
Elverfors, A. and Nissbrandt, H. (1991) Reserpine-insensitive dopamine release in the substantia nigra? Brain Res.
\ 5 7  \ - 1 )
Geffen, L. B.,Jessel, T. M., Cuello, A. C., and Iversen, L.L. (1976) Release of dopanime from dendrites in rat
substantia nigra. Nature 260, 258-260.
Gonon, F.G., Buda, MJ. (1985). Regulation of dopamine release by impulse flow and by autoreceptors as studies
by in vivo voltammatry in the rat striatum. Neuroscience 14,765-774.
Grace, A. A. 0990) Evidence for the functional companment,lization of spike generating regions of rat midbrain
doparnine neurons recorded in vitro. Brain Res.524,31-41..
Kato, T., B. Dong, K. Ishii and H Kinemuchi (1986) Brain dialpis: in vivo metabolism of dopamine and
serotonine by monoamine oxidase A but not by B in the striatum of unrestrained rats. J. Neurochem. 46: 1,277-
1282.
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NARCIS 

ARTS repository - University of Groningen

   University of GroningenSomatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterizationand effects of dopaminergic agentsHeeringa, MartenIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1999Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Heeringa, M. (1999). Somatodendritic dopamine in the substnatia nigra of the rat. Biochemicalcharachterization and effects of dopaminergic agents. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-2022Dopaminergic neurons of the substantia nigra do not only release dopamine from nerveterminals in the striatum, but also from soma and dendrites in substantia nigra. Although theconcept of release of somatodendritic dopamine in the substantia nigra arose nearly twenty five)raÍs ago, many questions regarding its biochemistry and its role within normal andpathological basal ganglia remain (Geffen et a1,., !976; Korf et dl., 1976). This relative lack ofknowledge is, at least partly, related to technical difficulties; the extracellular level of dopaminein somatodendritic areas is about 6 times lower as compared to the striatum, a nerve terminalarea. In this thesis, an attempt has been made to characterize the storage and release ofsomatodendritic dopamine in the substantia nigra, and to elucidate its role within the basalganglia circuitry. The role of somatodendritic dopamine release in the pathophysiology ofdisabling motor ryndromes, like Parkinson's disease and neuroleptic induced tardivedyskinesias, was investigated by using animil models. These studies will increase ourunderstanding of basal ganglia pathologz and might lead to more effective(pharmaco)therapeutic strategies in the future.Chapter 2 of this thesis describes an extensive study on the nature of storage and release ofsomatodendritic dopamine. At the dopaminergic nerve terminal in the striatum, thephysiological release of dopamine generally is accepted as occuning via depolarization-inducedexog,tosis ffesterink and DeVries, 1988). Based exclusively on indirect indices, the storageand release of somatodendritic dopamine has been suggested to be non-vesicular in nature(Eiverfors and Nissbrand, 199I). We directly examined, by using in vivo microdialysis, whetherthe storage and/or release of somatodendritic dopamine is dependent upon a vesicular pool oftransmitter. The storage of dopamine appeared to be vesicular in nature in all brain areasexamined, since reserpine, a compound that disrupts vesicular sequestration of monoamines,significandy decreased the tissue levels of dopamine in substantia nigra reticulata, substantianigra compacta and striatum. Administration of reserpine also resulted in a rapid decrease ofextracellular dopamine in substantia nigra as well as in the striatum, both to non-detectablelevels. In order to further chatactenze and compare the intracellular compartmentalization ofsomatodendritic dopamine versus nerve terminal dopamine, we also employed microdialysis todetermine the effects of reserpine pretreatment on amphetamine-stimulated dopamine insubstantia nigra and striatum. In contrast to the effects of a low dose of amphetamine,dopamine efflu-r in response to a high dose of amphetamine was significantly attenuated byreserpine pretreatment both in substantia nigra and in the striatum. Previous studies haveshown that a low dose of amphetamine only induces release of the cytoplasmic store, while ahigh dose also releases from vesicular stores. Thus, our data support the idea of vesicularstorage of somatodendritic dopamine, similar to nerve terminal dopamine.In chdopatechrare ltexPe(the e.extrademcof sccondhowesimilithat ïcoulcthe eadmirBesidneur(rhar 1PaftelsomaAdmdopahavegenernecesexplaheterthe plre uraffertspikirchargsomaBecarpath<Chapinflut1 1 6nerveqh thpD__ " ' -ty fiveLl andack of,aminerminalase of: basal'tsr .