Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms

Robertson, G.S.; Robertson, Hugh A.

doi:10.1523/jneurosci.09-09-03326.1989

Cited by 189 publications

(98 citation statements)

References 22 publications

(26 reference statements)

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“…In support of this hypothesis, L-DOPA-induced rotations can be blocked by intranigral infusion of SCH23390 (37). However; intrastriatal microinjection of SCH23390 delayed the C͞L-DOPA transition from locomotor activity to stereotypy and reduced the induction of c-fos mRNA.…”

Section: Discussionmentioning

confidence: 76%

Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation

Chartoff

Marck

Matsumoto

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Motor stereotypies are abnormally repetitive behaviors that can develop with excessive dopaminergic stimulation and are features of some neurologic disorders. To investigate the mechanisms required for the induction of stereotypy, we examined the responses of dopamine-deficient (DD) mice to increasing doses of the dopamine precursor L-DOPA. DD mice lack the ability to synthesize dopamine (DA) specifically in dopaminergic neurons yet exhibit robust hyperlocomotion relative to wild-type (WT) mice when treated with L-DOPA, which restores striatal DA tissue content to Ϸ10% of WT levels. To further elevate brain DA content in DD mice, we administered the peripheral L-amino acid decarboxylase inhibitor carbidopa along with L-DOPA (C͞L-DOPA). When striatal DA levels reached >50% of WT levels, a transition from hyperlocomotion to intense, focused stereotypy was observed that was correlated with an induction of c-fos mRNA in the ventrolateral and central striatum as well as the somatosensory cortex. WT mice were unaffected by C͞L-DOPA treatments. A D1, but not a D2, receptor antagonist attenuated both the C͞L-DOPA-induced stereotypy and the c-fos induction. Consistent with these results, stereotypy could be induced in DD mice by a D1, but not by a D2, receptor agonist, with neither agonist inducing stereotypy in WT mice. Intrastriatal injection of a D1 receptor antagonist ameliorated the stereotypy and c-fos induction by C͞L-DOPA. These results indicate that activation of D1 receptors on a specific population of striatal neurons is required for the induction of stereotypy in DD mice.M otor stereotypies, which are excessive and repetitive behaviors, can be induced with repeated or high doses of psychomotor stimulants and are features of some psychiatric and neurologic disorders such as schizophrenia, obsessivecompulsive disorder, and Lesch-Nyhan disease (1, 2). The last is characterized by a substantial reduction in brain dopamine (DA) levels early in development, with subsequent behavioral spasticity and self-injurious behavior (2). Stereotypic behaviors due to L-DOPA therapy have also been observed in Parkinson's disease patients (3). Lesion experiments using the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA), in adult or neonatal rats, reproduced some of the motor dysfunctions of Parkinson's and Lesch-Nyhan diseases, respectively (4-6). In each case, the chronic reduction of DA leads to a compensatory increase in the sensitivity to DA (7-9). The hypersensitivity to DA promotes susceptibility to stereotypy when dopaminergic circuits are activated, as may occur in schizophrenia (10) and with chronic exposure to psychomotor stimulants like cocaine and amphetamine (11).The role of DA and the striatum in the expression of stereotypy is well established, primarily from studies of animal models of dopaminergic supersensitivity (12)(13)(14). Yet, there are substantial differences, depending on the model system studied, particularly in the relative roles of D1 and D2 receptors. In 6-OHDA lesion experiments, the severity of...

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Section: Discussionmentioning

confidence: 76%

Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation

Chartoff

Marck

Matsumoto

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…In unilaterally MPTP-lesioned rhesus monkeys, a single intraventricular injection of GDNF produced improvement in motor function, which was correlated with DOPAC and HVA levels in the lesioned nigra but not in the striatum (Gerhardt et al, 1999). In unilaterally 6-OH-dopamine-lesioned rats, l-DOPA-induced rotational behavior was temporally correlated to the duration of increased DA levels in the substantia nigra rather than the striatum (Robertson and Robertson, 1989). In rats, neuroleptic-induced increases in hind limb muscle tone, a measure of rigidity, requires blockade of nigral DA D 2 /D 3 receptors (Double and Crocker, 1995).…”

Section: Discussionmentioning

confidence: 92%

“…These include the ability of olanzapine (Stockton and Rasmussen, 1996), like clozapine (Chiodo and Bunney, 1983), but unlike haloperidol (Chiodo and Bunney, 1983), to produce a selective depolarization of DA neurons in the VTA, but not in the substantia nigra, and the role of dopaminergic neurotransmission in the substantia nigra in motor behaviors (Gerhardt et al, 1999(Gerhardt et al, , 2002Robertson and Robertson, 1989). Studies in animals have demonstrated that a number of motor behaviors require normal nigral as well as normal striatal dopaminergic function.…”

Section: Discussionmentioning

confidence: 99%

Occupancy of Striatal and Extrastriatal Dopamine D2/D3 Receptors by Olanzapine and Haloperidol

Kessler

Ansari

Riccardi

et al. 2005

Neuropsychopharmacol

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There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D 2 /D 3 receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D 2 /D 3 receptors. We performed [18 F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [18 F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT 2A receptor occupancy. Occupancy of dopamine D 2 /D 3 receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D 2 /D 3 receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D 2 /D 3 receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p ¼ 0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D 2 /D 3 receptor occupancy than the putamen, that is, 40.2 vs 69.2% (po0.001, corrected for multiple comparison). Occupancy of 5-HT 2A receptors was 85-93% in the olanzapine-treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D 2 /D 3 receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D 2 /D 3 receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

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“…Being the output nuclei of the basal ganglia, the EP and the SNr mediate motor stimulant effects of antiparkinsonian drug treatment (Marti et al, 2004;Robertson and Robertson, 1989). In these two structures, there is a high density of D1 receptors on the terminals of 'direct pathway' (striatonigral) axon fibers (Dawson et al, 1988;Savasta et al, 1986a, b), promoting the release of both GABA and dynorphin (reviewed in Cenci and Lindgren, 2007).…”

Section: Discussionmentioning

confidence: 99%

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Lindgren

Ohlin

Cenci

2009

Neuropsychopharmacol

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Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1-or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1-but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.

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Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms

Cited by 189 publications

References 22 publications

Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation

Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation

Occupancy of Striatal and Extrastriatal Dopamine D2/D3 Receptors by Olanzapine and Haloperidol

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

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