í' ó J  - 'ardivee our[ective:ase of.  th"rducedtoragenaturehetherrool of. areasmines,stantiaase of:ctableion ofysis toine inrmine,;ed byr haveÀile a;icularIn chapter 3 and 4, we examined both reguiation and effects of the release of somatodendriticdopamine within the intact basal ganglia circuitry. Chapter 3 utilizes the microdialysistechnique in order to examine whether somatodendritic autoreceptors in the substantia nigraare involved in the regulation of the release of somatodendritic dopamine. Contrary to theexpectations, local blockade of nigral dopamine D2 receptors by haloperidol failed to increasethe extracellular levels of nigral dopamine. This haloperidol treatment abolished the decrease inextracellular levels of dopamine induced by local perfusion of the D2 agonist quinpirole, thusdemonstrating effective blockade of D2 receptors. These observations suggest that the releaseof somatodendritic dopamine is not under tonic inhibitory control, at least under basalconditions. The results were verified by systemic administration of haloperidol. This treatment,however, resulted in a dose dependent increase of extracellular dopamine in substantia nigra. Asimilar increase was observed after microinjection of haloperidol in the striatum, suggestingthat blockade of striatal dopamine D2 receptors, rather thanD2 receptors in substantia nigra,could underlie the effect caused by qystemic administration of the drug. Our observation thatthe effect of intrastriatal microinjection of haloperidol was not altered by simultaneousadministration of haloperidol via the systemic route, is in agreement with this hlpothesis.Besides these direct conclusions, the studies could also shed light on the relationship betweenneurona-l firing and release of somatodendritic dopamine. Gonon and coworkers have shownthat the release o{ nmx terminal dopamine depends, among others, on changes in the firingpattern of dopaminergic neurons. 'Whether a similar mechanism also underlies the release ofsomatodendritic dopamine is questionable, at least under the curent experimental conditions.Administration of 0.05 mglkg haloperidol did not alter the release of somatodendriticdopamine in substantia nigra. Flowever, other studies using similar experimental conditionshave shown that this dose causes a maximal increase in striatal dopamine release, an effectgenerally accepted to reflect autoreceptor blockade. A ten times higher dose, 0.5 mg,/kg, wasnecessary to cause an increase in somatodendritic dopamine release. This effect is likely to beexplained by blockade of heteroreceptors; Skirboll and collegues demonstrated thatheteroreceptors might be ten times less sensitive as compared to autoreceptors. Thus, underthe present experimental conditions, the basal release of somatodendritic dopamine may notl,e under influence of substantia nigra neuronal firing, but instead under influence of nigralafferent projections. Evidence for functional compartmentilization of dendritic and axonalspiking regions on dopaminergic neurons, which may differentially utilize Na* and Ca** ascharge carriers, may support such a differential release mechanism for the release ofsomatodendritic dopamine (Llinás et d,., 1,984; Nedergaard et al., 1988; Grace, 1990).Because a "dopamine-acety'lcholine imbalance" is likely to play a role in basal gangliapatholory, the dopaminergic regulation of striatal acerylcholine has been studied extensively.Chapter 4 addresses the question whether striatal or nigral D1 receptors, the latter being underinfluence of somatodendritic dopamine, are involved in the inhibitorv effect of direadopamine agonists on striatal acerylcholine release. Therefore, the dose-related effect of thedirect dopamine D2 agonist quinpirole on the extracellular concentration of dopamine insubstantia nigra and striatum and oÍ acetylcholine in the striatum were measured using inaiwmicrodialysis. If the inhibitory effect of systemic administration of quinpirole would be due toa diminished stimulation of D1 receptors, a low, autoreceptor sensitive dose of quinpirolewould be expected to cause an inhibition of the release of dopamine and of acetylcholine. Incontrast, we observed an increase of the ertracellular levels of acetylcholine in the strianrm by alow dose of quinpirole. These data argue strongly in favor of a directly mediated inhibition ofstriatal acerylcholine by dopamine D2 receptor agonists. The data also elucidate some issuesconcerning the autoregulation of somatodendritic dopamine in comparison with nerveterminal dopamine. Perhaps one of the most remarkable differences is the ma-ximum decreaseof dopamine release in substantia nigra and striatum after administration of systemicquinpirole; dopamine levels in substantia nigra decrease to 5Oo/o f basal levels, whereas striataldopamine decreases to 20o/o of basal levels. Thus, autoregulation of somatodendritic dopaminerelease might be less imponant when compared to release of dopamine from nerve terminals.The lack of endogenous tone at D2 receptors in the substantia nigra, as suggested by thefailure to increase locai dopamine levels by intranigral administration of D2 antagonists inchapter 3, suppons this hlpothesis.The concept of a dopaminergic involvement in motor behavior arose from two importantclinical observations nearly three decades ago. First, Birkmayer and Hornykiewicz observed adopamine deficienry in the striatum of parkinsonian brains. This finding led to treatment withthe dopamine precursor levodopa, which appeared to diminish the ryrnptoms of this motordisease. Secondly, the discovery that (qpical) antipsychotics, which treatment is accompaniedby ertraplramidal motor s).rnptoms, are in fact dopaminergic antagonists also suggested thatan intact dopaminergic neurotransmission is essential for normal motor behavior (Burt et al.,1977). Snce these key observations, many studies have been performed in an attempt toelucidate the role of dopaminergic neurotransmission in normal motor behavior and inparticular in motor disease. In chapter 5 and 6, the dopaminergic system is examined n ani,rwlnrdels of Parkinson's disease and antipsychotics-induced tardive dyskinesias, respectively.Levodopa-induced contralateral rurning in 6-OHDA-lesioned rats, the animal model used inchapter 5, has been widely used as a behavioral testing paradigm for the potency of anti-parkinsonian agents (I-lngerstedt and Arbuthnon, 1,97A). In order to know whether enry-tneinhibition may potentiate levodopa-induced contralateral turning, and thus possibly increasethe therapeutic benefit of levodopa in humans, er,.zyme inhibitors involved in the metabolicinactivation of levodopa or dopamine were co-administered. Inhibition of MAO-A with Ro41.-1049 potentiated levodopa-induced contralateral turning, in contrast to MAO-B-inhibitionwhich only increased the duration of turning but not the total number of turns. Indeed, MAGA appears to be, at least in the rat, the predominant subq?e for oxidative deamination of1 1 8:ffect of thelopamine inusing inainLId be due to,f quinpiroleylcholine. In;triatum by arrlibition ofsome issueswith nerveum decreaseof qystemicereas triatalic dopaminere terminals.:sted by theLtagonists inc importantobserved aatment withthis motor:companied;gested that(Burt et al.,attempt toior and in:dn anirulespectively.Cel used incy of anti-ler en4./rnely increasemetabolic{ with Ro-inhibitioned, MAOination ofendogenous dopamine and ievodopa derived dopamine (Kato et aJ., 1,986; Butcher et aI., I99a;CoIà et aI., l99a; Mannisto and Toumainen, 1991; \lachtel and Abercrombte, 1994). COMT-inhibition with Ro 4A-7592 resulted in the largest potentiation of levodopa-induced turningwhen compared to inhibition of MAO, which suggests a potential role for COMT-inhibitors asadjuvants to the levodopa therapy in the treatment of Parkinson's disease. The site of action ofthe COMT-inhibitor is not yet known. Earlier studies have shown that Ro 40-7592 might notonly inhibit the metaboiic inactivation of levodopa in the periphery, but also of dopamine inthe striatum (Acquas et d,., 1992). Flowever, the observation that turning behavior can beelicited by an increase in the amount of dopamine in the substantia nigra, together with a majorrole of COMT in the catabolism of nigral dopamine, suggests a contributary role ofsomatodendritic dopamine to be likely (\Testerink and Korf, 1976; Robertson et aJ., 1991.;Robertson and Robertson, 1988, 1989; Kelly eÍ aJ,., 1,999).Ro 40-7592, known as tolcapone,was registered in 1997 for the treatment of Parkinson's disease.The potentiai role of somatodendritic dopamine in the mediation of antipsychotics-inducedtardive dyskinesias is examined in chapter 6, using the vacuous chewing movement trCN4)animal model. Long term treatment with antipsychotics results in tardive dyskinesia in some,but not all individuals. Such an individual suscepdbiliryis also observed in rats, a characteristicexploited in the VCM-model. After long-term treatment with the antipsychotic haloperidol,some rats exhibit vacuous chewing movements (VCM-positive), while others fail to show thesedyskinesias (VCM-negative). Since previous neuroanatomical studies have shown that theoccurrence of dyskinesias correlates with specific decreases in dopamine D1 receptors in thesubstantia nigra, we hlpothesized a potentiation of the release of somatodendritic dopamine inthe VCM-positive group. Flowever, our results showed that both basal release and the releaseinduced by an acute haloperidol challenge or tail-pinch stress were unaltered in the VOvI-positive group. In contrast, the effect of these challenges on the release of striatal acetylcholineappeared to be significantlypotentiated in the VCM-positive group. The basal levels of striatalacetylcholine showed a tendenry to increase in VCM-positive rats, which did not reachsignificance. The exact way in which these changes in cholinergic transmission are broughtabout is not exactly known. Several lines of evidence suggest that an enhanced glutamatergicdrive by cortical efferents might play a role (Yamamoto and Cooperman, 1994, Roberts et al.,1995). Since previous studies have shown neurochemical correlates of the occurrence of VCMsin both substantia nigra and thalamus, these brain areas are also likely to be involved(Shirakawa and Tamminga, 1994). Recently, it was shown that striatal acerylcholine is underexcitatory control of somatodendritic dopamine, a proces depending on striatal glutamarergicafferents. In this way, alterations in the nigrothalamocortical circuitry might underlie theenhanced release of striatal acetylcholine rather than a potentiated release of somatodendriticdopamine in the substantia nigra (Abercrombie and DeBoer, 1992).Taken together, the present thesis characterizes the release of somatodendritic dopamine in thesubstantia nigra, and elucidates the mechanisms underlying the effects of dopaminergic agentsin both normal basal ganglia circuitry and animal models of basal ganglia diseases. The mainconclusion that can be drawn from the results of this thesis, is that the pharmacologicalprofiles of antiparkinsonian and antipsychotic agents are not only determined by dopaminergicreceptors in nerve terminal areas like the striatum, but also by dopamine receptors in thesubstantia nigra: the targets of somatodendritic dopamine.REFERENCESAbercrombie, E.D., DeBoer, P. (1997). Substantia nigra D1 Íeceptors and stimulation of striatal cholinergicinterneurons by dopamine: a proposed circuit mechanism. J Neurosci. 17:8498-8505.Acquas, E., E. Carboni, R.H.A. de Ree, M. Da Prada and G. Di Cfuara (1992) Extracellular concentr*ions ofdopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methy'ltransferaseinhibitor Ro 40 -7 59 2. I. Neurochem. 59 (1) : 3 26 -3 3 A.Birkmayer,'Sí. and Hornykiecz, O (eds). 1976. Advances in Parkinsonism: Biochemnistry, Physiolory, Treatment.Fifth International Syrnposium on Parkinson's Disease. Vienna, Basel: Roche.Bun, D.R., Creese, I., Snyder, S.H. (1972). Antischizophrenic drugs: chronic treatment elevates dopaminereceptor binding in brain. Science 196:326-328.Butcher, S.P., I.S. Fairbrother, J.S. Kelly and G.V. Arbuthnon (1990) EÍfect of selective monoamine oxidaseinhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J. Neurochem. 55: 981-988.Crlzi, A., F. dAgostini, R. Kettler, E. Borroni and M. DaPrada (199A) Effect of selective and reversible MAOinhibitors on dopamine outflow in rat striatum: a microdialysis study. J. Neural Transmission 32 (suppl): 79-84.Elverfors, A. and Nissbrandt, H. (1991) Reserpine-insensitive dopamine release in the substantia nigra? Brain Res.\ 5 7  \ - 1 )Geffen, L. B.,Jessel, T. M., Cuello, A. C., and Iversen, L.L. (1976) Release of dopanime from dendrites in ratsubstantia nigra. Nature 260, 258-260.Gonon, F.G., Buda, MJ. (1985). Regulation of dopamine release by impulse flow and by autoreceptors as studiesby in vivo voltammatry in the rat striatum. Neuroscience 14,765-774.Grace, A. A. 0990) Evidence for the functional companment,lization of spike generating regions of rat midbraindoparnine neurons recorded in vitro. Brain Res.524,31-41..Kato, T., B. Dong, K. Ishii and H Kinemuchi (1986) Brain dialpis: in vivo metabolism of dopamine andserotonine by monoamine oxidase A but not by B in the striatum of unrestrained rats. J. Neurochem. 46: 1,277-1282.Necmo(BraiKor258Llinsub,MádoPmetRoLhalcRohnigRobNer-Roto n lShirhal(Skirev(Undol'sí;stflinl'Sírdia120

English

   University of GroningenSomatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterizationand effects of dopaminergic agentsHeeringa, MartenIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1999Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Heeringa, M. (1999). Somatodendritic dopamine in the substnatia nigra of the rat. Biochemicalcharachterization and effects of dopaminergic agents. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 09-09-2023Dopaminergic neurons of the substantia nigra do not only release dopamine from nerveterminals in the striatum, but also from soma and dendrites in substantia nigra. Although theconcept of release of somatodendritic dopamine in the substantia nigra arose nearly twenty five)raÍs ago, many questions regarding its biochemistry and its role within normal andpathological basal ganglia remain (Geffen et a1,., !976; Korf et dl., 1976). This relative lack ofknowledge is, at least partly, related to technical difficulties; the extracellular level of dopaminein somatodendritic areas is about 6 times lower as compared to the striatum, a nerve terminalarea. In this thesis, an attempt has been made to characterize the storage and release ofsomatodendritic dopamine in the substantia nigra, and to elucidate its role within the basalganglia circuitry. The role of somatodendritic dopamine release in the pathophysiology ofdisabling motor ryndromes, like Parkinson's disease and neuroleptic induced tardivedyskinesias, was investigated by using animil models. These studies will increase ourunderstanding of basal ganglia pathologz and might lead to more effective(pharmaco)therapeutic strategies in the future.Chapter 2 of this thesis describes an extensive study on the nature of storage and release ofsomatodendritic dopamine. At the dopaminergic nerve terminal in the striatum, thephysiological release of dopamine generally is accepted as occuning via depolarization-inducedexog,tosis ffesterink and DeVries, 1988). Based exclusively on indirect indices, the storageand release of somatodendritic dopamine has been suggested to be non-vesicular in nature(Eiverfors and Nissbrand, 199I). We directly examined, by using in vivo microdialysis, whetherthe storage and/or release of somatodendritic dopamine is dependent upon a vesicular pool oftransmitter. The storage of dopamine appeared to be vesicular in nature in all brain areasexamined, since reserpine, a compound that disrupts vesicular sequestration of monoamines,significandy decreased the tissue levels of dopamine in substantia nigra reticulata, substantianigra compacta and striatum. Administration of reserpine also resulted in a rapid decrease ofextracellular dopamine in substantia nigra as well as in the striatum, both to non-detectablelevels. In order to further chatactenze and compare the intracellular compartmentalization ofsomatodendritic dopamine versus nerve terminal dopamine, we also employed microdialysis todetermine the effects of reserpine pretreatment on amphetamine-stimulated dopamine insubstantia nigra and striatum. In contrast to the effects of a low dose of amphetamine,dopamine efflu-r in response to a high dose of amphetamine was significantly attenuated byreserpine pretreatment both in substantia nigra and in the striatum. Previous studies haveshown that a low dose of amphetamine only induces release of the cytoplasmic store, while ahigh dose also releases from vesicular stores. Thus, our data support the idea of vesicularstorage of somatodendritic dopamine, similar to nerve terminal dopamine.In chdopatechrare ltexPe(the e.extrademcof sccondhowesimilithat ïcoulcthe eadmirBesidneur(rhar 1PaftelsomaAdmdopahavegenernecesexplaheterthe plre uraffertspikirchargsomaBecarpath<Chapinflut1 1 6nerveqh thpD__ " ' -ty fiveLl andack of,aminerminalase of: basal'tsr .í' ó J  - 'ardivee our[ective:ase of.  th"rducedtoragenaturehetherrool of. areasmines,stantiaase of:ctableion ofysis toine inrmine,;ed byr haveÀile a;icularIn chapter 3 and 4, we examined both reguiation and effects of the release of somatodendriticdopamine within the intact basal ganglia circuitry. Chapter 3 utilizes the microdialysistechnique in order to examine whether somatodendritic autoreceptors in the substantia nigraare involved in the regulation of the release of somatodendritic dopamine. Contrary to theexpectations, local blockade of nigral dopamine D2 receptors by haloperidol failed to increasethe extracellular levels of nigral dopamine. This haloperidol treatment abolished the decrease inextracellular levels of dopamine induced by local perfusion of the D2 agonist quinpirole, thusdemonstrating effective blockade of D2 receptors. These observations suggest that the releaseof somatodendritic dopamine is not under tonic inhibitory control, at least under basalconditions. The results were verified by systemic administration of haloperidol. This treatment,however, resulted in a dose dependent increase of extracellular dopamine in substantia nigra. Asimilar increase was observed after microinjection of haloperidol in the striatum, suggestingthat blockade of striatal dopamine D2 receptors, rather thanD2 receptors in substantia nigra,could underlie the effect caused by qystemic administration of the drug. Our observation thatthe effect of intrastriatal microinjection of haloperidol was not altered by simultaneousadministration of haloperidol via the systemic route, is in agreement with this hlpothesis.Besides these direct conclusions, the studies could also shed light on the relationship betweenneurona-l firing and release of somatodendritic dopamine. Gonon and coworkers have shownthat the release o{ nmx terminal dopamine depends, among others, on changes in the firingpattern of dopaminergic neurons. 'Whether a similar mechanism also underlies the release ofsomatodendritic dopamine is questionable, at least under the curent experimental conditions.Administration of 0.05 mglkg haloperidol did not alter the release of somatodendriticdopamine in substantia nigra. Flowever, other studies using similar experimental conditionshave shown that this dose causes a maximal increase in striatal dopamine release, an effectgenerally accepted to reflect autoreceptor blockade. A ten times higher dose, 0.5 mg,/kg, wasnecessary to cause an increase in somatodendritic dopamine release. This effect is likely to beexplained by blockade of heteroreceptors; Skirboll and collegues demonstrated thatheteroreceptors might be ten times less sensitive as compared to autoreceptors. Thus, underthe present experimental conditions, the basal release of somatodendritic dopamine may notl,e under influence of substantia nigra neuronal firing, but instead under influence of nigralafferent projections. Evidence for functional compartmentilization of dendritic and axonalspiking regions on dopaminergic neurons, which may differentially utilize Na* and Ca** ascharge carriers, may support such a differential release mechanism for the release ofsomatodendritic dopamine (Llinás et d,., 1,984; Nedergaard et al., 1988; Grace, 1990).Because a "dopamine-acety'lcholine imbalance" is likely to play a role in basal gangliapatholory, the dopaminergic regulation of striatal acerylcholine has been studied extensively.Chapter 4 addresses the question whether striatal or nigral D1 receptors, the latter being underinfluence of somatodendritic dopamine, are involved in the inhibitorv effect of direadopamine agonists on striatal acerylcholine release. Therefore, the dose-related effect of thedirect dopamine D2 agonist quinpirole on the extracellular concentration of dopamine insubstantia nigra and striatum and oÍ acetylcholine in the striatum were measured using inaiwmicrodialysis. If the inhibitory effect of systemic administration of quinpirole would be due toa diminished stimulation of D1 receptors, a low, autoreceptor sensitive dose of quinpirolewould be expected to cause an inhibition of the release of dopamine and of acetylcholine. Incontrast, we observed an increase of the ertracellular levels of acetylcholine in the strianrm by alow dose of quinpirole. These data argue strongly in favor of a directly mediated inhibition ofstriatal acerylcholine by dopamine D2 receptor agonists. The data also elucidate some issuesconcerning the autoregulation of somatodendritic dopamine in comparison with nerveterminal dopamine. Perhaps one of the most remarkable differences is the ma-ximum decreaseof dopamine release in substantia nigra and striatum after administration of systemicquinpirole; dopamine levels in substantia nigra decrease to 5Oo/o f basal levels, whereas striataldopamine decreases to 20o/o of basal levels. Thus, autoregulation of somatodendritic dopaminerelease might be less imponant when compared to release of dopamine from nerve terminals.The lack of endogenous tone at D2 receptors in the substantia nigra, as suggested by thefailure to increase locai dopamine levels by intranigral administration of D2 antagonists inchapter 3, suppons this hlpothesis.The concept of a dopaminergic involvement in motor behavior arose from two importantclinical observations nearly three decades ago. First, Birkmayer and Hornykiewicz observed adopamine deficienry in the striatum of parkinsonian brains. This finding led to treatment withthe dopamine precursor levodopa, which appeared to diminish the ryrnptoms of this motordisease. Secondly, the discovery that (qpical) antipsychotics, which treatment is accompaniedby ertraplramidal motor s).rnptoms, are in fact dopaminergic antagonists also suggested thatan intact dopaminergic neurotransmission is essential for normal motor behavior (Burt et al.,1977). Snce these key observations, many studies have been performed in an attempt toelucidate the role of dopaminergic neurotransmission in normal motor behavior and inparticular in motor disease. In chapter 5 and 6, the dopaminergic system is examined n ani,rwlnrdels of Parkinson's disease and antipsychotics-induced tardive dyskinesias, respectively.Levodopa-induced contralateral rurning in 6-OHDA-lesioned rats, the animal model used inchapter 5, has been widely used as a behavioral testing paradigm for the potency of anti-parkinsonian agents (I-lngerstedt and Arbuthnon, 1,97A). In order to know whether enry-tneinhibition may potentiate levodopa-induced contralateral turning, and thus possibly increasethe therapeutic benefit of levodopa in humans, er,.zyme inhibitors involved in the metabolicinactivation of levodopa or dopamine were co-administered. Inhibition of MAO-A with Ro41.-1049 potentiated levodopa-induced contralateral turning, in contrast to MAO-B-inhibitionwhich only increased the duration of turning but not the total number of turns. Indeed, MAGA appears to be, at least in the rat, the predominant subq?e for oxidative deamination of1 1 8:ffect of thelopamine inusing inainLId be due to,f quinpiroleylcholine. In;triatum by arrlibition ofsome issueswith nerveum decreaseof qystemicereas triatalic dopaminere terminals.:sted by theLtagonists inc importantobserved aatment withthis motor:companied;gested that(Burt et al.,attempt toior and in:dn anirulespectively.Cel used incy of anti-ler en4./rnely increasemetabolic{ with Ro-inhibitioned, MAOination ofendogenous dopamine and ievodopa derived dopamine (Kato et aJ., 1,986; Butcher et aI., I99a;CoIà et aI., l99a; Mannisto and Toumainen, 1991; \lachtel and Abercrombte, 1994). COMT-inhibition with Ro 4A-7592 resulted in the largest potentiation of levodopa-induced turningwhen compared to inhibition of MAO, which suggests a potential role for COMT-inhibitors asadjuvants to the levodopa therapy in the treatment of Parkinson's disease. The site of action ofthe COMT-inhibitor is not yet known. Earlier studies have shown that Ro 40-7592 might notonly inhibit the metaboiic inactivation of levodopa in the periphery, but also of dopamine inthe striatum (Acquas et d,., 1992). Flowever, the observation that turning behavior can beelicited by an increase in the amount of dopamine in the substantia nigra, together with a majorrole of COMT in the catabolism of nigral dopamine, suggests a contributary role ofsomatodendritic dopamine to be likely (\Testerink and Korf, 1976; Robertson et aJ., 1991.;Robertson and Robertson, 1988, 1989; Kelly eÍ aJ,., 1,999).Ro 40-7592, known as tolcapone,was registered in 1997 for the treatment of Parkinson's disease.The potentiai role of somatodendritic dopamine in the mediation of antipsychotics-inducedtardive dyskinesias is examined in chapter 6, using the vacuous chewing movement trCN4)animal model. Long term treatment with antipsychotics results in tardive dyskinesia in some,but not all individuals. Such an individual suscepdbiliryis also observed in rats, a characteristicexploited in the VCM-model. After long-term treatment with the antipsychotic haloperidol,some rats exhibit vacuous chewing movements (VCM-positive), while others fail to show thesedyskinesias (VCM-negative). Since previous neuroanatomical studies have shown that theoccurrence of dyskinesias correlates with specific decreases in dopamine D1 receptors in thesubstantia nigra, we hlpothesized a potentiation of the release of somatodendritic dopamine inthe VCM-positive group. Flowever, our results showed that both basal release and the releaseinduced by an acute haloperidol challenge or tail-pinch stress were unaltered in the VOvI-positive group. In contrast, the effect of these challenges on the release of striatal acetylcholineappeared to be significantlypotentiated in the VCM-positive group. The basal levels of striatalacetylcholine showed a tendenry to increase in VCM-positive rats, which did not reachsignificance. The exact way in which these changes in cholinergic transmission are broughtabout is not exactly known. Several lines of evidence suggest that an enhanced glutamatergicdrive by cortical efferents might play a role (Yamamoto and Cooperman, 1994, Roberts et al.,1995). Since previous studies have shown neurochemical correlates of the occurrence of VCMsin both substantia nigra and thalamus, these brain areas are also likely to be involved(Shirakawa and Tamminga, 1994). Recently, it was shown that striatal acerylcholine is underexcitatory control of somatodendritic dopamine, a proces depending on striatal glutamarergicafferents. In this way, alterations in the nigrothalamocortical circuitry might underlie theenhanced release of striatal acetylcholine rather than a potentiated release of somatodendriticdopamine in the substantia nigra (Abercrombie and DeBoer, 1992).Taken together, the present thesis characterizes the release of somatodendritic dopamine in thesubstantia nigra, and elucidates the mechanisms underlying the effects of dopaminergic agentsin both normal basal ganglia circuitry and animal models of basal ganglia diseases. The mainconclusion that can be drawn from the results of this thesis, is that the pharmacologicalprofiles of antiparkinsonian and antipsychotic agents are not only determined by dopaminergicreceptors in nerve terminal areas like the striatum, but also by dopamine receptors in thesubstantia nigra: the targets of somatodendritic dopamine.REFERENCESAbercrombie, E.D., DeBoer, P. (1997). Substantia nigra D1 Íeceptors and stimulation of striatal cholinergicinterneurons by dopamine: a proposed circuit mechanism. J Neurosci. 17:8498-8505.Acquas, E., E. Carboni, R.H.A. de Ree, M. Da Prada and G. Di Cfuara (1992) Extracellular concentr*ions ofdopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methy'ltransferaseinhibitor Ro 40 -7 59 2. I. Neurochem. 59 (1) : 3 26 -3 3 A.Birkmayer,'Sí. and Hornykiecz, O (eds). 1976. Advances in Parkinsonism: Biochemnistry, Physiolory, Treatment.Fifth International Syrnposium on Parkinson's Disease. Vienna, Basel: Roche.Bun, D.R., Creese, I., Snyder, S.H. (1972). Antischizophrenic drugs: chronic treatment elevates dopaminereceptor binding in brain. Science 196:326-328.Butcher, S.P., I.S. Fairbrother, J.S. Kelly and G.V. Arbuthnon (1990) EÍfect of selective monoamine oxidaseinhibitors on the in vivo release and metabolism of dopamine in the rat striatum. J. Neurochem. 55: 981-988.Crlzi, A., F. dAgostini, R. Kettler, E. Borroni and M. DaPrada (199A) Effect of selective and reversible MAOinhibitors on dopamine outflow in rat striatum: a microdialysis study. J. Neural Transmission 32 (suppl): 79-84.Elverfors, A. and Nissbrandt, H. (1991) Reserpine-insensitive dopamine release in the substantia nigra? Brain Res.\ 5 7  \ - 1 )Geffen, L. B.,Jessel, T. M., Cuello, A. C., and Iversen, L.L. (1976) Release of dopanime from dendrites in ratsubstantia nigra. Nature 260, 258-260.Gonon, F.G., Buda, MJ. (1985). Regulation of dopamine release by impulse flow and by autoreceptors as studiesby in vivo voltammatry in the rat striatum. Neuroscience 14,765-774.Grace, A. A. 0990) Evidence for the functional companment,lization of spike generating regions of rat midbraindoparnine neurons recorded in vitro. Brain Res.524,31-41..Kato, T., B. Dong, K. Ishii and H Kinemuchi (1986) Brain dialpis: in vivo metabolism of dopamine andserotonine by monoamine oxidase A but not by B in the striatum of unrestrained rats. J. Neurochem. 46: 1,277-1282.Necmo(BraiKor258Llinsub,MádoPmetRoLhalcRohnigRobNer-Roto n lShirhal(Skirev(Undol'sí;stflinl'Sírdia120

Somatodendritic dopamine in the substnatia nigra of the rat. Biochemical charachterization and effects of dopaminergic agents

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